Plants and cancer - ZyXEL NSA210

PLANTS THAT 

FIGHT CANCER

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PLANTS THAT 

FIGHT CANCER 


and Maria G. Barberaki 

CRC PRESS 

Boca Raton London New York Washington, D.C.

Library of Congress Cataloging-in-Publication Data 

Plants that Þght cancer / edited by Spiridon E. Kintzios and 

Maria G. Barberaki. 

p. ; cm. 

Includes bibliographical references and index. 

ISBN 0-415-29853-9 (hardback: alk. paper) 

1. Herbs—Therapeutic use. 2. Cancer—Treatment. 3. Medicinal 

plants. 4. Materia medica, Vegetable. 5. Pharmacognosy. 

[DNLM: I. Neoplasms—drug therapy. 2. Phytotherapy. 3. Plant 

Extracts—therapeutic use. QZ 267 P714 2003] I. Kintzios, Spiridon E. 

II. Barberaki, Maria G. 

RC271.H47 P56 2003 

616.99'4061—dc21 2003005700 

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Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 

Printed on acid-free paper

Eleni Grafakou, Vaggelis Kintzios and all people giving their personal fight 

against cancer

Contents 

List of contributors 

Preface 

ix 

x 

1 What do we know about cancer and its therapy 1 

1. A brief overview of the disease and its treatment 1 

1.1. Incidence and causes 1 

1.2. Classification of cancer types 3 

1.3. Therapy 4 

1.3.1. Conventional cancer treatments 4 

1.3.2. Advanced cancer treatments 6 

1.3.3. Other advanced therapies 9 

1.3.4. Alternative cancer treatments 9 

1.4. From source to patient: testing the efficiency of 

a candidate anticancer drug 10 

1.4.1. Preclinical tests 10 

1.4.2. Phases of clinical trials 13 

1.4.3. Clinical trial protocols 13 

2 Plants and cancer 15 

2. The plant kingdom: nature’s pharmacy for cancer treatment 15 

2.1. Brief overview of the general organization of the plant cell 15 

2.2. The chemical constituents of the plant cell 16 

2.2.1. Primary metabolites 16 

2.2.2. Secondary metabolites 17 

2.3. Why do plant compounds have an anticancer activity 17 

2.4. Chemical groups of natural products with anticancer properties 19 

2.5. Biotechnology and the supply issue 32 

3 Terrestrial plant species with anticancer activity: 

a presentation 35 

3.1. Introduction: general botanical issues 35 

3.2. Species-specific information 36 

3.2.1. The guardian angels: plant species used in 

contemporary clinical cancer treatment 36

viii 

Contents 

3.2.2. Promising candidates for the future: plant species with a 

laboratory-proven potential 72 

3.2.3. The fable: where tradition fails to meet reality 160 

3.2.4. Other species with documented anticancer activity 166 

4 Cytotoxic metabolites from marine algae 195 

4.1. Cytotoxic metabolites from marine algae 195 

4.2. Cytotoxic metabolites from chlorophyta 198 

4.3. Cytotoxic metabolites from rhodophyta 211 

4.4. Cytotoxic metabolites from phaeophyta 221 

4.5. Cytotoxic metabolites from microalgae 227 

Conclusions 240 

Appendix: chemical structures of selected compounds 242 

References 274 

Index 289

Contributors 

Spiridon E. Kintzios 

Agricultural University of Athens 

Faculty of Agricultural Biotechnology 

Laboratory of Plant Physiology 

Iera Odos 75, Athens, Greece 

Tel. 3-010-5294292 

E-mail: skin@aua.gr 

Maria G. Barberaki 





Tel. 3-010-5294292 

E-mail: maria.barberaki@serono.com 

Olga G. Makri 





Tel. 3-010-5294292 

E-mail: olmak@hotmail.com 

Theodoros Matakiadis 





Tel. 3-010-5294292 

E-mail: teomatas@hotmail.com 

Vassilios Roussis 

University of Athens 

School of Pharmacy 

Department of Pharmacognosy and 

Chemistry of Natural Products 

Panepistimiopolis Zografou 

Athens 157 71, Greece 

Tel. 3-010-7274592 

E-mail: roussis@pharm.uoa.gr 

Costas Vagias 






Athens 157 71, Greece 

Leto – A. Tziveleka 






Athens 157 71, Greece

Preface 

This is a book about the most fearsome disease of modern times, which will strike every fourth 

citizen of a developed country sometime during his life: cancer. It is not a book about the prevention 

of cancer, but rather its treatment with plant-derived chemicals. It is an up-to-date and 

extensive review of plant genera and species with antitumor and antileukemic properties that 

have been documented in a strictly scientific sense. From the layman to the medical expert, the 

book is addressed to people seeking information on novel opportunities on disease therapy in 

order to make decisions about care programs. Purpose-wise, the book is written in colloquial 

style. 

The volume comprises four chapters. In the first chapter, the current knowledge of the nature of 

cancer and the main types of the disease are briefly described. In the second chapter, the various 

approaches for treating cancer – including conventional, advanced and alternative methods – are 

presented, while a relative emphasis is given on the chemotherapy of cancer. The restrictions and 

risks of each approach are comparatively reviewed. The second chapter of the book is a general 

review of plant-derived groups of compounds with anticancer properties, including their chemistry, 

biosynthesis and mode of action. Evolutionary aspects of the anticancer properties of plants 

are presented and a separate chapter is devoted on the application of biotechnology in this field. 

The third, most extensive chapter of the book contains detailed information on each of more 

than 150 anticancer terrestrial plant genera and species. Topics include tradition and myth, distribution, 

botany, culture, active ingredients and product application (including an analysis of 

expected results and risks) along with photographs and illustrations of each species. In addition, 

further information can be found on plant species with equivocal or minor anticancer value. 

Although the traditional sources of secondary metabolites were terrestrial higher plants, animals 

and microorganisms, marine organisms have been the major targets for natural products research 

in the past decade. In the fourth chapter of the book, algal extracts and isolated metabolites having 

cytotoxic and antineoplastic activity and with the potential for pharmaceutical exploitation 

are reviewed, along with the phylogeny and physiology of the organisms. Emphasis is given to 

the chemical nature of these compounds, the novelty and complexity of which has no counterpart 

in the terrestrial world. 

The chemical structures of the most important compounds derived from terrestrial higher 

plants are given in the Appendix of the book. An extensive list of publications provides an 

overview of published research for each species, to be used as extensive background information 

for the expert reader. 

Finally, we feel compelled to state that this volume, as concise as it is, cannot include all existing 

plant species with anticancer properties; even during the stage of the final editing of the

Preface 

xi 

manuscript, many novel substances from other species have been identified as potential 

chemotherapeutic agents against various tumors. This fact is an evidence in itself for the rapidly 

growing interest of the international scientific and medical community in the utilization of 

plant-derived chemicals in cancer treatment. 

The Editors 

Athens, 2002

Chapter I 

What do we know about cancer 

and its therapy 

Spiridon E. Kintzios 

1. A BRIEF OVERVIEW OF THE DISEASE AND ITS TREATMENT 

1.1. Incidence and causes 

Everybody thinks it cannot happen to them. And yet, six million people die of cancer every year. 

Approximately every fourth citizen of a developed country will be stricken sometime during his 

life and approximately 400 new incidents emerge per 100,000 people annually. 

Once considered a mysterious disease, cancer has been eventually revealed to investigators 

(Trichopoulos and Hunter, 1996). Disease development begins from a genetic alteration 

(mutation) of a cell within a tissue. This mutation allows the cell to proliferate at a very high 

rate and to finally form a group of fast reproducing cells with an otherwise normal appearance 

(hyperplasia). Rarely, some hyperplastic cells will mutate again and produce abnormally looking 

descendants (dysplasia). Further mutations of dysplastic cells will eventually lead to the 

formation of a tumor, which can either remain localized at its place of origin, or invade 

neighboring tissues (malignant tumor) and establish new tumors (metastases). 

Cancer cells have some unique properties that help them compete successfully against normal 

cells: 

1 Under appropriate conditions cancer cells are capable of dividing almost infinitely. Normal 

cells have a limited life span. As an example, human epithelial cells cultured in vitro are 

commonly capable of sustaining division for no more than 50 times (the so-called Hayflick 

number) (Hayflick and Hayflick, 1961). 

2 Normal cells adhere both to one another and to the extracellular matrix, the insoluble 

protein mesh that fills the space between cells. Cancer cells fail to adhere and, in addition, 

they possess the ability to migrate from the site where they began, invading nearby tissues 

and forming masses at distant sites in the body, via the bloodstream. This process is known 

as metastasis and examples include melanoma cells migrating to the lung, colorectal 

cancer cells to the liver and prostrate cancer cells to bone. Although metastatic cells are 

indeed a small percentage of the total of cancer cells (e.g. 10 4 or 0.0001%), tumors 

composed of such malignant cells become more and more aggressive over time. 

In a general sense, cancer arises due to specific effects of environmental factors (such as 

smoking or diet) on a certain genetic background. In the hormonally related cancers like breast 

and prostate cancer, genetics seem to be a much more powerful factor than lifestyle.

2 Spiridon E. Kintzios 

Two gene classes play major roles in triggering cancer. Proto-oncogenes encourage such 

growth, whereas tumor suppressor genes inhibit it. The coordinated action of these two gene 

classes normally prevents cells from uncontrolled proliferation; however, when mutated, oncogenes 

promote excessive cell division, while inactivated tumor suppressor genes fail to block the 

division mechanism (Table 1.1). On a molecular level, control of cell division is maintained by 

the inhibitory action of various molecules, such as pRB, p15, p16, p21 and p53 on proteins 

promoting cell division, essentially the complex between cyclins and cyclin-dependent kinases 

(CDKs) (Meijer et al., 1997). Under normal conditions, deregulation of the cell control mechanism 

leads to cellular suicide, the so-called apoptosis or programmed cell death. Cell death 

may also result from the gradual shortening of telomeres, the DNA segments at the ends of 

chromosomes. However, most tumor cells manage to preserve telomere length due to the 

presence of the enzyme telomerase, which is absent in normal cells. 

Some oncogenes force cells to overproduce growth factors, such as the platelet-derived growth 

factor and the transforming growth factor alpha (sarcomas and gliomas). Alternatively, oncogenes 

such as the ras genes distort parts of the signal cascade within the cell (carcinoma of the 

colon, pancreas and lung) or alter the activity of transcription factors in the nucleus. In addition, 

suppressor factors may be disabled upon infection with viruses (e.g. a human papillomavirus). 

Tumor development is a step-wise process in that it requires an accumulation of mutations in a 

Table 1.1 Examples of genes related to cancer incidence in humans 

Type of gene Gene Cancer type 

Oncogene PDGF Glioma 

Oncogene Erb-B Glioblastoma, breast 

Oncogene RET Thyroid 

Oncogene Ki-ras Lung, ovarian, colon, 

pancreatic 

Oncogene CDKN2 Melanoma 

Oncogene HPC1 Prostate 

Oncogene N-ras Leukemia 

Oncogene c-myc Leukemia, breast, stomach, 

lung 

Oncogene N-myc Neuroblastoma, glioblastoma 

Oncogene Bcl-1 Breast, head, neck 

Oncogene MDM2 Sarcomas 

Oncogene BCR-ABL Leukemia 

Tumor suppressor gene p53 Various 

Tumor suppressor gene RB Retinoblastoma, bone, 

bladder, small cell lung, 

breast 

Tumor suppressor gene BRCA1 Breast, ovarian 

Tumor suppressor gene BRCA2 Breast 

Tumor suppressor gene APC Colon, stomach 

Tumor suppressor gene MSH2, MSH6, MLH1 Colon 

Tumor suppressor gene DPC4 Pancreas 

Tumor suppressor gene CDK4 Skin 

Tumor suppressor gene VHL Kidney 

Other Chromosome 3 (deletions) Lung

What do we know about cancer and its therapy 3 

number of these genes. Altered forms of other classes of genes may also participate in the creation 

of a malignancy, particularly in enabling the emergence of metastatic cancer forms. 

Environmental causes of cancer comprise an extremely diverse group of factors that may act 

as carcinogens, either by mutating genes or by promoting abnormal cell proliferation (Nagao 

et al., 1985; Sugimura, 1986; Koehnlechner, 1987; Wakabayashi et al., 1987; Greenwald, 1996). 

Most of these agents have been identified through epidemiological studies, although the exact 

nature of their activity on a biological level remains obscure. These factors include chemical substances 

(such as tobacco, asbestos, industrial waste and pesticides), diet (saturated fat, read meat, 

overweight), ionizing radiation, pathogens (such as the Epstein–Barr virus, the hepatitis B or C 

virus, papillomaviruses and Helicobacter pylori). However, in order for environmental factors to 

have a significant effect, one must be exposed to them for a relatively long time. 

Cancer may also arise, or worsen, as a result of physiological stress. For example, a recent 

large-scale study in Israel demonstrated that survival rates declined for patients having lost at 

least one child in war (Anonymous, 2000). 

1.2. Classification of cancer types 

There are several ways to classify cancer. A general classification relates to the tissue type where 

a tumor emerges. For example, sarcomas are cancers of connective tissues, gliomas are cancers 

of the nonneuronal brain cells and carcinomas (the most common cancer forms) originate in 

epithelial cells. In the following box, a classification of major cancer diseases is given according 

to the currently estimated five-year survival rate of the affected patient. 

Cancers with less than 20% five-year survival rate (at all stages) 

1 Lung cancer is associated with exposure to environmental toxins like cigarette smoke 

and various chemicals and has an incidence higher than 17%. It can be distinguished 

in two types, small cell (rapidly spreading) and non-small cell disease. With a 

percentage of terminally affected patients more than 26%, it is one of the less curable 

cancer diseases. 

2 Pancreatic cancer is associated with increasing age, smoking, consumption of fats, race 

and pancreatic diseases. Diagnosis usually lags behind metastasis. 

Cancers with five-year survival rates (at all stages) between 40% and 60% 

1 Non-Hodgkin’s lymphoma is associated with dysfunctions of the immune system, 

including many different types of disease. 

2 Kidney cancer is associated with sex (males), smoking and obesity. 

3 Ovarian cancer is associated with increasing age and heredity, especially as far as 

mutations in the BRCA1 or BRCA2 genes are concerned. 

Cancers with five-year survival rates (at all stages) between 60% and 80% 

1 Uterine (cervical and endometrial cancer) cancer is associated with hormonal treatment 

(such as estrogen replacement therapy), race, sexual activity and pregnancy history. 

Can be efficiently predicted by the Pap test (named after its inventor, the physician 

G. Papanikolaou).


2 Leukemia is distinguished in acute lymphocytic (common among children), acute 

myelogenous and chronic lymphocytic leukemia. The disease is associated with 

genetic abnormalities, viral infections and exposure to environmental toxins or 

radiation. 

3 Colorectal cancer is associated with heredity, obesity, polyps and infections of the 

gastrointestinal tract. Prevention of metastases in the liver is crucial. The disease is 

presumably associated with elevated concentrations of the cancer embryonic antigen 

(CEA). 

4 Bladder cancer is associated with race, smoking and exposure to environmental toxins. 

Cancers with five-year survival rates (at all stages) higher than 80% 

1 Prostate cancer is associated with increasing age, obesity and race. The incidence of the 

disease is high (15%). The disease can be efficiently detected at an early stage by 

using the prostate-specific antigen (PSA) blood test. 

2 Breast cancer is associated with increasing age, heredity (especially as far as mutations 

in the BRCA1 or BRCA2 genes are concerned), sexual activity, obesity and pregnancy 

history. Although the incidence of the disease is high (24%), survival rates 

have been remarkably increased. The disease can be efficiently detected at an early 

stage by self-examination and mammography. In addition, the disease is presumably 

associated with elevated concentrations of CA15-3. 

3 Skin cancer (basal cell skin cancer, squamous cell skin cancer, melanoma) is mainly associated 

with prolonged exposure to the sun and race. Detection at an early stage is extremely 

crucial. 

Most cancers are currently increasing in incidence. However, growth in the major 

pharmacologically treated cancers, namely breast, colorectal, lung, ovarian and prostate cancer 

is driven by shifting demographics rather than any underlying increase in the risk of developing 

the disease. Breast cancer is the most prevalent cancer today, followed by cancer of the 

prostate, colon/rectum, lung and ovaries respectively. Unsurprisingly, given that cancer is a disease 

driven by imperfections in DNA replication, the risk of developing most cancers increases 

with increasing age. For some hormonally driven female cancers, the risk of developing the 

disease increases rapidly around the time of the menopause. 

Diagnosis rates are consequently very high, at over 95% of the prevalent population 

diagnosed for prostate cancer, and over 99% for breast, colorectal, lung and ovarian cancers 

(Sidranski, 1996). The stage of the patient’s cancer at diagnosis varies highly with each 

individual cancer with survival times associated with the disease falling rapidly with increasing 

stage of diagnosis. 

1.3. Therapy 

1.3.1. Conventional cancer treatments 

Conventional cancer treatments include surgery, radiation and chemotherapy. 

Surgery is used for the excision of a tumor. It is the earliest therapy established for cancer and 

the most widely used. Its disadvantages include the possible (and often unavoidable) damage of


healthy tissues or organs (such as lymph nodes) and the inability to remove metastasized cancer 

cells or tumors not visible to the surgeons. In addition, surgery can activate further proliferation 

of “latent” small tumors, the so-called “pet-cancers” (Koehnlechner, 1987). 

Radiation (X-rays, gamma rays) of a cancerous tumor, thus causing cancer cell death or 

apoptosis preserves the anatomical structures surrounding the tumor and also destroy nonvisible 

cancer cells. However, they cannot kill metastasized cancer cells. Radiation treatment 

presents some side effects (such as neurotoxicity in children), but patients usually recover faster 

than from surgery. Additional side effects include weakening of the immune system and 

replacement of damaged healthy tissue by connecting tissue (Koehnlechner, 1987). 

Chemotherapy is based on the systemic administration of anticancer drugs that travel 

throughout the body via the blood circulatory system. In essence, chemotherapy aims to wipe 

out all cancerous colonies within the patients body, including metastasized cancer cells. 

However, the majority of the most common cancers are not curable with chemotherapy alone. 

This kind of treatment also has many side effects, such as nausea, anemia, weakening of the 

immune system, diarrhea, vomiting and hair loss. Finally, cancer cells may develop resistance to 

chemotherapeutic drugs (Koehnlechner, 1987; Barbounaki-Konstantakou, 1989). 

Drugs in adjunct therapy do not attack the tumor directly, but instead treat side effects and 

tolerance problems associated with the use of chemotherapy. For example, anti-emetics such as 

ondansetron or granisetron reduce levels of nausea associated with some chemotherapies. This 

improves compliance rates, and enables patients to tolerate higher doses of chemotherapy than 

would normally be the case. Similarly, some drugs such as epoetin alpha target deficiencies in red 

blood cell counts that often result from the use of chemotherapy and enable normal physical 

function to be restored to some degree. 

Many different compounds are currently used (often in combination). Chemotherapy is the 

most rapidly developing field of cancer treatment, with new drugs being constantly tested and 

screened. These include also plant metabolites (the topic of this book) and regulators of the 

endocrine system (important in cases of hormone-dependent cancers, like breast and prostate 

cancer). Chemotherapeutic drugs are classified in ten general groups: 

1 Antimetabolites act as nonfunctional analogues of essential metabolites in the cell, thus 

blocking physiological functions of the tumor. 

2 Alkylating agents chemically bond with DNA through alkyl groups, thus disrupting gene 

structure and function, or with proteins, thus inhibiting enzymes. 

3 Topoisomerase inhibitors inhibit DNA replication in rapidly dividing cells, as in the case 

of tumors. 

4 Plant alkaloids also inhibit tumor cell division by blocking microtubule depolymerization, 

an essential step for chromosome detachment during mitosis. However, novel plant alkaloids 

act through other mechanisms as well, which will be analyzed further in this book. 

5 Antibiotics are derived from diverse groups of microorganisms or synthesized and block 

DNA replication and protein synthesis. 

6 Anthracyclins are a subgroup of antibiotics, associated with considerable toxic side effects 

on the heart and bone marrow. 

7 Enzymes, in particular proteolytic and fibrinolytic ones, as well as tyrosinase inhibitors, 

such as Gleevec, a new cytotoxic drug used for treating chronic myeloid leukemia. 

8 Hormones are substances interfering with other chemotherapeutic agents by regulating 

the endocrine system. They find specific application against carcinomas of breast, prostate 

and endometrium.


9 Immunomodulators act by inhibiting tumor proliferation through the stimulation of the 

host’s immune system (see section on immunotherapy). 

10 Various substances not falling in any of the above categories. 

Some representative chemotherapeutic agents are listed in Table 1.2. 

The success of chemotherapy depends on the type of cancer that is being treated. It can have 

curative effects on some less common cancers, like Burkitt-Lymphoma, Wilms-Tumor, 

teratomas and lymphoblastic leukemia. A less satisfactory, though life-prolonging effect is 

observed on myloblastic leukemia, multiple myeloma, ovarian, prostate, and cervical and breast 

cancer. Much poorer results must be expected against bronchial, lung, stomach, colorectal, 

pancreatic, kidney, bladder, brain, glandular and skin cancer, as well as against bone sarcomas. 

Use of pharmacological therapy for cancer vary by both geographic area and tumor type. Lung 

cancer patients are most likely to be treated with drugs, with around 99% of them being treated 

with drugs at the first-line treatment stage. Prostate cancer patients are least likely to be treated 

with drugs, with only around 42% of them being treated with drugs at the first-line treatment 

stage. 

For those cancers which manifest themselves as a solid tumor mass, the most efficient way to 

treat them is to surgically resect or remove the tumor mass, since this reduces both the tumor’s 

ability to grow and metastasize to distant sites around the body. If a tumor can be wholly resected, 

there are theoretically no real advantages in administering drug treatment, since surgery has 

essentially removed the tumor’s ability to grow and spread. For early stage I and II tumors, which 

are usually golf ball sized and wholly resectable, drug therapy is therefore infrequently used. At 

stages III and IV, the tumor has usually grown to such a size and/or has spread around the body 

to such an extent that it is not wholly resectable. For example, rectal tumors at stage III have usually 

impinged upon the pelvis, which reduces the ability of the surgeon to wholly remove the 

tumor. In these cases, drug therapy is used either to reduce the size of the tumor before resection, 

or else “mop up” stray cancer cells. Drug therapy therefore features prominently for tumors 

diagnosed at stage III and IV, together with those cancers that have recurred following initial 

first-line treatment and/or metastasized to distant areas around the body. 

1.3.2. Advanced cancer treatments 

Immunotherapy 

Infectious agents entering the body are encountered by the immune system. They bear distinct 

molecules called antigens, which are the target of antigen-presenting cells, such as macrophages, 

that roam the body and fragment antigens into antigenic peptides. These, in turn, are joined to 

the major histocompatibility complex (MHC) molecules which are displayed on the cell surface. 

Macrophages bearing different MHC-peptide combinations activate specific T-lymphocytes, 

which divide and secrete lymphokines. Lymphokines activate B-lymphocytes, which can also 

recognize free-floating antigens in a molecule-specific manner. Activated B-cells divide and secrete 

antibodies, which can bind to antigens and neutralize them in various ways (Nossal, 1993). 

Lymphocytes are produced in primary lymphoid organs: the thymous (T cells) and the bone 

marrow (B cells). They are further processed in the secondary lymphoid organs, such as the lymph 

nodes, spleen and tonsils before entering the bloodstream. 

In an ideal situation, cancer cells would constitute a target of the patient host immune system. 

To single out cancer cells, an immunotherapy must be able to distinguish them from normal cells. 

During the last years, monoclonal antibodies have revealed a large array of antigens that exist

Table 1.2 Some of the compounds currently used in cancer chemotherapy 

Class 

Antimetabolites 

Alkylating agents 

Topoisomerase inhibitors 

Plant alkaloids 

Antibiotics 

Anthracyclines 

Enzymes 

Hormones 

Immunomodulators 

Various 

Compound 

Azathioprin 

Cytosine arabinoside 

5-fluorouracile 

6-mercaptopurine 

6-thioguanine 

Methotrexate 

Hydroxyurea 

Busulfan 

Chlorambucile 

Cyclophosphamide 

Ifosfamide 

Melphalan hydrochloride 

Thiotepa 

Mechlorethamine hydrochloride 

Nitrosoureas: 

Lomustine 

Carmustine 

Streptozocin 

Amsacrine 

Etoposide 

Teniposide 

Vinblastine 

Vincristine 

Vindesine 

Bleomycin 

Plicamycin 

Mitomycin 

Dactinomycin 

Daunorubicin 

Doxorubicin hydrochloride 

Rubidazone 

Idarubicine 

Epirubicin (investigational drug) 

Aclarubicin chlorhydrate 

L-aspariginase 

Tyrosine kinase inhibitors 

Adrenocorticoids 

Estrogens 

Anti-androgens 

Luteinizing hormone release hormone 

(LHRH) analogues 

Progestogens 

Antiestrogens (investigational) 

Aromatase inhibitors 

Interferons 

Interleukins 

Cisplatin 

Dacarbazine 

Procarbazine 

Mitoxantrone


on human cancer cells. Many of them are related to abnormal proteins resulting from genetic 

mutations which turn normal cells into cancer ones. However, cancer cells can elude attack by 

lymphocytes even if they bear distinctive antigens, due to the absence of proper co-stimulatory 

molecules, such as B7 or the employment of immunosuppression mechanisms. The ultimate goal 

of cancer immunotherapy research is the production of an effective vaccine. This may include 

whole cancer cells, tumor peptides or DNA molecules, other proteins or viruses (Koehnlechner, 

1987; Old, 1996). The idea of a vaccine is an old one, indeed. In 1892, William B. Coley at the 

Memorial Hospital in New York treated cancer patients with killed bacteria in order to elicit a 

tumor-killing immunoresponse. 

The immunotherapy of cancer can be roughly classified in four categories: 

1 Non-specific: involves the general stimulation of the immune system and the production of 

cytokines, such as interferons, tumor necrosis factor (TNF), interleukins (IL-2, IL-12) and 

GM-CSF. 

2 Passive: involves the use of “humanized” mice-derived monoclonal antibodies bearing a 

toxic agent (such as a radioactive isotope or a chemotherapeutic drug). 

3 Active: vaccines are made on the basis of human antitumor antibodies. 

4 Adoptive: involves lymphocytes from the patient himself. 

Table 1.3 Substances that stimulate the immune system 

Substances 

Bordetella pertussis 

Bacillus–Calmette–Guerin (BCG) 

(tuberculosis bacterium a.d. Rind.) 1 

Escherichia coli 

Vitamin A 

Corynobacterium parvum 2 

C. granulosum 

Bordetella pertussi 


Vitamin A 3 

Bordetella pertussis 

BCG (tuberculosis bacterium a.d. Rind.) 1 


Vitamin A 3 

Poly-adenosin-poly-urakil 

Saponine 

Levamisol 4 

Lentinan 

Diptheriotoxin 

Thymus factors 

They activate 

Macrophages 

B-lymphocytes 

T-lymphocytes 

Notes 

1 In combination with radiotherapy can cause a 40% reduction of leukemia incidence in mice. 

Has been reported to prolong life expectancy in cancer and leukemia patients who received 

conventional treatment. 

2 Has been used for the treatment of melanomas, lung and breast cancer. 

3 Has been used for the treatment of various skin cancers. 

4 A former anti-worm veterinarian drug, levamisol has displayed slight post-operative 

immunostimulatory and survival-increasing properties in patients suffering from bronchial, 

lung and intestinal cancer.


Apart from plant-derived compounds, several other agents can stimulate the immune system 

in a more or less antitumor specific manner. Some of the most prominent substances and/or 

organisms are presented in Table 1.3 (adapted from Koehnlechner, 1987). Other compounds 

include trace elements (selenium, zinc, lithium), hemocyanin, propionibacteria. 

Angiogenesis inhibition 

A promising therapeutic strategy focuses on blocking tumor angiogenesis, that is, the inhibition 

of the growth of new blood vessels in tumors. Such drugs have not only performed impressively in 

experimental animal models but also offer an alternative means of tackling multidrug-resistant 

tumors that have proved intractable to conventional chemotherapy. The link between angiogenesis 

and tumor progression was first established by Judah Folkman of Boston Children’s Hospital 

(Folkman, 1996; Brower, 1999). His observations led to the notion of an “angiogenic switch”, a 

complex process by which a tumor mass expands and overtakes the rate of internal apoptosis by 

developing blood vessels, thereby changing into an angiogenic phenotype. Drugs that target blood 

vessel growth should have minimal side effects, even after prolonged treatments. The ready accessibility 

of the vasculature to drugs and the reliance of potentially hundreds of tumor cells on one 

capillary add to the benefits of such therapies, which however are limited to the subfraction of 

tumor capillaries expressing the immature angiogenic phenotype. Another problem is the heterogeneity 

of the vasculature within tumors. Many approaches for inhibiting angiogenesis are still 

very early in development, approximately 30 antiangiogenic drugs are in clinical trial. Among 

them, endogenous angiogenic inhibitors such as angiostatin, troponin-I and endostatin are in Phase I 

trials, while synthetic inhibitors, such as TNP-470, various proteolysis inhibitors and signaling 

antagonists are in Phase II and III trials. At this point it is worth mentioning that the angiogenesisinhibitor 

squalamine is based on dogfish shark liver. Shark cartilage has been sold as an alternative 

treatment for cancer since the early 1990s when a book entitled “Sharks Don’t Get Cancer” by 

William Lance was published. It suggested that a protein in shark’s cartilage kept the fish from 

getting cancer by blocking the development of small blood vessels that cancer cells need to survive 

and grow. The idea spawned a market for shark cartilage supplements that is estimated to be worth 

$50 million a year. Researchers have since discovered that sharks do get cancer but they have a 

lower rate of the disease than other fish and humans. Danish researchers tested the treatment on 

17 women with advanced breast cancer that had not responded to other treatments. The patients 

took 24 shark cartilage capsules a day for three months, but the disease still progressed in 15 and 

one developed cancer of the brain. The Danish results support earlier research that found powdered 

shark cartilage did not prevent tumor growth in 60 patients with an advanced cancer. 

1.3.3. Other advanced therapies 

Advanced cancer therapies also include the use of tissue-specific cytotoxic agents. For example, 

novel mutagenic cytotoxins (interleukin 13 – IL13) have been developed against brain tumors, 

which do not interact with receptors of the normal tissue but only with brain gliomas (Beljanski 

and Beljanski, 1982; Beljanski et al., 1993). 

1.3.4. Alternative cancer treatments 

These include diverse, mostly controversial methods for treating cancer while avoiding the 

debilitating effects of conventional methods. The alternative treatment of cancer will probably


gain in significance in the future, since it has been estimated that roughly half of all cancer 

patients currently turn to alternative medicine. The most prominent alternative cancer 

treatments include: 

1 The delivery of antineoplastons, peptides considered to inhibit tumor growth and first 

identified by Stanislaw Burzynski in blood and urine. According to the Food and Drug 

Administration (FDA) the drug can be applied only in experimental trials monitored by the 

agency and only on patients who have exhausted conventional therapies. However, the 

therapy has found a significant amount of political support, while attracting wide publicity 

(Keiser, 2000). 

2 Hydrazine sulfate, a compound reversing cachexia of cancer patients, thus improving 

survival. 

3 Various herbal extracts, some of which are dealt with in this book. 

1.4. From source to patient: testing the efficiency of 

a candidate anticancer drug 

Drug development is a very expensive and risky business. On average, a new drug takes 15 years 

from discovery to reach the market, costing some $802 m. Considerable efforts have been made 

by public organizations and private companies to expedite the processes of drug discovery and 

development, by expanding on promising results from preliminary in vitro screening tests. The 

United States National Cancer Institute (NCI) has set forward exemplary strategies for the discovery 

and development of novel natural anticancer agents. Over the past 40 years, the NCI has 

been involved with the preclinical and/or clinical evaluation of the overwhelming majority of 

compounds under consideration for the treatment of cancer. During this period, more than 

4,00,000 chemicals, both synthetic and natural, have been screened for antitumor activity 

(Dimitriou, 2001). 

Plant materials under consideration for efficacy testing are usually composed of complex 

mixtures of different compounds with different solubility in aqueous culture media. 

Furthermore, inert additives may also be included. These properties render it necessary to search 

for appropriate testing conditions. In the past, model systems with either high complexity 

(animals, organ cultures) or low molecular organization (subcellular fractions, organ and cell 

homogenates) were used for evaluating the mechanism of action of phytopharmaceuticals. The 

last decade, however, has seen an enormous trend towards isolated cellular systems, primary cells 

in cultures and cell lines (Gebhardt, 2000). In particular, the combination of different in vitro 

assay systems may not only enhance the capacity to screen for active compounds, but may also 

lead to better conclusions about possible mechanisms and therapeutic effects. 

1.4.1. Preclinical tests 

Preclinical tests usually comprise evaluating the cytotoxicity of a candidate antitumor agent 

in vitro, that is, on cells cultured on a specific nutrient medium under controlled conditions. 

Certain neoplastic animal cell lines have been repeatedly used for this purpose. Alternatively, 

animal systems bearing certain types of cancer have been used. For example, materials entering 

the NCI drug discovery program from 1960 to 1982 were first tested using the L1210 and P-388 

mouse leukemia models. Most of the drugs discovered during that period, and currently


available for cancer therapy, are effective predominantly against rapidly proliferating tumors, 

such as leukemias and lymphomas, but with some notable exceptions such as paclitaxel, show 

little useful activity against the slow-growing adult solid tumors, such as lung, colon, prostatic, 

pancreatic and brain tumors. 

A more efficient, disease-oriented screening strategy should employ multiple disease-specific 

(e.g. tumor-type specific) models and should permit the detection of either broad-spectrum or 

disease-specific activity. The use of multiple in vivo animal models for such a screen is not practical, 

given the scope of requirements for adequate screening capacity and specific tumor-type 

representation. The availability of a wide variety of human tumor cell lines representing many 

different forms of human cancer, however, offered a suitable basis for development of a diseaseoriented 

in vitro primary screen during 1985 to 1990. The screen developed by NCI currently 

comprises 60 cell lines derived from nine cancer types, and organized into subpanels representing 

leukemia, lung, colon, central nervous system, melanoma, ovarian, renal, prostate and breast 

cancer. A protein-staining procedure using sulforhodamine B (SRB) is used as the method of 

choice for determining cellular growth and viability in the screen. Other, more sophisticated 

methods are referred to in the literature. In addition, cell lines used in the in vitro screen can be 

analyzed for their content of molecular targets, such as p-glycoprotein, p53, Ras and BCL2. Each 

successful test of a compound in the full screen generates 60 dose–response curves, which are 

printed in the NCI screening data report as a series of composites comprising the tumor-type 

subpanels, plus a composite comprising the entire panel. Data for any cell lines failing quality 

control criteria are eliminated from further analysis and are deleted from the screening report. 

The in vitro human cancer line screen has found widespread application in the classification of 

compounds according to their chemical structure and/or their mechanism of action. Valuable 

information can be obtained by determining the degree of similarity of profiles generated on the 

same or different compounds. 

Some of the most commonly used animal and cell culture lines used for primary screening 

are listed in following: (for more detailed information on each method see Miyairi et al., 

1991; Mockel et al., 1997; Gebhardt, 2000, and cited references in Chapter 3) 

● 

● 

● 

● 

● 

● 

● 

● 

● 

● 

● 

● 

● 

● 

Ehrlich Ascites tumor bearing mice 

P-388 lymphocytic leukemia bearing mice 

The 9KB carcinoma of the nasopharynx cell culture assay 

The human erythroleukemia K562 cell line 

The MOLT-4 leukemic cell line 

The RPMI, and TE671 tumor cells 

ras-expressing cells 

Alexander cell line (a human hepatocellular carcinoma cell line secreting HbsAg) 

The human larynx (HEp-2) and lung (PC-13) carcinoma cells 

The mouse B16 melanoma, leukemia P-388, and L5178Y cells 

The liver-metastatic variant (L5) 

7,12-dimethyl benzanthracene (DMBA) induced rat mammary tumors 

Ehrlich ascites carcinoma (EAC), Dalton’s lymphonia ascites (DLA) and Sarcoma-180 

(S-180) cells 

MCA-induced soft tissue sarcomas in albino mice.


Sophisticated methods for determining cellular growth and viability in primary screens 

include: 

● Suppression of 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated 

32 Pi-incorporation into phospholipids of cultured cells. 

● Epstein–Barr virus activation. 

● Suppression of the tumor-promoting activity induced by 7,12- 

dimethylbenz[a]anthracene (DMBA) plus TPA, (calmodulin involved systems). 

● Production of TNF, possibly through stimulation of the reticuloendothelial system 

(RES). 

● Stimulation of the uptake of tritiated thymidine into murine and human spleen cells. 

● Inhibition of RNA, DNA and protein synthesis in tumoric cells. 

● Analysis of endogenous cyclic GMP: cyclic GMP is thought to be involved in 

lymphocytic cell proliferation and leukemogenesis. In general, the nucleotide is 

elevated in leukemic vs. normal lymphocytes and changes have been reported to 

occur during remission and relapse of this disease. 

● Determination of DNA damage in Ehrlich ascites tumor cells by the use of an alkaline 

DNA unwinding method, followed by hydroxylapatite column chromatography of 

degraded DNA. 

● The brine shrimp lethality assay for activity-directed fractionation. 

● Suppression of the activities of thymidylate synthetase and thymidine kinase 

involved in de novo and salvage pathways for pyrimidine nucleotide synthesis. 

● Suppression of the induction of the colonic cancer in rats treated with a chemical 

carcinogen 1,2-dimethylhydrazine (DMH). 

● Inhibition of Epstein–Barr virus early antigen (EBV-EA) activation induced by 

12-O-tetradecanoylphorbol-13-acetate (TPA). 

● Inhibition of calmodulin-dependent protein kinases(CaM kinase III). These enzymes 

phosphorylate certain substrates that have been implicated in regulating cellular 

proliferation, usually via phosphorylation of elongation factor 2. The activity of 

CaM kinase III is increased in glioma cells following exposure to mitogens and is 

diminished or absent in nonproliferating glial tissue. 

● Inhibition of the promoting effect of 12-O-tetradecanoylphorbol-13-acetate on skin 

tumor formation in mice initiated with 7,12-dimethylbenz-[a]anthracene. 

● Inhibition of two-stage initiation/promotion [dimethylbenz[a]anthracene 

(DMBA)/croton oil] skin carcinogenesis in mice. 

● The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] 

colorimetric assay. 

Clinical trials are studies that evaluate the effectiveness of new interventions. There are 

different types of cancer clinical trials. They include: 

● 

● 

prevention trials designed to keep cancer from developing in people who have not 

previously had cancer; 

prevention trials designed to prevent a new type of cancer from developing in people who 

have had cancer;


● 

● 

● 

● 

early detection trials to find cancer, especially in its early stages; 

treatment trials to test new therapies in people who have cancer; 

quality of life studies to improve comfort and quality of life for people who have cancer; 

studies to evaluate ways of modifying cancer-causing behaviors, such as tobacco use. 

1.4.2. Phases of clinical trials 

Most clinical research that involves the testing of a new drug progresses in an orderly series of steps 

(Dimitriou, 2001; NCI, 2001). This allows researchers to ask and answer questions in a way that 

expands information about the drug and its effects on people. Based on what has been learned in 

laboratory experiments or previous trials, researchers formulate hypotheses or questions that need to 

be answered. Then they carefully design a clinical trial to test the hypothesis and answer the research 

question. It is customary to separate different kinds of trials into phases that follow one another in 

an orderly sequence. Generally, a particular cancer clinical trial falls into one of three phases. 

Phase I trials 

These first studies in people evaluate how a new drug should be administered (orally, intravenously, 

by injection), how often, and in what dosage. A Phase I trial usually enrols only a small number 

of patients, as well as about 20 to 80 normal, healthy volunteers. The tests study a drug’s safety 

profile, including the safe dosage range. The studies also determine how a drug is absorbed, distributed, 

metabolized and excreted, and the duration of its action. This phase lasts about a year. 

Phase II trials 

A Phase II trial provides preliminary information about how well the new drug works and 

generates more information about safety and benefit. Each Phase II study usually focuses on a 

particular type of cancer. Controlled studies of approximately 100 to 300 volunteer patients 

assess the drug’s effectiveness and take about two years. 

Phase III trials 

These trials compare a promising new drug, combination of drugs, or procedure with the 

current standard. Phase III trials typically involve large numbers of people in doctors’ offices, 

clinics, and cancer centers nationwide. This phase lasts about three years and usually involves 

1,000 to 3,000 patients in clinics and hospitals. Physicians monitor patients closely to 

determine efficacy and identify adverse reactions. 

Some use the term Phase IV to include the continuing evaluation that takes place after FDA 

approval, when the drug is already on the market and available for general use (post-marketing 

surveillance). 

1.4.3. Clinical trial protocols 

Clinical trials follow strict scientific guidelines. These guidelines deal with many areas, 

including the study’s design, who can be in the study, and the kind of information people must 

be given when they are deciding whether to participate. Every trial has a chief investigator, who


is usually a doctor. The investigator prepares a study action plan, called a protocol. This plan 

explains what the trial will do, how and why. For example, it states: 

● 

● 

● 

● 

● 

How many people will be in the study. 

Who is eligible to participate in the study. 

What study drugs participants will take. 

What medical tests they will have and how often. 

What information will be gathered.

Chapter 2 

Plants and cancer 

Spiridon E. Kintzios and Maria G. Barberaki 

2. THE PLANT KINGDOM: NATURE’S PHARMACY 

FOR CANCER TREATMENT 

2.1. Brief overview of the general organization of 

the plant cell (see also Figure 2.1) 

Although plant cells exhibit considerable diversity in their structure and function, their basic 

morphology is relatively unique. A typical plant cell consists of a cell wall (primary and secondary) 

surrounding a protoplast, which is delineated by the plasma membrane (or plasmalemma). 

The protoplasm (the protoplast without the plasmalemma) contains bodies bounded by membranes, 

known as organelles, as well as membrane structures, which do not enclose a body. The 

cytoplasm is the part of the protoplasm including various membrane structures, filaments and 

various particles, but not organelles. The cytosol is the aqueous phase of the cytoplasm, devoid of 

all particulate material. All membranes (including plasmalemma) chemically consist of a phospholipid 

bilayer carrying various proteins. Thanks to the existence of these internal compartments, 

specific functions can be executed in different parts or organelles of the plant cell 

(Anderson and Beardall, 1991). For example, the cell membrane permits the controlled entry 

and exit of compounds into and out of the cell while preventing excessive gain or loss of water 

and metabolic products. The nucleus is a large organelle containing chromatin, a complex of 

DNA and protein. It is the main center for the control of gene expression and replication. 

Chlorophyll-containing chloroplasts are the site for photosynthesis. Mitochondria contain enzymes 

important for the process of oxidative phosphorylation, that is, the phosphorylation of ADP to 

ATP with the parallel consumption of oxygen. Vacuoles are large organelles (usually only one 

vacuole is found in mature cells, representing up to 90% of the cell volume). They store water, 

salts, various organic metabolites, toxic substances or waste products and water-soluble 

pigments. Generally, the vacuole content (the cell sap) is considered to represent, together with 

the cytosol, the hydrophilic part of the plant cell. Ribosomes are small spheroid particles (attached 

to the cytoplasmic side of the endoplasmic reticulum, mitochondria and chloroplasts), which serve 

as sites for protein synthesis. Golgi bodies (or dictyosomes) consist of a stack of about five flattened 

sacs (cisternae) and are the sites for the synthesis of most of the matrix polysaccharides of cell 

walls, glycoproteins and some enzymes. Microbodies are small organelles containing various oxidases. 

Finally, microtubules are tubular inclusions within the cytoplasm, consisting of filamentous 

polymers of the protein tubulin, which can polymerize and depolymerize in a reversible manner. 

They direct the physical orientation of various components within the cytoplasm.

16 Spiridon E. Kintzios and Maria G. Barberaki 

Cell wall 

Plasmalemma 

Dictyosomes 

Vacuole 

Endoplasmic 

reticulum 

Nucleolus 

Nucleus 

Ribosomes 

Protein 

Mitochondrion 

Chloroplast 

Figure 2.1 General outline of the structure of a plant cell. 

2.2. The chemical constituents of the plant cell 

Throughout human history, plants have been an indispensable source of natural products for 

medicine. The chemical constituents of the plant cell that exert biological activities on human 

and animal cells fall into two distinct groups, depending on their relative concentration in the 

plant body, as well as their major function: primary metabolites, the accumulation of which 

satisfies nutritional and structural needs, and secondary metabolites, which act as hormones, 

pharmaceuticals and toxins. 

2.2.1. Primary metabolites 

By definition, primary metabolism is the total of processes leading to the production of sugars 

(carbohydrates) (structural and nutritional elements), amino acids (structural elements and

Plants and cancer 17 

enzymes), lipids (constituents of membranes, nutritional elements) and nucleotides 

(constituents of genes). These account for about 90% of the biological matter and are required 

for the growth of plant cells (Payne et al., 1991). These compounds occur principally as components 

of macromolecules, such as cellulose or amylose (from sugars), proteins (from amino acids) 

and nucleic acids, such as DNA (from nucleotides). Primary metabolites mainly contain carbon, 

nitrogen and phosphorous, which are assimilated into the plant cell by three main catabolic 

pathways: glycolysis, the pentose phosphate pathway and the tricarboxylic (TCA) cycle. Primary 

metabolism in plants is distinct from its animal counterpart, since it is a light-dependent 

process, known as photosynthesis. In other words, carbon assimilation in plant biological matter 

is mediated by chlorophyll and other photosynthetic pigments, which are found in chloroplasts 

of mesophyll cells. 

2.2.2. Secondary metabolites 

Secondary metabolites are compounds belonging to extremely varied chemical groups, such as 

organic acids, aromatic compounds, terpenoids, steroids, flavonoids, alkaloids, carbonyles, etc., 

which are described in detail in Section 2.4. Their function in plants is usually related to metabolic 

and/or growth regulation, lignification, coloring of plant parts and protection against 

pathogen attack (Payne et al., 1991). Even though secondary metabolism generally accounts for 

less than 10% of the total plant metabolism, its products are the main plant constituents with 

pharmaceutical properties. 

Despite the diversity of secondary metabolites, a few key intermediates in primary metabolism 

supply the precursors for most secondary products. These are mainly sugars, acetyl-CoA, 

nucleotides and amino acids (Robinson, 1964; Jakubke and Jeschkeit, 1975; Payne et al., 1991). 

● 

● 

● 

● 

● 

Cyanogenic glycosides and glucosinolates are derived from sugars. 

Terpenes and steroids are produced from isoprene units which are derived from acetyl-CoA. 

Nucleotide bases are precursors to purine and pyrimidine alkaloids. 

Many different types of aromatic compounds are derived from shikimic acid pathway 

intermediates. 

The non-aromatic amino acid arginine is the precursor to plyamines and the tropane alkaloids. 

In addition, many natural products are derived from pathways involving more than one of 

these intermediates: 

● 

● 

● 

Phenylpropanoids are derived from the amino acid phenylalanine, with acetyl-CoA and 

sugar units being added later in the biosynthetic pathway. 

The indole and the quinoline alkaloids are derived from the amino acid tryptophan and 

from monoterpenes. 

The aglycon moieties of cyanogenic glycosides and glucosinolates are derived from amino acids. 

Primary and secondary metabolic pathways in plants are summarized in Figure 2.2. 

2.3. Why do plant compounds have an anticancer activity 

Some secondary metabolites are considered as metabolic waste products, for example, alkaloids 

may function as nitrogen waste products. However, a significant portion of the products derived


Summary of plant primary metabolism 

NH 3 , PO 4 

Glucose (C 6 ) 

NH 3 

Nucleotides 

Serine 

NH 3 

Pyruvate 

Alanine 

 

Aspartate 

NH 3 

Acetyl-CoA 

NH 3 

Lipids 

Glutamate 

Asparigine 

Oxaloacetate 

TCA cycle 

α-ketoglutarate 

Glutamine 

Summary of plant secondary metabolism 

Glucose (C 6 ) 

 

Sugar derived 

Glusosinolates 

Nucleoside derived 

Cyanogenic glycosides 

Pyrimidine alkaloids 

Purine alkaloids 

Shikimik acid derived 

Quinones 

Flavonoids 

Tannins 

Betalains 

Malonate (C 3 ) Acetate (C 2 ) Mevalonate (C 6 ) 

 

 

 

Polyketides 

TCA cycle 

Terpenes and Steroids 

 

Arginine 

Polyamines 

Tropane 

alkaloides 

Figure 2.2 Summary of primary and secondary metabolic pathways in plants (adapted from 

Payne et al., 1991). 

form secondary pathways serve either as protective agents against various pathogens (e.g. insects, 

fungi or bacteria) or growth regulatory molecules (e.g. hormone-like substances that stimulate or 

inhibit cell division and morphogenesis). Due to these physiological functions, secondary 

metabolites are potential anticancer drugs, since either direct cytotoxicity is effected on cancer 

cells or the course of tumor development is modulated, and eventually inhibited. 

Administration of these compounds at low concentrations may be lethal for microorganisms and 

small animals, such as herbivorous insects, but in larger organisms, including humans, they may 

specifically affect the fastest growing tissues such as tumors.

2.4. Chemical groups of natural products with 

anticancer properties 


Plant-derived natural products with documented anticancer/antitumor properties can be 

classified into the following 14 chemical groups: 

1 Aldehydes 

2 Alkaloids 

3 Annonaceous acetogenins 

4 Flavonoids 

5 Glycosides 

6 Lignans 

7 Lipids 

8 Lipids (unsaponified) 

9 Nucleic acids 

10 Phenols and derivatives 

11 Polysaccharides 

12 Proteins 

13 Terpenoids 

14 Unidentified compounds. 

Aldehydes are volatile substances found (along with alcohols, ketones and esters) in 

minute amounts and contributing to the formation of odor and flavor of plant parts. 

Structure and properties: They are aliphatic, usually unbranched molecules, with up to 

twelve carbon atoms (C 12 ). They can be extracted from plants by distillation, solvent 

extraction or aeration. 

Biosynthesis in plant cells: It is suggested that the biosynthesis of aldehydes is related 

to fatty acids. 

Basis of anticancer/antitumor activity: Some aldehydes are cytotoxic against certain 

cancer types in vitro, mainly due to inhibition of tyrosinase. Immunomodulatory properties 

have been also ascribed to this group of secondary metabolites. 

Some plants containing aldehydes with anticancer properties are indicated in Table 2.1 

(for more details on each plant, please consult Chaper 3 of this book). 

Table 2.1 Plants containing aldehydes with anticancer properties 

Species Target disease or cell line Mode of action Page 

(if known) 

(if known) 

Cinnamomum cassia Human cancer lines, SW-620 Cytotoxic, 68 

xenograft 

immunomodulatory 

Mondia whitei Under investigation in Tyrosinase 183 

various cell lines 

inhibitor 

Rhus vulgaris Under investigation in Tyrosinase 183 


inhibitor 

Sclerocarya caffra Under investigation in Tyrosinase 183 


inhibitor


Alkaloids are widely distributed throughout the plant kingdom and constitute a 

very large group of chemically different compounds with diversified pharmaceutical 

properties. 

Many alkaloids are famous for their psychotropic properties, as very potent narcotics 

and tranquilizers. Examples are morphine, cocaine, reserpine and nicotine. Several alkaloids are 

also very toxic. 

Structure and properties: They are principally nitrogen-containing substances with a 

ring structure that allows their general classification in the groups described in 

Table 2.2 ( Jakubke and Jeschkeit, 1975). Most alkaloids with anticancer activity are 

either indole, pyridine, piperidine or aminoalkaloids. 

Table 2.2 General structural classification of alkaloids 

Group name 

Pyrrolidine 

Base structure 

N 

Pyrrolizidine 

N 

Tropane 

N 

OR 

Piperidine 

N 

Punica, Sedum and Lobelia alkaloids 

Quinolizidine 

N 

N 

Isoquinolizidine 

N 

Indole 

N 

N 

Rutaceae alkaloids 

N 

O 

Terpene alkaloids 

N


Alkaloids are weak bases, capable of forming salts, which are commonly extracted from 

tissues with an acidic, aqueous solvent. Alternatively, free bases can be extracted with 

organic solvents. 

Distribution: Quite abundant in higher plants, less in gymnosperms, ferns, fungi and 

other microorganisms. Particularly rich in alkaloids are plants of the families 

Apocynaceae, Papaveraceae and Fabaceae. 

Biosynthesis in plant cells: Rather complicated, with various amino acids (phenylalanine, 

tryptophan, ornithine, lysine and glutamic acid) serving as precursor substances. 

Basis of anticancer/antitumor activity: Alkaloids are mainly cytotoxic against various 

types of cancer and leukemia. They also demonstrate antiviral properties. More rarely, they 

demonstrate immuno-modulatory properties. 

Some plants containing alkaloids with anticancer properties are indicated in Table 2.3 

(for more details on each plant, please consult Chapter 3 of this book). 

Table 2.3 Plants containing alkaloids with anticancer properties 


(if known) 

(if known) 

Aconitum napellus Under investigation in Poisonous 160 


Acronychia baueri, Possible against KB cells Cytotoxic 74 

A. haplophylla 

Annona purpurea Under investigation in Cytotoxic 81 


Brucea antidysenterica Leukemia Cytotoxic 81 

Calycodendron milnei Antiviral Cytotoxic 182 

Cassia leptophylla Under investigation in DNA-damaging 86 


(piperidine) 

Chamaecyparis sp. P-388 Cytotoxic: 169 

inhibition of 

cyclic GMP 

formation 

Chelidonium majus Various cancers, lung Immunomodulator 86 

(clinical) 

Colchicum autumnale P-388, esophageal Tubulin inhibitor 93 

Ervatamia microphylla k-ras-NRK (mice) cells Growth inhibition 101 

Eurycoma longifolia Various human cell lines Cytotoxic 172 

in vitro 

Fagara macrophylla P-388 Cytotoxic 101 

Nauclea orientalis Antitumor, in vitro human Antiproliferative 178 

bladder carcinoma 

Psychotria sp. Antiviral 181 

Strychnos usabarensis Various in vitro Cytotoxic 162 

(liver damage)


Annonaceous acetogenins are antitumor and pesticidal agents of the Annonaceae 

family. 

Structure and properties: They are a series of C-35/C-37 natural products derived from 

C-32/C-34 fatty acids that are combined with a 2-propanol unit. They are usually characterized 

by a long aliphatic chain bearing a terminal methyl-substituted ,-unsaturated 

-lactone ring with 1-3 tetrahydrofuran (THF) rings located among the hydrocarbon 

chain and a number of oxygenated moieties and/or double bonds. Annonaceous acetogenins 

are classified according to their relative stereostructures across the THF rings 

(Alali et al., 1999). 

Annonaceous acetogenins are readily soluble in most organic solvents. Ethanol 

extraction of the dried plant material is followed by solvent partitions to concentrate the 

compounds. 

Distribution: Exclusively in the Annonaceae family. 

Biosynthesis in plant cells: Derived from the polyketide pathway, while the tetrahydrofuran 

and epoxide rings are suggested to arise from isolated double bonds through 

epoxidation and cyclization. 

Basis of anticancer/antitumor activity: Annonaceous acetogenins are cytotoxic against 

certain cancer species and leukemia. They are the most powerful inhibitors of complex I 

in mammalian and insect mitochondrial electron transport system, as well as of NADH 

oxidase of the plasma membranes of cancer cells. Therefore they decrease cellular ATP 

production, causing apoptotic cell death. 

Some plants containing Annonaceous acetogenins are indicated in Table 2.4 (for more 

details on each plant, please consult Chapter 3 of this book). 

Table 2.4 Plants containing Annonaceous acetogenins 

Species Target disease or cell line Mode of action Pages 

(if known) 

(if known) 

Annona muricata, Prostate adenocarcinoma, Cytotoxic 81 

A. squamosa pancreatic carcinoma 

A. bullata Human solid tumors Cytotoxic 80 

in vitro (colon cancer) 

Eupatorium Leukemia Cytotoxic 99 

cannabinum, 

E. semiserratum, 

E. cuneifolium 

Glyptopetalum In vitro various human Non-specific 173 

sclerocarpum cancers cytotoxic 

Goniothalamus sp. Breast cancer, in vitro Cytotoxic 109 

various human cancers 

Helenium Leukemia Cytotoxic 112 

microcephalum 

Passiflora tetrandra P-388 Cytotoxic 179 

Rabdosia ternifolia Various human cancer Cytotoxic 141 

cells


Flavonoids are widely distributed colored phenolic derivatives. Related compounds 

include flavones, flavonols, flavanonols, xanthones, flavanones, chalcones, aurones, anthocyanins 

and catechins. 

Structure and properties: Flavonoids may be described as a series of C 6 –C 3 –C 6 

compounds, that is, they consist of two C 6 groups (substituted benzene rings) connected by 

a three-carbon-aliphatic chain. The majority of flavonoids contain a pyran ring linking the 

three-carbon chain with one of the benzene rings. Different classes within the group are distinguished 

by additional oxygen-heterocyclic rings and by hydroxyl groups distributed in 

different patterns. Flavonoids frequently occur as glycosides and are mostly water-soluble or 

at least sufficiently polar to be well extracted by methanol, ethanol or acetone; however they 

are less polar than carbohydrates and can be separated from them in an aqueous solution. 

Distribution: They are widely distributed in the plant kingdom, since they include 

some of the most common pigments, often fluorescent after UV-irradiation. They also act 

as metabolic regulators and protect cells from UV-radiation. Finally, flavonoids have a key 

function in the mechanism of biochemical recognition and signal transduction, similar to 

growth regulators. 

Biosynthesis in plant cells: Flavonoids are derived from shikimic acid via the phenylpropanoid 

pathway. Related compounds are produced through a complex network of reactions: 

isoflavones, aurones, flavanones and flavanonols are produced from chalcones, 

leucoanthocyanidins, flavones and flavonols from flavanonols and anthocyanidins from 

leucoanthocyanidins. 

Basis of anticancer/antitumor activity: Flavonoids are cytotoxic against cancer cells, 

mostly in vitro. 

Some plants containing flavonoids with anticancer properties are indicated in Table 2.5 

(for more details on each plant, please consult Chapter 3 this book). 

Table 2.5 Plants containing flavonoids with anticancer properties 


(if known) 

(if known) 

Acrougehia porteri KB Cytotoxic 72 

Angelica keiskei Antitumor promoting activity (mice) Calmodulin inhibitor 78 

Annona densicoma, Various mammalian cell cultures Cytotoxic 80 

A. reticulata 

Claopodium crispifolium Potential anticarcinogenic agent Cytotoxic 80 

Eupatorium altissimum P-338, KB Cytotoxic 99 

Glycyrrhiza inflata HeLa cells (mice) Cytotoxic 68 

Gossypium indicum B16 melanoma Cytotoxic 111 

Polytrichum obioense Hela, leukemia (mice) Cytotoxic 80 

Psorospermum febrifigum KB Cytotoxic 80 

Rhus succedanea Under investigation in various cell lines Cytotoxic 182 

Zieridium KB Cytotoxic 74 

pseudobtusifolium


Glycosides are carbohydrate ethers that are readily hydrolyzable in hot water or weak 

acids. Most frequently, they contain glucose and are named by designating the attached 

alkyl group first and replacing the –ose ending of the sugar with –oside. 

Basis of anticancer/antitumor activity: Glycosides are mainly cytotoxic against certain 

types of cancer and also demonstrate antiviral and antileukemic properties. 

Some plants containing glycosides with anticancer properties are indicated in Table 2.6 


Lignans are colorless, crystalline solid substances widespread in the plant kingdom 

(mostly as metabolic intermediaries) and having antioxidant, insecticidal and medicinal 

properties. 

Structure and properties: They consist of two phenylpropanes joint at their aliphatic 

chains and having their aromatic rings oxygenated. Additional ring closures may also be 

present. Occasionally they are found as glycosides. 

Lignans may be extracted with acetone or ethanol and are often precipitated as 

slightly soluble potassium salts by adding concentrated potassium hydroxide to an 

alcoholic solution. 

Distribution: Wide. 

Biosynthesis in plant cells: Lignans are originally derived from shikimic acid via the 

phenylpropanoid pathway, with p-hydroxycinnamyl alohol and coniferyl alcohol being 

key intermediates of their biosynthesis. 

Basis of anticancer/antitumor activity: Some lignans are cytotoxic against certain 

cancer types, such as mouse skin cancer, or tumor and leukemic lines in vitro. 

Some plants containing lignans with anticancer properties are indicated in Table 2.7 


Table 2.6 Plants containing glycosides with anticancer properties 


(if known) 

(if known) 

Phlomis armeniaca Liver cancer, Dalton’s Antiviral, cytotoxic, 154 

lymphoma (mice), 

chemopreventive 

Leukemia 

(human) 

Phyllanthus sp. Liver cancer, Dalton’s Cytotoxic 136 

lymphoma (mice), 

P-388 

Plumeria rubra P-388, KB Cytotoxic 138 

(iridoids) 

Scutellaria salviifolia Various cancer cell lines Cytotoxic 154 

Wikstroemia indica Leukemia, Ehrlich ascites Antitumor 159 

carcinoma (mice), P-388


Table 2.7 Plants containing lignans with anticancer properties 


(if known) 

(if known) 

Brucea sp. KB, P-388 Cytotoxic 81 

Juniperus virginiana Liver cancer (mice) Tumor inhibitor 117 

Magnolia officinalis Skin (mice) Tumor inhibitor 178 

Plumeria sp. P-388, KB Cytotoxic 138 

Wikstroemia foetida P-388 Cytotoxic 160 

Table 2.8 Plants containing lipids with anticancer properties 


(if known) 

(if known) 

Nigella sativa Ehrilch ascites carcinoma Cytotoxic in vitro 96 

Sho-saiko-to, Dalton’s lymphoma, Immunomodulator, 68 

Juzen-taiho-to sarcoma-180 (clinical) antitumor 

(extract) 

Lipids (saponifiable) include fatty acids (aliphatic carboxylic acids), fatty acid esters, 

phospholipids and glycolipids. 

Structure and properties: By definition, lipids are soluble only in organic solvents. 

On heating with alkali, they form water-soluble salts (therefore the designation 

saponifiable lipids). Fatty acids are usually found in their ester form, mostly having an 

unbranched carbon chain and differ from one another in chain length and degree of 

unsaturation. 

Distribution: Lipids are widely distributed in the plant kingdom. They both 

serve as nutritional reserves (particularly in seeds) and structural elements 

(i.e.phospholipids of the cell membrane, fatty acid esters in the epidermis of leaves, stems, 

fruits etc.). 

Biosynthesis in plant cells: They are derived by condensation of several molecules of 

acetate (more specifically malonyl-coenzyme A), thus being related to long-chain fatty 

acids. 

Basis of anticancer/antitumor activity: Saponifiable lipids are cytotoxic against a 

limited number of cancer types. 

Some plants containing lipids with anticancer properties are indicated in Table 2.8 (for 

more details on each plant, please consult Chapter 3 of this book).


Unsaponifiable lipids (in particular quinones) are a diverse group of substances 

generally soluble in organic solvents and not saponified by alkali. They are yellow to 

red pigments, often constituents of wood tissues and have toxic and antimicrobial 

properties. 

Structure and properties: Naphthoquinones are yellow-red plant pigments, extractable 

with non-polar solvents, such as benzene. They can be separated from lipids by stem distillation 

with weak alkali treatment. Anthraquinones represent the largest group of natural 

quinines, are usually hydroxylated at C-1 and C-2 and commonly occur as glycosides 

(water-soluble). Thus, their isolation is carried out according to the degree of glycosidation. 

Hydrolysis of glycosides (after extraction in water or ethanol) takes place by heating 

with acetic acid or dilute alcoholic HCl. Phenanthraquinones have a rather more complex 

structure and can be extracted in methanolic solutions. 

Distribution: Anthraquinones are particularly found in the plant families Rubiaceae, 

Rhamnaceae and Polygonaceae. Phenanthraquinones are rare compounds having important 

medicinal properties (e.g. hypericin from Hypericum perforatum, tanshinone from Salvia 

miltiorrhiza). 

Biosynthesis in plant cells: They are derived by condensation of several molecules of 

acetate (more specifically malonyl-coenzyme A), thus being related to long-chain fatty 

acids. 

Basis of anticancer/antitumor activity: Several quinines are cytotoxic against certain 

cancer types, such as melanoma, or tumor lines in vitro. 

Some plants containing quinones with anticancer properties are indicated in Table 2.9 


Table 2.9 Plants containing quinones with anticancer properties 


(if known) 

(if known) 

Kigelia pinnata In vitro melanoma, renal Tumor inhibitor 174 

cell carcinoma 

Koelreuteria henryi Src-Her-2/neu, ras Tumor inhibitor 174 

oncogenes 

Landsburgia quercifolia P-388 Cytotoxic 176 

Mallotus japonicus In vitro: human lung Cytotoxic 120 

carcinoma, 

B16 melanoma, 

P-388, KB 

Nigella sativa MDR human tumor Cytotoxic in vitro 96 

Rubia cordifolia In vitro human cancer Antitumor 142 

lines 

Sargassum tortile P-388 Cytotoxic 150 

Wikstroemia indica Ehrlich ascites Antitumor 159 

carcinoma, 

MK, P-388


Nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are known as the 

“genetic molecules,” the building blocks of genes in each cell or virus. 

Structure and properties: Each nucleic acid contains four different nitrogen bases (purine 

and pyrimidine bases), phosphate and either deoxyribose or ribose. DNA contains the bases 

adenine, quanine, cytosine, thymine and 5-methylcytosine. The macromolecular structure of 

DNA is a two-stranded helix with the strands bound together by hydrogen bonds. 

Like proteins and polysaccharides, nucleic acids are water-soluble and non-dialyzable. 

They can be separated from a water extract by denaturating proteins in chloroform-octyl 

alcohol and then precipitate polysaccharides in a weakly basic solution. 


Biosynthesis in plant cells: Bases are derived originally from ribose-5-phosphate, 

purines from inosinic acid and pyrimidines from uridine-5-phosphate. Nucleic acids are 

formed after nucleotide transformation and condensation. 

Basis of anticancer/antitumor activity: Some nucleotides, like cyclopentenyl cytosine 

(derived from Viola odorata), present cytotoxicity against certain cancer species in vitro. 

Phenols and derivatives are the main aromatic compounds of plants, whose structural 

formulas contain at least one benzene ring. They serve as odors, fungicidals or germination 

inhibitors. Coumarins are especially common in grasses, orchids, citrus fruits and legumes. 

Structure and properties: Simple phenols are colorless solids, which are oxidized by air. 

Water solubility increases with the number of hydroxyl groups present, but solubility in 

organic solvents is generally high. Natural aromatic acids are usually characterized by 

having at least one aliphatic chain attached to the aromatic ring. 

Coumarins are lactones of o-hydroxycinnamic acid. Almost all natural coumarins have 

oxygen (hydroxyl or alkoxyl) at C-7. Other positions may also be oxygenated and alkyl 

side-chains are frequently present. Furano- and pyranocoumarins have a pyran or furan ring 

fused with the benzene ring of a coumarin. 

Phenolic acids may be extracted from plant tissues or their ether extract in 2% sodium 

bicarbonate. Upon acidification, acids often precipitate or may be extracted with ether. 

After removal of carboxylic acids, phenols may be extracted with 5% sodium hydroxide 

solution. Phenols are usually not steam-distillable, but their ethers or esters can be. 

Coumarins can be purified from a crude extract by treatment with warm dilute alkali 

which will open the lactone ring and form a water-soluble coumarinate salt. After removal 

of organic impurities with ether, coumarins can be reconstituted by acidification. 

Distribution: Wide, abundant in herbs of the families Lamiaceae and Boraginaceae. 

Biosynthesis in plant cells: Phenolic compounds generally are derived from shikimic 

acid via the phenylpropanoid pathway. 

Basis of anticancer/antitumor activity: Phenolic compounds are cytotoxic against certain 

cancer types in vitro. They usually interfere with the integrity of the cell membrane or 

inhibit various protein kinases. Coumarins, in particular furanocoumarins, are highly toxic. 

Some plants containing phenols with anticancer properties are indicated in Table 2.10 

(for more details on each plant, please consult Chapter 3 of this book).


Table 2.10 Plants containing phenols with anticancer properties 


(if known) 

(if known) 

Acronychia laurifolia Under investigation in Under 73 


investigation 

Angelica gigas, No data Cytotoxic 77 

A. decursiva, A. keiskei 

Gossypium indicum Murine B16 melanoma, Cytotoxic 111 

L1210 lymphoma 

Polysaccharides and generally carbohydrates represent the main carbon sink in the plant 

cell. Polysaccharides commonly serve nutritional (e.g. starch) and structural 

(e.g. cellulose) functions in plants. 

Structure and properties: They are polymers of monosaccharides (and their derivatives) 

containing 10 or more units, usually several thousand. Despite the vast number of possible 

polysaccharides, only few of the structural possibilities actually exist. Generally, 

structural polysaccharides are strait-chained (not very soluble in water), while nutritional 

(reserve food) polysaccharides tend to be branched, therefore forming viscous hydrophilic 

colloid systems. Plant gums and mucilages are hydrophilic heteropolysaccharides (i.e. they 

contain more than one type of monosaccharide), with the common presence of uronic acid 

in their molecule. 

Depending on their degree of solubility in water, polysaccharides can be extracted from 

plant tissues either with hot water (pectic substances, nutritional polysaccharides, 

mucilages, fructans) or alkali solutions (hemicelluloses). 

Distribution: They are universally distributed in the plant kingdom. Structural polysaccharides 

are the main constituents of the plant cell wall (cellulose, hemicelluloses, 

xylans, pectins, galactans). Nutritional polysaccharides include starch, fructans, mannans 

and galactomannans. Mucilages abound in xerophytes and seeds. Polysaccharides also have 

a key function in the mechanism of biochemical recognition and signal transduction, 

similar to growth regulators. 

Biosynthesis in plant cells: There exists a complex network of interrelated biosynthetic 

pathways, with various monosaccharides (glucose, fructose, mannose, mannitol, ribose 

and erythrose) serving as precursor substances. Phosphorylated intermediates are found in 

subsequent biosynthetic steps and branching points. The glycolytic, pentose and 

UDP-glucose pathways have been defined in extend. 

Basis of anticancer/antitumor activity: Some polysaccharides are cytotoxic against 

certain types of cancer, such as mouse skin cancer, or tumor lines in vitro (e.g. mouse 

Sarcoma-180). However, most polysaccharides exert their action through stimulation of 

the immune system (cancer immunotherapy). 

Some plants containing polysaccharides with anticancer properties are indicated in 

Table 2.11 (for more details on each plant, please consult Chapter 3 of this book).


Table 2.11 Plants containing polysaccharides with anticancer properties 


(if known) 

(if known) 

Angelica acutiloba Epstein–Barr, skin(mice) Cytotoxic, 78 

immunological 

Angelica sinensis Ehrlich Ascites (mice) Cytotoxic, 77 

immunological 

Brucea javanica Leukemia, lung, colon, Cytotoxic 83 

CNS, melanoma, brain 

Cassia angustifolia Solid Sarcoma-180 (mice) Cytotoxic 86 

Sargassum thunbergii Ehrlich Ascites (mice) Immunostim activates the 150 

reticuloenthothelial system 

S. fulvellum Sarcoma-180 (mice) Immunomodulator 150 

Tamarindus indica Potential activity in various cell lines Immunomodulator 184 

Proteins, like carbohydrates, belong to the most essential constituents of the plant body, 

since they are the building molecules of structural parts and the enzymes. 

Structure and properties: Proteins are made up from amino acids, the particular combination 

of which defines the physical property of the protein. Thus, protein sequences 

differing in only one amino acid will correspond to entirely different molecules, both 

structurally (tertiary structure) and functionally. Peptides are small proteins, amino acid 

oligomers with a molecular weight below 6000. In nature, 24 different amino acids are 

widely distributed. Sixteen to twenty different amino acids are usually found on hydrolysis 

of a given protein, all having the L-configuration. Conjugate proteins comprise other 

substances along with amino acids. Particularly important are glycoproteins, partially 

composed of carbohydrates. Proteins may be soluble in water and dilute salt solutions 

(albumins), in dilute salt solutions (globulins), in very dilute acids and bases (glutelins) 

or in ethanolic solutions (prolamines). 

Peptides and proteins can be isolated from a plant tissue by aqueous extraction or in 

less polar solvents (depending on the water solubility of a particular protein). 

Fractionation of the proteins can frequently be achieved by controlling the ionic strength 

of the medium through the use of salts. However, one must always take precautions 

against protein denaturation (due to high temperature). 

Distribution: Extremely wide. 

Biosynthesis in plant cells: Proteins are synthesized in ribosomes from free amino acids 

under the strict, coordinated control of genomic DNA, mRNA and tRNA (gene transcription 

and translation). 

Basis of anticancer/antitumor activity: Proteins are indirectly cytotoxic against certain 

cancer types, acting mainly through the inhibition of various enzymes or by inducing 

apoptotic cell death. 

Some plants containing proteins with anticancer properties are indicated in Table 2.12 

(for more details on each plant, please consult Chapter 3 of this book).


Table 2.12 Plants containing proteins with anticancer properties 


(if known) 

(if known) 

Acacia confusa Sarcoma 180/HeLa cells Trypsin inhibitor 167 

Ficus cunia Under investigation in White cell 103 


aglutination 

Glycyrrhiza uralensis Under investigation SDR-enzymes 68 

(antimutagenic) 

Momordica charantia Leukemia Inhibits DNA 124 

synthesis in vitro, 

immunostimulant 

Momordica indica Leukemia Antiviral, 124 

cytotoxic 

Rubia sp. R. cordifolia P338 Under investigation 142 

Terpenoids are diverse, widely distributed compounds commonly found under groups 

such as essential oils, sterols, pigments and alkaloids. They exert significant ecological 

functions in plants. Mono- and sesquiterpenoids are found as constituents of steam-distillable 

essential oils. Di- and triterpenoids are found in resins. 

Structure and properties: They are built up of isoprene or isopentane units linked 

together in various ways and with different types of ring closures, degrees of unsaturation 

and functional groups. Depending on the number of isoprene molecules in their structure, 

terpenoids are basically classified as monoterpenoids (2), sesquiterpenoids (3), diterpenoids (4) 

and triterpenoids (6). Sterols share the core structure of lanosterol and other tetracyclic 

triterpenoids, but with only two methyl groups at positions 10 and 13 of their ring 

system. Steroids occur throughout the plant kingdom as free sterols and their lipid 

esters. 

There exists no general method for isolating terpenoids from plants, however many of 

them are non-polar and can be extracted in organic solvents. After saponification in 

alcoholic alkali and extraction with ether, most terpenoids will accumulate into the ether 

fraction. 


Biosynthesis in plant cells: Terpenoids are all derived from mevalonic acid or a closely 

related precursor. The pyrophosphate of alcohol farnesol is a key intermediate in terpenoid 

biosynthesis, particularly leading to the formation of diterpenoids, triterpenoids and 

sterols. Monoterpenoids are derived from geranyl pyrophosphate. 

Basis of anticancer/antitumor activity: Terpenoids and sterols often possess alkaloidal 

properties, thus being cytotoxic in vivo and in vitro against various cancer types, such as 

human prostate cancer, pancreatic cancer, lung cancer and leukemia. 

Some plants containing terpenoids and sterols with anticancer properties are indicated 

in Table 2.13 (for more details on each plant, please consult Chapter 3 of this book).


Unidentified compounds usually refer to complex mixtures or plant extracts the 

composition of which has not been elucidated in detail or the bioactive properties 

of which can not be assigned to a particular substance only. Ironically, unidentified 

extracts are usually more potent against various types of cancer than single, well-studied 

molecules. 

Some plants containing unidentified compounds with anticancer properties are 

indicated in Table 2.14 (for more details on each plant, please consult Chapter 3 of this 

book). 

Table 2.13 Plants containing terpenoids and sterols with anticancer properties 


(if known) 

(if known) 

Aristolochia versicolar Under investigation Under investigation 169 

Brucea antidysenterica Under investigation Cytotoxic 81 

Casearia sylvestris Under investigation Cytotoxic in vitro, apoptotic 172 

Crocus sativus KB, P-388, human prostate, Cytotoxic 93 

pancreatic, in vitro 

Glycyrrhiza sp. P-388 No data 68 

Mallotus anomalus P-388 No data 120 

Melia sp. Carcinoma, sarcoma, Apoptotic/inhibits 122 

leukemia, AS49, VA13 DNA synthesis 

Maytenus sp. Leukemia Cytotoxic 121 

Neurolaena lobata Human carcinoma in vitro Cytotoxic 178 

Polyalthia barnesii Human carcinoma in vitro Cytotoxic 180 

Rabdosia trichocarpa HeLa cells, P-388 Cytotoxic 141 

Seseli mairei KB, P-388, L1210 183 

Stellera chamaejasme Human leukemia, stem, lung, Proteinokinase C 

P-388, L1210 activator 154 

Table 2.14 Plants containing unidentified compounds with anticancer properties 


(if known) 

(if known) 

Chelidonium majus Esophageal squamous cell Immunostimulant 86 

carcinoma clinical 

Menispernum dehuricum Intestinal metaplasia, Anti-estrogen, LH-RH 90 

atypical hyperplasia of the antagonist (mice) 

gastric 

Paeonia sp. Esophageal squamous cell Immunostimulant 131 

carcinoma clinical 

Phyllanthus amarus Antiviral (HBV) 136 

Phyllanthus emblica NK cells Immunostimulant 136 

Trifolium pratense Various human cell lines Chemopreventive 155


2.5. Biotechnology and the supply issue 

In spite of the plethora of plant metabolites with tumor cytotoxic or immuno-stimulating 

properties, plants may not be an ideal source of natural anticancer drugs. There are a number of 

reasons that make the recovery of plant-derived products less attractive than the alternative 

methods of biotechnology and chemical synthesis. 

First of all, there is the supply issue. In several cases, compounds of interest come from slow 

growing plant species (e.g. woody species), or species that are endangered. In addition, in vivo 

productivity can be considerably low, thus necessitating the use of an overwhelming amount of 

plant biomass in order to obtain a satisfactory portion of the natural product (especially in the 

case of secondary metabolites). For example, taxol concentration in needles and dried bark of 

Taxus brevifolia is approx. 0.01–0.1%. Supply can also be hindered due to inadequate plant production, 

which, in turn, may be caused by a number of problems related to disease, drought or 

socioeconomic factors. As demonstrated previously for taxol the issue of supply can be partly 

resolved by breeding for high-yielding varieties, introduction of wild species or derivation (in 

abundant amounts) of precursors for the hemisynthesis of the desired product (Cragg et al., 

1993; Gragg, 1998). 

Second, plant-derived pharmaceutical extracts frequently lack the necessary standardization 

that could render them reliable for large-scale, clinical use. This problem is related to a 

number of factors, such as the dependence of the production on environmental factors and the 

plant developmental stage (e.g. flowering), as well as the heterogeneity of the extracts, which 

makes further isolation and purification of the product an indispensable, though costly step. 

A representative example is mistletoe lectin extract, which presents a remarkable seasonal 

variation in the levels of ML isolectins (ML I, ML II and ML III). Furthermore, the specific 

bioactivity of the extract fluctuates over a prolonged (e.g. two-year) storage time (Lorch and 

Troger, 2000). 

Biotechnology could offer an alternative method for the production of considerable plant 

biomass or natural products in a relatively short time (Payne et al., 1991; Kintzios and 

Barberaki, 2000). In vitro techniques are a major component of plant biotechnology, since they 

permit artificial control of several of the parameters affecting the growth and metabolism of cultured 

tissues. Plainly put, plant tissue culture works on the principle of inoculating an explant 

(that is a piece of plant tissue, such as a leaf or stem segment) from a donor plant on a medium 

containing nutrients and growth regulators and causing thereof the formation of a more or less 

dedifferentiated, rapidly growing callus tissue. Production of plant-derived anticancer agents 

could be advantageous over derivation from plants in vivo since: 

1 By altering the culture parameters, it might be possible to control the quantity, composition 

and timing of production of mistletoe extracts. In this way, problems associated with 

the standardization of plant extracts could be overcome. 

2 By feeding cultures with precursor substances for the biosynthesis of certain metabolites, 

a higher productivity can be achieved from cultured cells (in vitro) than from whole plants. 

3 Potentially, entirely novel substances can be synthesized through biotransformation or by 

taking advantage of somaclonal variation, that is, a transient or heritable variability of 

metabolic procedures induced by the procedure of in vitro culture. 

4 The establishment of a callus culture is the first step required in order to obtain genetically 

modified cells or plants, for example, crop plants able to specifically produce a desired 

product in excessive amount.


5 Protoplasts are plant cells having their cell wall artificially removed. In this way, they can be 

used in gene transfer experiments and for the creation of hybrid cells that result from the 

direct fusion of two protoplast cells that might have been derived from entirely different 

species. 

6 Plant species that are difficult to propagate (such as mistletoe, which is exclusively accomplished 

with the aid of birds, carrying distantly mistletoe seeds) could be clonally micropropagated, 

thus obtaining thousands of seedlings from a very limited mass of donor tissue 

(essentially from one donor plant only). This can be achieved by plant regeneration via 

organogenesis (induction of shoots and roots from callus cultures) or somatic embryogenesis 

(the process of embryo formation from somatic (sporophytic) tissues without fertilization). 

Promising as the perspectives of plant cell culture may be, established plant-derived 

commercial anticancer drugs (such as vinblastine and vincristine from Catharanthus roseus) are still 

produced by isolation from growing plants; eventually drugs are semisynthetically produced 

from natural precursors also isolated from plant sources in vivo. Currently, there are only a few 

plant-derived natural compounds with antineoplastic properties that are being produced 

biotechnologically, mostly on the laboratory level: 

Periwinkle (Vinca rosea or Catharanthus roseus): Numerous studies have been conducted on the 

scale-up indole alkaloid production from cell suspension cultures of C. roseus. Several factors 

affecting production have been evaluated, including medium nutrient and growth regulator 

composition, elicitors, osmotic stress and precursor (tryptophan) feeding. Vinblatine, an 

antileukemic dimeric indole alkaloid dimmer cannot be directly produced from C. roseus in vitro, 

due to under-expression of the enzyme acetyl CoA:deacetylvindoline O-acetyl transferase, which 

catalyzes the formation of vindoline, one of the substrates leading to anhydrovinblastine. Yield 

values of catharanthine (the second substrate for vinblastine synthesis) up to 17gl 1 after 

fungal induction have been reported (Bhadra et al., 1993). 

Pacific Yew (Taxus brevifolia): In 1977, NCI awarded contracts for the investigation of plant 

tissue culture as a source of anticancer drugs, and two of these studies related to taxol production. 

Unfortunately, these contracts were terminated in 1980 before any positive results had 

been obtained. Considerable research effort has once more been focused on the application of this 

technology to taxol production. Ketchum et al. (1999) reported the production of up to 1.17% 

of paclitaxel within five days of elicitation with methyl jasmonate, along with other taxoids, 

such as 13-acetyl-9-dihydrobaccatin, 9-dihydrobaccatin III and baccatin VI. Two companies 

(ESCAgenetics Corporation and Phyton Catalytic) reported on their plans for a scale-up 

production of taxol in the near future. 

American mandrake (Podophyllum hexandrum): Cell suspensions of P. hexandrum have been 

established which accumulate up to 0.1% podophyllotoxin, a cytotoxic lignan used for the 

hemisynthesis of etoposide and teniposide. Accumulation of podophyllotoxin has been increased 

twelve-fold after precursor feeding with coniferin, a glucosylated intermediate of the phenylpropanoid 

pathway (Smollny et al., 1998). 

Mistletoe (Viscum album L.): Becker and Schwarz (1971) were the first to mention the possible 

use of mistletoe callus cultures as a source of bioactive products. In 1990, Fukui et al. 

reported on the induction of callus from leaves of V. album var. lutescens: they were able to identify 

in the callus two galactose-binding lectins which were originally observed in mistletoe leaves. 

Kintzios and Barberaki (2000) succeeded in inducing callus and protoplast cultures from mistletoe 

leaves and stems in a large number of different growth regulator and media treatments.


They have also studied the effects of different plant parts (stems and leaves), harvest time 

(winter or summer), explant disinfection methods, growth regulators, culture medium composition 

and cell wall digestion treatments. Finally, they observed a relatively low (8%) somaclonal 

variation, in the aspect of both the quantitative and the qualitative mistletoe protein production 

in vitro (Kintzios and Barberaki, 2000; Kintzios et al., 2002). Langer et al. (1997) cloned different 

fragments of the ML gene from mistletoe genomic DNA, constructed expression vectors (A- and 

B-chain coding region) and the single chains were expressed in E. coli separately. Experimental 

investigations on the activity of recombinant mistletoe lectin (rML) were promising.

Chapter 3 

Terrestrial plant species with 

anticancer activity 

A presentation 

Spiridon E. Kintzios*, Maria G. Barberaki* 

and Olga G. Makri 

3.1. Introduction: general botanical issues 

In this chapter a detailed analysis will be given on a number of species with documented 

anticancer properties either in vitro or in clinical use. Before we proceed with analysis, however, 

and for the purpose of a better understanding of the description of each species, a brief overview 

of botanical terms is given in following: 

Life cycle 

Plants can be distinguished according to their life cycle (germination, growth, flowering and 

seed production) as annuals, biennials and perennials. Annuals complete their life-cycle within 

a year. Biennials grow without flowering in the first year, coming into flowering in the second. 

Both these groups are herbs, which flower only once, produce seeds, and then die. Perennials 

flower for several or many years in succession. 

Plant anatomy 

The stem is made up of internodes, separated by nodes. The leaves arise at these nodes. The stem 

is either unbranched, or has side branches emerging from buds in the leaf axils. The side branches 

may themselves branch. Shoots continue to grow at the tip, and develop new leaves, with buds 

in the axils, which can grow into branches. The shoot can either be hairless, or it may carry hairs 

of various kinds, often glandular. 

Roots serve to anchor a plant (in the soil or another host plant) and to facilitate the uptake of 

water and mineral salts. The main or tap root is normally vertical. From this grow lateral roots, 

which may themselves branch, and in this way the full root system develops. Many plants have 

swollen roots which contain stores of food. 

A fully developed leaf consists of the blade, the leafstalk (petiole) and leaf base. Sometimes 

there is no leafstalk, in which case the leaf is termed sessile, or unstalked; otherwise it is known 

as petiolate, or stalked. The leaf base is often inconspicuous, but sometimes has a leaf sheath. The 

leaf base may have blunt or pointed extensions at either side of the stem (amplexicaul), or even 

completely encircle and fuse with the stem ( perfoliate). In decurrent leaves, the leaf blade extends 

some distance down the sides of the stem. 

Leaves can have different shapes, which often serve as taxonomic characters. They are 

distinguished in simple leaves with undivided blade, and compound leaves, consisting of several 

separate leaflets. Some have parallel or curved veins, without a central midrib; others have 

pinnate veins, with an obvious midrib and lateral veins. A leaf can have anyone of a number of 

shapes, including linear, lanceolate, elliptic, ovate, hastate (spear-shaped), reniform (kidney-shaped), 

cordate (heart-shaped), rhombic, spatulate or spathulate (spoon-shaped) or sagittate (arrow-shaped). 

There are also differences in leaf margins including entire, crenate (bluntly toothed margins), serrate 

* These authors contributed equally to this chapter.

36 Spiridon E. Kintzios et al. 

(serrated), dentate (toothed), sinuate/undulate (wavy margins), pinnately lobed, or palmately lobed leaves. 

Accordingly, compound leaves can be found as pinnate (imparipinnate if there is a terminal 

leaflet and paripinnate if not). Leaves grow as lateral appendages of the stem, from nodes. In the 

case of alternate leaves, there is a single leaf at each node, and successive leaves are not directly 

above each other. Opposite leaves are placed as a pair, one at each side of the node. When there 

are three or more leaves at each node, they are described as whorls (in whorls) (Podlech, 1996). 

The inflorescence is the part of the stem which carries the flowers. A spike is a flowerhead in 

which the individual flowers are stalkless. It can be short and dense, or long and loose. A raceme 

is similar, but consists of stalked flowers. A panicle is an inflorescence whose main branches are 

themselves branched. In an umbel, the flower stalks are of equal length and arise from the same 

point on the stem (Podlech, 1996). A head consists of many unstalked or short-stalked flowers 

growing close together at the end of a stem. The particularly densely clustered head of composites 

is known as a capitulum. 

The flower is a thickened shoot which carries the reproductive parts of the plant. Its individual 

parts can be interpreted as modified leaves. The perianth consists either of perianth segments, or of 

sepals and petals. More commonly, these are differentiated into an outer ring of usually green 

sepals (the calyx), and an inner ring of usually coloured petals (the corolla). The male part of the 

flower (androecium) consists of the stamens; the female part (gynoecium) consists of the ovary, style and 

stigma, together known as the pistil. Each stamen consists of a thin filament and an anther, the latter 

containing the pollen. In the center of the flower is the pistil (gynoecium). This consists of at 

least one carpel, often more, either free or fused. The pistil is divided into ovary, style and stigma. 

The fruit develops from the ovary, after pollination. It protects the seeds until they are ripe 

and often also has particular adaptations for seed dispersal. Dehiscent fruits open to release the 

seeds, while indehiscent do not (Podlech, 1996). 

3.2. Species-specific information 

3.2.1. The guardian angels: plant species used in contemporary clinical 

cancer treatment 

Camptotheca acuminata (Camptotheca) (Nyssaceae) 

Synonyms: It is well known as the Chinese happy tree – xi shu, or Cancer Tree. 

Antitumor 

Tumor inhibitor 

Location: Most provinces south of the Yangtze River. Origin: Asia, specially in Southern China 

and Tibet. Degree of rarity: low as it is commonly cultivated, mainly on roadsides. It is also cultivated 

for the production of camptothecins (CPTs). 

Appearance: 

Stem: trees, deciduous, to 20m high; the bark is light gray. 

Leaves: simple, alternate, exstipulate; blade oblong-ovate or oblong-elliptic. 

Flowers: calyx cup-shaped, shallowly 5-lobed; petals 5, light green. 

In bloom: May–July 

Tradition: It has been used in medications prepared for centuries, in China, to treat different 

kind of cancers, especially cancers of the stomach, liver and leukemia. 

Part used: Bark, wood and lately young leaves.

Terrestrial plant species with anticancer activity 37 

The status of mistletoe application in cancer therapy: During a screening program conducted by 

the National Cancer Institute in late 50s, it was confirmed that a compound from Camptotheca 

acuminata had anticancer properties (in 1958 by Dr Monroe E. Wall of the USDA and Jonathon 

Hartwell of the NCI). Later, in 1966, a quinoline alkaloid camptothecin (CPT) was isolated from 

bark (and wood), by Wall and other researchers of the Research Triangle Institute (‘Description 

and Natural History of Camptotheca’, Duke and Ayensu, 1985). Although animal studies confirmed 

anti-cancer properties, clinical trials were suspended because of high toxicity and severe 

side effects. Only in 1985 was interest renewed, when it was discovered that CPT inhibited 

topoisomerase I and therefore inhibited DNA replication; and CPT was developed as an anticancer 

drug. Because of the high toxicity of CPT itself, researchers developed several semisynthetic 

derivatives that had fewer side effects. After that CPTs became the second most important source 

of anti-cancer drugs. 

Three semi-synthetic drugs from CPT have been approved by the FDA: 

1 topotecan, as a treatment for advanced ovarian cancers (approved in May 1996). It is 

manufactured by Smith Kline Beecham Pharmeceuticals and sold under the trade name 

Hycamtin. 

2 injectable irinotecan HCl, as a treatment for metastatic cancer of the colon or rectum 

(approved in June 1996). It is usually prescribed in cases that have not responded to standard 

chemotherapy treatment. It is marketed by Pharmacia & Upjohn under the trade name 

Camptosar. It helps fight cancer but also has more tolerable side effects than the original 

plant extract. (Information for Patients from Pharmacia & Upjohn Company.) 

3 9-nitro camptothecin, as a treatment for pancreatic cancer. It is marketed as Rubitecan. 

There are more CPTs used in clinical trials for the treatment of breast cancer, colon cancers, 

malignant melanoma, small-cell lung cancer and leukemia, and also testing for antiviral (anti-HIV) 

uses. Although, many attempts for the chemical synthesis of CPT have been made with success, 

because of their high cost, natural supplies are still the main source of production (Cyperbotanica: 

Plants used in cancer treatment). Because of the production of CPTs, C. acuminata is a protected 

species and export of its seeds is prohibited. In US the cultivation of this tree has been successfully 

carried out, but the yields of CPT levels seem to be lower than that growing in China. 

Active ingredients: quinoline alkaloid camptothecin (CPT): topotecan, irinotecan HCl, 9-nitro 

camptothecin. 

Particular value: It is known and used in medicine as a chemotherapeutic drug. It is used against 

tumors of the esophagus, stomach, rectum, liver, urinary bladder and ovary, chronic granulocytic 

leukemia, acute lymphatic leukemia and lymphosarcoma. Also, against psoriasis (20 percent 

of ointment of the fruit is used for external application; injection of seed for intramuscular 

injection). (Ovarian Cancer Research Notebook: Fructus Camptothecae.) 

Precautions: It must be used carefully, as it is poisonous. The major potential side effects of 

camptothecin drugs are severe diarrhea, nausea and lowered leukocyte counts. It can also damage 

bone marrow. 

Indicative dosage and application (against ovarian cancer) 

● 

1.25mgm 2 /day 1 (topotecan as a 30min infusion for 5 days, every 3 weeks) (Goldwasser 

et al., 1999)


● 

Intravenous (i.v.) dose of 1.5mgm 2 was administered as a 30min continuous infusion on 

day 2. 

Further doses are under investigation for ovarian cancer, lung cancer and other types of cancer. 

Documented target cancers 

● 

● 

● 

Ovarian cancer 

Lung cancer 

Pancreatic cancer. 

Further details 

Related compounds 

● Topotecan has shown relative effectiveness when compared to taxol, in several clinical 

trials, although when combined with taxol, it may not have the desired dose intensity 

because of toxicity. Response rates between 13% and 25% are comparable to 

paclitaxel (Heron, 1998). 

● Topotecan has demonstrated value as a second-line therapy in recurrent / refractory 

ovarian cancer, although the hematologic toxicity of topotecan is significant. In a 

clinical trial decreased topotecan platelet toxicity with successive topotecan treatment 

cycles in advanced ovarian cancer patients:patients were treated with 

1.25 mg m 2 /day 1 topotecan as a 30min infusion for 5 days, every 3 weeks 

(Goldwasser, 1999). Mean platelet nadir values were significantly less after the second 

and subsequent treatment cycles, suggesting that current treatment schedules 

are feasible without G-CSF support and that treatment should be able to continue 

without dose reduction. Other clinical trials have shown that twenty-one-day infusion 

is a well-tolerated method of administering topotecan. The objective response 

rate of 35–38% in this small multicenter study is at the upper level for topotecan 

therapy in previously treated ovarian cancer. Prolonged topotecan administration 

therefore warrants further investigation in larger, randomized studies comparing this 

21-day schedule with the once-daily-for-5-days schedule. 

● CPT-11 (Irinotecan) is a drug similar in activity to topotecan. CPT-11 combined 

with platinum has demonstrated significant response in ovarian cancer trials. 

CPT-11 combined with mitomycin-c is active for clear cell ovarian cancer. CPT-11 are 

derivatives of camptothecin, derived from the bark of the Chinese tree C. accuminata. 

Both topotecan and CPT-11 are unique in their ability to inhibit topoismerase I (topoisomerases 

are responsible for the winding and unwinding of the supercoiled DNA 

composing the chromosomes. If the chromosomes cannot be unwound, transcription 

of the DNA message cannot occur and the protein cannot be synthesized.). Both of 

these drugs have shown significant activity in advanced malignancies (Ovarian 

Cancer Research Book: Camptothecin). DNA Topoisomerase I (Topo I) is the unique target 

for both topotecan and CPT-11. Topo I transiently breaks a single strand of DNA, 

thereby reducing the torsional strain (supercoiling) and unwinding the DNA 

ahead of the replication fork. Although eukaryotic cell lines lacking Topo I can survive


● 

in culture, the enzyme has an important role in chromatic organization, in mitosis, 

and in DNA replication, transcription and recombination. Topo I binds to the nucleic 

acid substrate (DNA) noncovalently. The bound enzyme then creates a transient 

break in one DNA strand and concomitantly binds covalently to the 3-phosphoryl end 

of the broken DNA strand. Topo I then allows the passage of the unbroken DNA 

strand through the break site and religates the cleaved DNA. The intermediate, covalently 

bound enzyme–DNA complex is called a “cleavable complex,” because protein-linked 

single DNA breaks can be detected when the reaction is aborted with a 

strong protein denaturant. The cleavable compound is in equilibrium with the noncovalently 

bound complex (the “noncleaveable complex”), which does not result in 

single-strand DNA breaks when exposed to denaturing conditions (Ovarian Cancer 

Research Book: Camptothecin). 

In recents clinical trials oral forms of topotecan have been tested. Results of the 

pharmacokinetic analyses showed that orally administered topotecan has a lower peak 

plasma concentration (C max ) and longer mean residence time than intravenously 

administered drug. Preliminary data suggest that the oral formulation has efficacy 

similar to that of the i.v. formulation in patients with recurrent or refractory ovarian 

and small-cell lung cancer. The type and degree of toxicity appeared to be related to 

the dosing schedule (number of days of consecutive treatment), but overall, oral 

topotecan appeared to be associated with less hematologic toxicity than the IV formulation 

(Burris 3rd, 1999). In another clinical trial from the Department of 

Medical Oncology, Rotterdam Cancer Institute, Netherlands by Schellens JH, and 

other researchers (1996), the results of preclinical and clinical studies indicate 

enhanced antineoplastic activity of topotecan (SKF 104864-A) when administered as 

a chronic treatment. We determined the apparent bioavailability and pharmacokinetics 

of topotecan administered orally to 12 patients with solid tumors in a two-part 

crossover study. The oral dose of 1.5mgm 2 was administered as a drinking solution 

of 200ml on day 1. The i.v. dose of 1.5mgm 2 was administered as a 30min continuous 

infusion on day 2. The bioavailability was calculated as the ratio of the oral 

to i.v. area under the curve (AUC) calculated up to the last measured time point. The 

oral drinking solution was well tolerated. The bioavailability revealed moderate 

inter-patient variation and was 30%7.7% (range 21–45%). The time to maximum 

plasma concentration after oral administration (T max ) was 0.78h (median, range 

0.33–2.5). Total i.v. plasma clearance of topotecan was 824154mlmin 1 (range 

535–1068mlmin 1 ). The AUC ratio of topotecan and the lactone ring-opened 

hydrolysis product (hydroxy acid) was of the same order after oral (0.34–1.13) and 

i.v. (0.47–0.98) administration. The bioavailability of topotecan after oral administration 

illustrates significant systemic exposure to the drug which may enable 

chronic oral treatment. 

Antineoplastic activity 

● 

A significant clinical trial is ongoing for Rubitens – Phase III – targeted at treating 

pancreatic cancer. The Phase II clinical data that has been presented on Rubitecan for 

pancreatic cancer has been nothing short of astounding. Rubitecan showed a 63%


● 

response or stable disease in pancreatic cancer patients. Median survival was 16.2 

months among responders, which is the longest survival rate ever reported among 

pancreatic cancer patients. Among stable patients, median survival was 9.7 months 

and among nonresponders, 5.9 months. Data shows that among 61 patients, 33% 

were responders, 30% were stable, and 37% were nonresponders following treatment 

with Rubitecan. 

Pancreatic cancer kills approximately 29,000 Americans annually, and is the fourth 

leading cause of cancer deaths. Duplicating the Phase II results in much larger Phase 

III trials. Currently, three separate Phase III trials (a total of 1,800 patients) for 

Rubitecan are going on. The largest of the three trials is the Rubitecan versus Gemzar 

comparison in patients who have not undergone chemotherapy. Rubitecan’s oncedaily 

oral formulation, which the patient takes his or her medication five days on followed 

by two days off, mild side effect profile, and antitumor activity could propel 

Rubitecan above the competition. Gemzar is a once-weekly, 30min i.v. administration 

that requires at least one trip per week to a medical facility (doctor’s office, 

hospital, clinic, etc.) (Tzavlakis, 2000). 

Antitumor activity: 

● 

● 

Antitumor effects of CPT-11 as a single drug was examined in 52 patients with prior 

chemotherapy including cisplatin-containing regimens who were enrolled in a Phase 

II study. These patients were randomly divided into two groups, and CPT-11 was 

administered once weekly at a dose of 100mgm 2 (Method A, 27 cases) or once 

biweekly at a dose of 150mgm 2 (Method B, 25 cases). Dose intensity was 72mg 

m 2 /week 1 in Method A and 61mgm 2 /week 1 in Method B. Method A was more 

effective than Method B, that is, response rates of Method A and B were 29.6% and 

16.0%, respectively. The duration with 50% response was 94 days, and the 50% survival 

time was 233 days. It was remarkable that cases of serous adenocarcinoma as 

well as those of mucinous carcinoma and clear-cell carcinoma which were considered 

to be less sensitive to cisplatin responded to CPT-11 (Sugiyama et al., 1997). At the 

end, it was considered that CPT-11 will be a useful drug for salvage chemotherapy 

for ovarian cancer. 

The cytotoxicity of CPT-11 on human ovarian epithelial malignancies was tested in 

vitro utilizing the ATP chemosensitivity assay. Flow cytometry was also performed on 

the fresh carcinoma specimens. 

Methods: Fresh tumor samples were obtained at laparotomy from 20 patients with 

primary adenocarcinoma of the ovary and 1 patient with heavily pretreated recurrent ovarian 

carcinoma. Tumors were plated in an in vitro system and treated with varying doses of 

both CPT-11 and its active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin), in 

addition to a panel of standard chemotherapeutic agents used in treating ovarian cancer. 

The results showed that it is a promising agent for further use in ovarian cancer (O’meara 

and Sevin, 1999) 

● 

Another study by Noriyuki Katsumata, and other researchers of the National Cancer 

Center Hospital, Tokyo, Japan, in 1999 was focused on the advantage of using CPT


11 against ovarian cancer. CPT-11 and CBDCA are active agents in the treatment of 

ovarian cancer. They conducted phase I trial of the CPT-11 and CBDCA in advanced 

ovarian cancer. The objective of the study was to determine the maximum tolerated 

dose (MTD) in escalating doses of CPT-11 and CBDCA. Eligible patients had ovarian 

cancer failing to first-line chemotherapy, adequate organ functions, and PS 0 and 

1, dose limiting toxicity (DLT) defined as grade 4 (G4) neutropenia or thrombocytopenia 

lasting 3 days or non-hematologic toxicity G3. CPT-11 and CBDCA 

were administered as i.v. infusion on d1, d8 and d15, respectively. CBDCA dosage 

was estimated by CBDCA clearance (CL)target AUC, and CL was calculated by 

Chatelut’s formula. The initial dose of CPT-11 was 50mgm 2 , and the dose was 

escalated to 50 and 60. Treatment was repeated at 28-day interval. Twelve patients 

were registered and evaluated for toxicity. Median age was 55 (range 40–63) and 

median number of previous treatment regimens were 2 (range 1–4). Symptoms of 

toxicity (G1–4) in 12 patients have been diarrhea (5/12, 42%) and nausea/vomiting 

(8/12, 67%). Grade 3/4 toxicities of diarrhea have not been observed. As of 12–98, 

MTD was not yet reached. No DLT or grade 3 non-hematologic toxicity was 

observed up to now. Further dose escalation is under evaluation. 

References 

Armstrong, D. and O’Reilly, S. (1998) Clinical guidelines for managing topotecan-related hematologic 

toxicity. Oncologist 3(1), 4–10. 

Berger, N.A. (2001) TOPO I Inhibitors in Breast, Ovary, and Lung Cancers. Project Number: 5 U01 

CA63200-03. Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106–4937. 

Bokkel, ten H.W., Carmichael, J., Armstrong, D. and Gordon, A. (1997) Malfetano J Efficacy and safety 

of topotecan in the treatment of advanced ovarian carcinoma. Semin Oncol. 24(1 Suppl 5), S5-19–25. 

Bookman, M.A. (1999) Extending the platinum-free interval in recurrent ovarian cancer: the role of 

topotecan in second-line chemotherapy. Oncologist 4(2), 87–94. 

Budavari, S. (ed.) (1989) The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals. Merck & Co., 

Rahway, NJ. 

Burris, H.A. 3rd (1999) The evolving role of oral topotecan. Semin. Hematol. 36(4 Suppl 8), 26–32. 

Chan, S., Carmichael, J., Ross, G., Wheatley, A.L. and Julian D., (1999) Sequential Hycamtin Following 

Paclitaxel and Carboplatin in Advanced Ovarian Cancer. American Society of Clinical Oncology Annual 

Meeting. Abstract: 1436. 

Creemers, G.J., Bolis, G., Gore, M., Scarfone, G., Lacave, A.J., Guastalla, J.P., Despax, R., Favalli, G., 

Kreinberg, R., Van Belle, S., Hudson, I., Verweij, J. and ten Bokkel Huinink, W.W. (1996) Topotecan, 

an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase 

II study. J. Clin. Oncol. 14, 3056–61. 

Dobelis, I.N. (ed.) (1989) Magic and Medicine of Plants. Reader’s Digest Books, Pleasantville, NY. 

Duke, J.A. and Ayensu, E.S. (1985) Medicinal Plants of China. Reference Publications, Inc., Algonac, MI. 

Duke, J.A. and Foster, S. (1990) A Field Guide to Medicinal Plants of Eastern and Central North America. 

Houghton Mifflin Co., New York, NY. 

Ferrari, S., Danova, M., Porta, C., Comolli, G., Brugnatelli, S., Pugliese, P. and Riccardi, A. (1999) Ascari 

E Circulating progenitor cell release and functional characterization after topotecan plus G-CSF and 

erythropoietin in small cell lung cancer patients. Int. J. Oncol. 15(4), 811–5.


Flora of North America Editorial Committee (1993) Flora of North America. Oxford University Press, 

Oxford, UK. 

Goldwasser, F., Buthaud, X., Gross, M., Bleuzen, P., Cvitkovic, E., Voinea, A., Jasmin, C., Romain, D. and 

Misset, J.L. (1999) Decreased topotecan platelet toxicity with successive topotecan treatment cycles in 

advanced ovarian cancer patients. Anticancer Drugs 10(3), 263–5. 

Goodman, L., Sanford, A., Goodman G.A. (eds) (1990) The Pharmacological Basis of Therapeutics, 8th 

edition. Pergamon Press, Elmsford, NY. 

Heron, J.F. (1998) Topotecan: an oncologist’s view. Oncologist 3(6), 390–402. 

Heywood, V.H. (ed.) (1993) Flowering Plants of the World. Oxford University Press, New York, NY. 

Hochster, H., Wadler, S., Runowicz, C., Liebes, L., Cohen, H., Wallach, R., Sorich, J., Taubes, B. and 

Speyer, J. (1999) Activity and pharmacodynamics of 21-Day topotecan infusion in patients with ovarian 

cancer previously treated with platinum-based chemotherapy. New York Gynecologic Oncology Group. 

J. Clin. Oncol., 17(8), 2553–61. 

Katsumata, N., Tsunematsu, R., Hida, K., Kasamatsu, T., Yamada, T., Tanemura, K. and Ohmi, K. (1999) 

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Society of Clinical Oncology Annual Meeting. Abstract: 1406 

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(2000) Chemosensitivity testing of irinotecan (CPT-11) in ovarian and endometrial carcinomas: a comparison 

with cisplatin. Anticancer Res 20(3A), 1353–8. 

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Therapy. American Society of Clinical Oncology Annual Meeting. Abstract: 1643. 

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Irinotecan (CPT-11) combined with cisplatin in patients with refractory or recurrent ovarian cancer. 

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Takeuchi, S. (1997) Is CPT-11 useful as a salvage chemotherapy for recurrent ovarian cancer (Meeting 

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N. Orleans, Louisiana, USA.


Catharanthus 

See in Vinca. 

Cephalotaxus 

See in Taxus under Further details. 

Podophyllum peltatum (Mandrake, American) 

Antitumor 

(Berberidaceae) 

Synonyms: Wild lemon, Ground lemon, May Apple, Racoonberry. 

Location: Of North America origin. Common in the eastern United States and Canada, North 

America, growing there profusely in wet meadows and in damp, open woods. 

Appearance (Figure 3.1) 

Stem: solitary, mostly unbranched, 0.3–0.5m high. 

Root: is composed of many thick tubers, fastened together by fleshy fibres, which spread greatly 

underground. 

Figure 3.1 Podophyllum peltatum.


Leaves: smooth, stalked, peltate in the middle like an umbrella, of the size of the hand, composed 

of 5–7 wedge-shaped divisions. 

Flowers: solitary, drooping white, about 2cm across, with nauseous odour. 

Fruit: size and shape of a common rosehip, being 3–6cm long. Yellow in colour, sweet in taste. 

In bloom: May. 

Tradition: North American Indians used it as an emetic and vermifuge. 

Biology: The rhizome develops underground for several years before a flowering stem emerges 

(only one shoot per root). The plant can be propagated either by runners or by seed. For cultivation, 

adequate fertilization is recommended. 

Part used: root, resin 

Active ingredients: podophyllotoxin (a neutral crystalline substance), podophylloresin (amorphous 

resin), diphyllin and aryltetralin (podophyllum lignan), etoposide (VP–16), teniposide (semisynthetic 

derivative of 4-demethylepipodophyllotoxin, naturally occurring compounds). 

Particular value: It was included in the British Pharmacopoeia in 1864. It is considered as one 

of the medicine with the most extensive service: it is used for all hepatic complaints, as antibilious, 

cathartic, hydragogue, purgative. 

Precautions: Leaves and roots are poisonous, podophyllotoxins are classical spindle poisons causing 

inhibition of mitosis by blocking mitrotubular assembly, and should be avoided during pregnancy. 

Indicative dosage and application 

● 

● 

Etoposide is used as etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, 

Princeton, NJ) and because it is water soluble can be made up to a concentration of 

20 mg ml 1 , however, it can be given as a 5min bolus, in high doses in small volumes, and 

as a continuous infusion. 

Penile warts in selected cases can be safely treated with 0.5–2.0% podophyllin self applied 

by the patient at a fraction of the cost of commercially available podophyllotoxin (White 

et al., 1997). 


● 

● 

● 

Antiproliferative effects on human peripheral blood mononuclear cells and inhibition of 

in vitro immunoglobulin synthesis. 

Etoposide appears to be one of the most active drugs for small cell lung cancer, testicular 

carcinoma (the Food and Drug Administration approved indication), ANLL and malignant 

lymphoma. Etoposide also has demonstrated activity in refractory pediatric neoplasms, 

hepatocellular, esophageal, gastric and prostatic carcinoma, ovarian cancer, chronic 

and acute leukemias and non-small-cell lung cancer, although additional single and 

combination drug studies are needed to substantiate these data (Schacter, 1996). 

Proresid (a mixture of natural extracts from Podophyllum sp.) has been used to a triple drug 

therapy with high doses of Endoxan and Methotrexate instead of the earlier long-term 

Endoxan treatment in addition of surgery (Vahrson et al., 1977).




● 

● 

Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum 

emodi and has long been known to possess medicinal properties. Etoposide (VP-16), a 

podophyllotoxin derivative, is currently in clinical use in the treatment of many cancers, 

particularly small-cell lung carcinoma and testicular cancer. This compound arrests cell 

growth by inhibiting DNA topoisomerase II, which causes double strand breaks in 

DNA. VP-16 does not inhibit tubulin polymerization, however, its parent compound, 

podophyllotoxin, which has no inhibitory activity against DNA topoisomerase II, is a 

potent inhibitor of microtubule assembly. In addition to these two mechanisms of 

action, an unknown third mechanism of action has also been proposed for some of the 

recent modifications of podophyllotoxins. Some of the congeners exhibited potent antitumor 

activity, of which etoposide and teniposide are in clinical use, NK 611 is in phase 

II clinical trials and many compounds are in the same line. Recent developments on 

podophyllotoxins have led structure–activity correlations which have assisted in the 

design and synthesis of new podophyllotoxin derivatives of potential antitumor activity. 

Modification of the A-ring gave compounds having significant activity but less than that 

of etoposide, whereas modification of the B-ring resulted in the loss of activity. One of 

the modifications in the D-ring produced GP-11 which is almost equipotent with 

etoposide. E-ring oxygenation did not affect the DNA cleavage which led to the postulation 

of the third mechanism of action. It has also been observed that free rotation of E- 

ring is necessary for the antitumor activity. The C4-substituted aglycones have a 

significant place in these recent developments. Epipodophyllotoxin conjugates with 

DNA cleaving agents such as distamycin increased the number of sites of cleavage. The 

substitution of a glycosidic moiety with arylamines produced enhanced activity. 

Modification in the sugar ring resulted in the development of the agent, NK 611 which 

is in clinical trial at present (Nudelman et al., 1997). 

Aryltetralin lignan is a constituent of the resins and roots/rhizomes of P. hexandrum 

and P. peltatum. A method confirms that P. hexandrum resins and roots/rhizomes contain 

approximately four times the quantity of lignans as do those of P. peltatum and 

also that there is a significant variation in the lignan content of P. hexandrum resins 

(But et al., 1997). 

Related species 

● 

Podophyllotoxin is also, one of the main Related compounds of the Bajiaolian root. 

Bajiaolian (Dysosma pleianthum), one species in the Mayapple family, has been widely 

used as a general remedy and for the treatment of snake bite, weakness, condyloma 

accuminata, lymphadenopathy and tumors in China for thousands of years. The herb 

was recommended by either traditional Chinese medical doctors or herbal pharmacies 

for postpartum recovery and treatment of a neck mass, hepatoma, lumbago and 

dysmenorrhea (Sarin et al., 1997).


● 

Podophyllum emodi: Indian Podophyllum, a native of Northern India. The roots are 

much stouter, more knotty, and twice as strong as the American. It contains twice as 

much podophyllotoxin. It is official in India and in close countries and it is used in 

place of ordinary Podophyllum (Grieve, 1994). 

Other medical activity 

● 

● 

A mixture of natural and semisynthetic (modified) glycosides from Podophyllum emodi 

has been used for many years in the treatment of rheumatoid arthritis, but its use is 

hampered by gastrointestinal side effects. Highly purified podophyllotoxin (CPH86) 

and a preparation containing two semisynthetic podophyllotoxin glycosides 

(CPH82) are currently being tested in clinical trials. In this study these drugs were 

shown to inhibit in vitro [3H]-thymidine uptake of human peripheral blood 

mononuclear cells stimulated by the mitogens concanavalin A, phytohemagglutinin 

and pokeweed mitogen. Complete inhibition was observed with CPH86 in concentrations 

20ng ml 1 and with CPH82 in concentrations 1gml 1 (Truedsson, 

et al., 1993). 

In conclusion, both CPH86 and CPH82 inhibit mitogen-induced lymphocyte 

proliferation and immunoglobulin synthesis and the results may be of help in 

determining optimal dose levels if related to treatment effects (Truedsson et al., 

1993). 

References 

Bhattacharya, P.K., Pappelis, A.J., Lee, S.C., BeMiller, J.N. and Karagiannis, C.S. (1996) Nuclear (DNA, 

RNA, histone and non-histone protein) and nucleolar changes during growth and senescence of may 

apple leaves. Mech. Ageing Dev. 92(2–3), 83–99. 

But, P.P., Cheng, L. and Kwok, I.M. (1997) Instant methods to spot-check poisonous podophyllum root 

in herb samples of clematis root. Vet. Hum. Toxicol. 39(6), 366. 

But, P.P., Tomlinson, B., Cheung, K.O., Yong, S.P., Szeto, M.L. and Lee, C.K. (1996) Adulterants of herbal 

products can cause poisoning. BMJ, 313(7049), 117. 

Damayanthi, Y. and Lown, J.W. (1998) Podophyllotoxins: current status and recent developments. Curr. 

Med. Chem. 5(3), 205–52. 

Dorsey, K.E., Gallagher, R.L., Davis, R. and Rodman, O.G. (1987) Histopathologic changes in condylomata 

acuminata after application of Podophyllum. J. Natl Med. Assoc. 79(12), 1285–8. 

Frasca, T., Brett, A.S. and Yoo, S.D. (1997) Mandrake toxicity. A case of mistaken identity. Arch. Intern. 

Med. 157(17), 2007–9. 

Goel, H.C., Prasad, J., Sharma, A. and Singh, B. (1998) Antitumour and radioprotective action of 

Podophyllum hexandrum. Indian J. Exp. Biol. 36(6), 583–7. 

Kadkade, P.G. (1981) Formation of podophyllotoxins by Podophyllum peltatum tissue cultures. 

Naturwissenschaften 68(9), 481–2. 

McDow, R.A. (1996) Cryosurgery and podophyllum in combination for condylomata. Am. Fam. Physician 

53(6), 1987–8. 

Mack, R.B. (1992) Living mortals run mad. Mandrake (podophyllum) poisoning. NC Med. J., 53(2), 98–9. 

Nudelman, A., Ruse, M., Gottlieb, H.E. and Fairchild, C. (1997) Studies in sugar chemistry. VII. 

Glucuronides of podophyllum derivatives. Arch. Pharm. (Weinheim), 30(9–10), 285–9.


Perkins, J.A., Inglis, A.F. Jr and Richardson, M.A. (1998) Latrogenic airway stenosis with recurrent 

respiratory papillomatosis. Arch. Otolaryngol. Head Neck Surg. 124(3), 281–7. 

Sarin, Y.K., Kadyan, R.S. and Simon, R. (1997) Condyloma accuminata. Indian Pediatr. 34(8), 741–2. 

Schacter, L. (1996) Etoposide phosphate: what, why, where, and how Semin. Oncol. 23(6 Suppl 13), 1–7. 

Takeya, T. and Tobinaga, S. (1997) Weitz’ aminium salt initiated electron transfer reactions and application 

to the synthesis of natural products. Yakugaku Zasshi. 117(6), 353–67. 

Truedsson, L., Geborek, P. and Sturfelt, G. (1993) Antiproliferative effects on human peripheral blood 

mononuclear cells and inhibition of in vitro immunoglobulin synthesis by Podophyllotoxin (CPH86) and 

by semisynthetic lignan glycosides (CPH82). Clin. Exp. Rheumatol. 11(2), 179–82. 

Vahrson, H., Wolf, A. and Jankowski, R. (1977) Combined therapy of ovarian cancer. Geburtshilfe 

Frauenheilkd 37(2), 131–8. 

White, D.J., Billingham, C., Chapman, S., Drake, S., Jayaweera, D., Jones, S., Opaneye, A. and Temple, C. 

(1997) Podophyllin 0.5% or 2.0% v podophyllotoxin 0.5% for the self treatment of penile warts: a double 

blind randomised study. Genitourin Med. 73(3), 184–7. 

Vinca rosea Linn. (Periwinkle) 

(Apocynaceae) 

Immunomodulator 

Cytotoxic 

Antitumor 

Madagascar periwinkle is a modern day success story in the search for naturally occurring anticancer 

drugs. 

Synonyms: Catharanthus roseus (G. Don), Lochnera rosea (Reichb.), Madagascar periwinkle, and 

rose periwinkle. 

Location: Of Madagascar, tropical Africa and generally Tropics origin. It can be found in East 

Indies, Madagascar and America. It has escaped cultivation and naturalized in most of the tropical 

world where it often becomes a rampant weed. Over the past hundreds of years, the periwinkle 

has been widely cultivated and can now be found growing wild in most warm regions of 

the world, including several areas of the southern United States. Madagascar periwinkle is 

grown commercially for its medicinal uses in Australia, Africa, India and southern Europe. 


Stem: small under-shrub up to 40–80cm high in its native habitat. the broken stem of 

Madagascar periwinkle exudes a milky latex sap. 

Leaves: retains its glossy leaves throughout the winter; are always placed in pairs on the stem. 

Flowers: springing from their axils, five-petaled flowers are typically rose pink, but among the 

many cultivars are those with pink, red, purple and white flowers. The flowers are tubular, with 

a slender corolla tube about an inch long that expands to about 25mm and a half across. They 

are borne singly throughout most of the summer. 

In bloom: Summer. 

Biology: It propagates itself by long, trailing and rooting stems, and by their means not only 

extends itself in every direction, but succeeds in obtaining an almost exclusive possession of the 

soil. Because of the dense mass of stems, the periwinkle deprives the weaker plants of light and air. 

Tradition: It was one of the plants believed to have power to exorcise evil spirits. Apuleius, in 

his Herbarium (printed 1480), writes: “this wort is of good advantage for many purposes, first 

against devil sinks and demoniacal possessions and against snakes and wild beasts and against 

poisons and for various wishes and for envy and for terror….” “The periwinkle is a great binder,” 

said an old herbalist, and both Dioscorides and Galen commended it against fluxes. It was


Figure 3.2 Vinca rosea. 

consider a good remedy for cramp. An ointment prepared from the bruised leaves with lard has 

been largely used in domestic medicine and is reputed to be both soothing and healing in all 

inflammatory ailments of the skin and an excellent remedy for bleeding piles. In India, juice from 

the leaves was used to treat wasp stings. In Hawaii, the plant was boiled to make a poultice to 

stop bleeding and throughout the Caribbean, an extract from the flowers was used to make a 

solution to treat eye irritation and infections. In France, it is considered an emblem of friendship. 

Parts used: leaves, stems, flower buds. 

Active ingredients 

● 

● 

Ajmalicine, vindoline, catharanthine. 

Vindoline is enzymatically coupled with catharanthine to produce the powerful cytotoxic 

dimeric alkaloids: vinblastine (VBL), vincristine (VCR) and leurosidine. 

Particular value: Cure for diabetes, anticancer drug. The plant has been used for centuries to 

treat diabetes, high blood pressure, asthma, constipation and menstrual problems. In the 1950s 

researchers learned of a tea that Jamaicans had been drinking to cure diabetes. A native who had 

been drinking the tea sent a small envelope full of leaves to researchers explaining that the leaves 

came from a plant known as the Madagascar periwinkle. The native explained that the tea was 

used in the absence of insulin treatment and apparently already had a worldwide reputation and 

was being sold as a remedy under the name Vinculin.


The status of vinca application in cancer therapy: The plant was used in traditional medicine. 

When tested in scientific studies it was demonstrated that it could be used in diabetes and 

anticancer research with great advantages. In the 1950s, a Dr Johnston who had been practicing 

in the Jamaica area, was quite convinced that his diabetic patients had received some benefit 

from drinking extracts of the periwinkle leaves. Therefore, it was decided among the researchers 

to send these leaves to a Dr Collip at the University of Western Ontario. The doctor had already 

been working with another group on insulin derived from a hormone, so it seemed logical to 

send the leaves of the periwinkle to him. Dr Collip decided to make a water extract to determine 

if, when given orally, they would lower blood sugar levels. These extracts were given to 

animals, but were not found to have any effect on the blood sugar or on the disease. One of 

Dr Collip’s colleagues, a Dr McAlpine decided to give the water extract to a few of his diabetic 

patients, who had volunteered to try it. There was no effect except in one mildly diabetic 

woman. In the absence of oral activity and as a final resort, Dr Collip decided to give the most 

concentrated dose to a few rats by intraperitoneal injection. The rats survived for about five days, 

but then died rather unexpectedly from diffuse multiple abscesses. This intrigued the doctor 

because the extracts that had been given had been sterilized. Dr Collip became very excited 

because another colleague of his had published that overdoses of cortisone in rats also led to their 

death from multiple abscesses. Dr Collip wondered if perhaps the periwinkle plant might be a 

source of cortisone. Unfortunately it was found that the two had very different mechanisms 

involved. In Cortisone, lymphocytes are destroyed resulting in its well-known immunosuppressive 

effect; in the case of the periwinkle extracts, it was found that after a single injection there 

was a rapid but transient depression of the WBC count, which was traced to the destruction of 

the bone marrow. In view of the dramatic effect on the bone marrow, it looked like there might 

be one or more compounds present in the periwinkle that might be useful in the treatment of 

cancers of the hematopoietic system such as lymphomas and leukemias. Therefore, it was 

decided to try and identify and isolate the component in the extracts responsible for the effects 

on the WBC counts and bone marrow. 

In 1954 Dr Charles T. Beer came to work in Dr Collip’s laboratory on a one-year fellowship. 

He looked at the problem of isolating active compounds from the periwinkle plant. When he 

started working on the project, the supply of periwinkle leaves was a problem. Dr Johnston in 

Jamaica was still convinced that the research was headed in the wrong direction. He felt like 

researchers should look for a cure for diabetes instead of a cure for cancer. So he decided to 

continue to supply Dr Beer with dried periwinkle leaves. Unfortunately it took so many leaves to 

make the extract that he decided to grow the periwinkle himself in Ontario. After working on 

the project for a year, Dr Beer finally isolated a small amount of unknown alkaloid. In rats, this 

alkaloid was highly active and there was a dramatic decrease in the WBC counts and a marked 

depletion of the bone marrow. He decided to name the alkaloid vincaleukoblastine (the name was 

shortened later to vinblastine). He found upon further observation of the plant that the periwinkle 

contained tons of useful alkaloids (70 in all at last count). Some of the alkaloids isolated contained 

properties that lowered blood sugar levels, others lowered blood pressure, some acted as 

hemostatics. Upon further investigation of VBL, Dr Beer also noted some activity but in smaller 

amounts. The related alkaloid was VCR, but was present in an amount insufficient for isolation 

in the laboratory. VCR was later isolated in crystalline form by chemists at the Eli Lilly Co. 

Later, there were isolated about 100 alkaloids, but there were not all suitable for clinical 

use. The most of the part of this investigation was done by the American pharmaceutical company: 

Eli Lilly and the responsible professor was: Dr Gordon H. Svoboda. The C. roseus bisindoles, 

VBL and VCR, were the first plant products to be approved by the FDA for cancer


treatment in the early of 1970, and are still currently used. The needs of production of final 

product for medical use are high, without satisfactory cover, because of the low concentration 

of vinblastine and vincristine in C. roseus, although it is cultivated in several tropical countries 

(Samuelsson, 1992). 

Precautions: Madagascar periwinkle is poisonous if ingested or smoked. It has caused poisoning 

in grazing animals. Even under a doctor’s supervision for cancer treatment, products from 

Madagascar periwinkle produce undesirable side effects. 

The principal DLT of VCR is peripheral neurotoxicity. In the beginning, only symmetrical 

sensory impairment and parasthesias may be encountered. However, neuritic pain and motor 

dysfunction may occur with continued treatment. Loss of deep tendon reflexes, foot and wrist 

drop, ataxia and paralysis may also be observed with continued use. These effects are almost 

always symmetrical and may persist for weeks to months after discontinuing the drug. These 

effects usually begin in adults who have received a cumulative dose of 5–6mg and the toxicity 

may occasionally be profound after a cumulative dose of 15–20mg. Children generally tolerate 

this toxicity better than adults do, and the elderly are particularly susceptible. Other toxicities 

involving VCR are gastrointestinal with symptoms such as constipation, abdominal cramps, 

diarrhea, etc. Cardiovascular symptoms include hypertension and hypotension and a few reports 

of massive myocardial infarction. The principle toxicity of VBL is myelosuppression or in particular 

neutropenia. Neurotoxicity occurs much less commonly with VBL than VCR and is generally 

observed in patients who have received protracted therapy. Hypertension is the most 

common cardiovascular toxicity of VBL. Sudden and massive myocardial infarctions and cerebrovascular 

events have also been associated with the use of single agent VBL and multiagent 

regimens. Pulmonary toxicities include acute pulmonary edema and acute bronchospasm. 

Pregnant women and people with neuromuscular disorders should steer clear of these drugs. 

With pregnant women, VCR and VBL have been found to cause severe birth defects. 


● VCR is routinely given to children as a bolus intravenous injection at doses of 2.0mgm 2 

weekly. 

● For adults, the conventional weekly dose is 1.4mgm 2 . 

● A restriction of the absolute single dose of VCR to 2.0mgm 2 has been adopted by many 

clinicians over the last several decades, mainly because of reports that show an increasing 

neurotoxicity at higher doses. 

● VBR has been given by several schedules. The most common schedule involves weekly 

bolus doses of 6mgm 2 incorporated into combination chemotherapy regimens such as 

ABVD (adriamycin, bleomycin, VBL, dacarbazine) and the MOPP–AVB hybrid regimen 

(nitrogen mustard, VCR, prednisone, procarbazine, adriamycin, bleomycin, VBL) 

(Canellos, 1992). 

Documented target cancers: extracts from Madagascar periwinkle have been shown to be effective 

in the treatment of various kinds of leukemia, skin cancer, lymph cancer, breast cancer and 

Hodgkin’s disease. 

VCR is used against childhood’s leukemia, Hodgkin’s disease and other lymphomas. VBL is 

mainly used for the treatment of Hodgkin’s disease, testicular cancer, breast cancer, Kaposi’s 

sarcoma and other lymphomas (Canellos, 1992; Samuelsson, 1992).




● 

● 

Vinca major (Apocynaceae family), with common names: large periwinkle, big 

periwinkle; it is a fast growing herbaceous perennial groundcover with evergreen 

foliage and pretty blue flowers. It is native to France and Italy, and eastward through 

the Balkans to northern Asia Minor and the western Caucasus. V. major and V. minor 

are the most commonly cultivated. Herbalists for curing diabetes have long used it, 

because it can prove an efficient substitute for insulin. It is used for in herbal practice 

for its astringent and tonic properties in menorrhagia and in hemorrhages 

generally. For obstructions of mucus in the intestines and lungs, diarrhea, 

congestions, hemorrhages, etc., periwinkle tea is a good remedy. In cases of scurvy 

and for relaxed sore throat and inflamed tonsils, it may also be used as a gargle. For 

bleeding piles, it may be applied externally. Apparently all the vincas are poisonous 

if ingested. Numerous alkaloids, some useful to man, have been isolated from big and 

common periwinkle (Grieve, 1994). 

Common periwinkle (V. minor) is similar but has smaller leaves (less than 5cm long) 

and smaller flowers (2.5cm or less across) than V. major, and is more cold hardy and 

more tolerant of shade. It is used for producing Catharanthus alkaloids. Also, a 

homoeopathic tincture is prepared from the fresh leaves of it and is given medicinally 

for the milk-crust of infants as well as for internal hemorrhages. Its flowers are gently 

purgative, but lose their effect on drying. If gathered in the spring and made into 

a syrup, they will impart thereto all their virtues and this is excellent as a gentle 

laxative for children and also for overcoming chronic constipation in grown-ups 

(Grieve, 1994). 


● 

● 

VBR and VCR are dimeric Catharanthus alkaloids isolated from Vinca plants. Both 

VBR and VCR are large, dimeric compounds with similar but complex structures. 

They are composed of an indole nucleus and a dihydroindole nucleus. They are both 

structurally identical with the exception of the substituent attached to the nitrogen 

of the vindoline nucleus where VCR possesses a formyl group and VBL has a methyl 

group. However, VCR and VBL differ dramatically in their antitumor spectrum and 

clinical toxicities. Both alkaloids are therapeutically proven to be effective in the 

treatment of various neoplastic diseases. Consequently, the determinations of these 

compounds in plant samples, as well as biological fluids, are of interest to many scientists. 

Many gas and high-performance liquid chromatographic (HPLC) and mass 

spectrometric methods have been developed for the determination of VCR and VBL 

in either plant samples or biological systems. The potential use of information-rich 

detectors such as mass spectrometry with capillary zone electrophoresis (CZE) has 

made this a more attractive separation method (Chu et al., 1996). 

VBL and VCR, which belong to the group of Vinca alkaloids, induce cytotoxicity by 

direct contact with tubulin, which is the basic protein subunit of microtubules.


● 

● 

Other biochemical effects that have been associated with VBL and VCR include: 

competition for transport of amino acids into cells; inhibition of purine biosynthesis; 

inhibition of RNA, DNA and protein synthesis; inhibition of glycolysis; inhibition 

of release of histamine by mast cells and enhanced release of epinephrine; and 

disruption in the integrity of the cell membrane and membrane functions. 

Microtubules are present in eukaryotic cells and are vital to the performance of 

many critical functions including maintenance of cell shape, mitosis, meiosis, secretion 

and intracellular transport. VBL and VCR exert their antimicrotubule effects 

by binding to a site on tubulin that is distinctly different from the binding sites of 

others. They have a binding constant of 5.610 5 M and initiate a sequence of 

events that lead to disruption of microtubules. The binding of VBL and VCR to 

tubulin, in turn, prevents the polymerization of these subunits into microtubules. 

The net effects of these processes include the blockage of the polymerization of 

tubulin into microtubules, which may eventually lead to the inhibition of vital cellular 

processes and cell death. Although most evidence suggests that mitotic arrest 

is the principal cytotoxic effect of the alkaloids, there is also evidence that suggests 

that the lethal effects of these agents may be attributed in part to effects on other 

phases of the cell cycle. The alkaloids also appear to be cytotoxic to nonproliferating 

cells in vitro and in vivo in both G1 and S cell cycle phases. In other words, VBL 

and VCR work by inhibiting mitosis in metaphase (Danieli, 1998; Garnier 

et al., 1996). 

Studies with germinating seedlings have suggested that alkaloid biosynthesis and 

accumulation are associated with seedling development. Studies with mature plants 

also reveal this type of developmental control. Furthermore, alkaloid biosynthesis in 

cell suspension cultures appears to be coordinated with cytodifferentiation. Vindoline 

biosynthesis in Catharanthus roseus also appears to be under this type of developmental 

control (Noble, 1990). Vindoline as well as the dimeric alkaloids are restricted to 

leaves and stems, whereas catharanthine is distributed equally throughout the aboveground 

and underground tissues. The developmental regulation of vindoline biosynthesis 

has been well documented in C. roseus seedlings, in which it is light inducible 

(Kutney et al., 1988). This is in contrast to catharanthine, which also accumulates in 

etiolated seedlings. Furthermore, cell cultures that accumulate catharanthine but not 

vindoline recover this ability upon redifferentiation of shoots. These observations 

suggest that the biosynthesis of catharanthine and vindoline is differentially regulated 

and that vindoline biosynthesis is under more rigid tissue–development and 

environment-specific control than is that of catharanthine. The early stages of alkaloid 

biosynthesis in C. roseus involve the formation of tryptamine from tryptophan 

and its condensation with secologanin to produce the central intermediate strictosidine, 

the common precursor for the monoterpenoid indole alkaloids. The enzymes catalyzing 

these two reactions are tryptophan decarboxylase (TDC) and strictosidine synthase 

(STR1), respectively. Strictosidine is the precursor for both the Iboga (catharanthine) 

and Aspidosperma (tabersonine and vindoline) types of alkaloids. The condensation of 

vindoline and catharanthine leads to the biosynthesis of the bisindole alkaloid vinblastine 

(St-Pierre et al., 1999). 

A successful attempt of production of Indole alkaloids by selected hairy root lines of 

C. roseus has been done. Approximately 150 hairy root clones from four varieties


were screened for their biosynthetic potential. Two key factors affecting productivity, 

growth rate and specific alkaloid yield. The detection of vindoline in these clones 

may potentially present a new source for the in vitro production of VBL. Production 

of vindoline and catharanthine by plant tissue culture and subsequent catalytic coupling 

in vitro is a possible alternative to using tissue culture alone to produce VBL 

and VCR. Recently, enzyme catalyzed techniques have been developed for the 

conversion of vindoline and catharanthine to bisindole alkaloids. Catharanthine is 

readily produced in cell suspension and hairy root cultures in amounts equal to or 

above that found in intact plant (Rajiv et al., 1993). 

References 

Bhadra, R., Vani, S., Jacqueline, V. and Shanks (1993) Production of indole alkaloids by selected hairy root 

lines of Catharanthus roseus. Biotech. Bioeng. 41, 581–92. 

Canellos, George P. (1992) Chemotherapy of Advanced Hodgkin’s Disease with MOPP, BVD, or MOPP 

alternating with ABVD. N Eng J. Med. 327, 1478–84. 

Chu, I., Bodnar, J.A., White, E.L. and Bowman, R.N. (1996) Quantification of vincristine and vinblastine 

in Catharanthus roseus plants by capillary zone electrophoresis. J. Chromat. A. 755, 281–8. 

Danieli, B. (1998) Vinblastine-type antitumor alkaloids: a method for creating new C17 modified analogues. 

J. Org. Chem., 63, 8586–8. 

Garnier, F., Label, Ph., Hallard, D., Chenieux, J.C., Rideau, M. and Hamdi, S. (1996) Transgenic 

periwinkle tissues overproducing cytokinins do not accumulate enhanced levels of indole alkaloids. 

Plant Cell, Tissue Organ Culture 45, 223–30. 

Gurr, Sarah J. (1996) The Hidden Power of Plants. The Garden 121, 262–4. 

Jageti, G.C., Krishnamurthy, H. and Jyothi, P. (1996) Evaluation of cytotoxic effects of different doses of 

vinblastine on mouse spermatogenesis by flow cytometry. Toxicology 112, 227–36. 

Jordan, M.A., Thrower, D. and Wilson, L. (1991) Mechanism of Inhibition of cell proliferation by Vinca 

alkaloids. Cancer Res. 51, 2212–22. 

Jordan, M.A., Thrower, D. and Wilson, L. (1992) Effects of vinblastine, podophyllotoxin and nocodzole on 

mitotic spindles. J. Cell Sci. 102, 401–16. 

Joyce, C. (1992) What past plants hunts produced. BioScience, 42, 402. 

Kallio, M., Sjoblom, T. and Lahdetie, J. (1995) Effects of vinblastine and colchicine on male rat meiosis 

in vivo: disturbances in spindle dynamics causing micronuclei and metaphase arrest. Environ Mol 

Mutagen. 25, 106–17. 

Kutney, J.P., Choi, L.S.L., Nakano, J., Tsukamoto, H., McHugh, M. and Boulet, A. (1988) A highly efficient 

and commercially important synthesis of the antitumor catharanthus alkaloids vinblastine and 

leurosidine from catharanthine and vindoline. Heterocycles, 27(8), 1845–53. 

Madoc-Jones, H. and Mauro, F. (1968) Interphase action of vinblastine and vincristine: differences in their 

lethal actions through the mitotic cycle of cultured mammalian cells. J. Cell Physiol 72, 185–96. 

Noble, R.L. (1990) The discovery of the vinca alkaloids – chemotherapeutic agents. Biochem Cell Biol., 68, 

1344–51. 

Pollner, F. (1990) Chemo edging up on four so-far intractable tumors: U.S. and European teams report the 

first clinical successes – some dramatic – from novel attacks. Medical World News 31, 13–16. 

Powell, J. (1991) Senior Seminar Presentation: Fall, BIOL 4900. 

Rowinsky, E.K. and Donehower, R.C. (1991) The clinical pharmacology and use of antimicrotuble agents 

in cancer therapeutics. Pharmacol. Therapeutics 52, 35–84.


Samuelsson, G. (1992) Drugs of Natural Origin – A textbook of Pharmacognosy. Third revised, enlarged and 

translated edition. Swedish Pharmaceutical Press. 

St-Pierre, B., Vazquez-Flota, F.A. and De Luca, V. (1999) Multicellular compartmentation of Catharanthus 

roseus alkaloid biosynthesis predicts intercellular translocation of a pathway intermediate. Plant Cell 11, 

887–900. 

Viscum album (Mistletoe) 


(Loranthaceae) 

Cytotoxic 

Location: Throughout Europe, Asia, N. Africa. It can be easily found, though not in abundant 

numbers. 

Appearance 

Stem: yellowish-green, branched, forming bushes 0.6–2m in diameter. 

Root: Nonexistent. The plant is a semiparasitic evergreen shrub growing on branches of various 

tree hosts, mostly apple, poplar, ash, hawthorn and lime, more rarely on oak and pear. 

Leaves: opposite, tongue-shaped, yellowish-green. 

Flowers: small, inconspicuous, clustered in groups of three. 

Fruit: globular, pea-sized white berry, ripening in December. 

In bloom: March–May. 

Biology: Mistletoe is propagated exclusively by seed, which is carried distantly with the aid of 

birds (mostly the thrush). According to host specifity three different races can be distinguished. 

The plant is dioecious with very reduced male and female flowers. The life cycle of V. album is 

described starting from seed germination to the development of the leaves. The parasitism 

affords special adaptation to mineral nutrition. 

Tradition: Following their visions, the Druids used to cut mistletoe from trees with a golden 

knife at the beginning of the year. They held that the plant protected its possessor from all evil. 

According to a Scandinavian legend, Balder, the god of Peace, was slain with an arrow made of 

mistletoe. Later, however, mistletoe was rendered an emblem of love rather than hate. Its poisonous 

nature has been further exploited for the construction of knifes as a defensive weapon. 

Parts used: Leaves and young twigs. 

Active ingredients: viscotoxin, mistletoe alkaloids and three lectins (lactose-specific lectin, 

galactose-specific lectin, N-acetylgalactosamine-specific lectin). 

Particular value: Mistletoe preparations are well-tolerated with no significant toxicities observed 

so far. 

The status of mistletoe application in cancer therapy: Mistletoe was introduced in the treatment 

of cancer in 1917. Rudolf Steiner (1861–1925), founder of the Society for Cancer Research, in 

Arlesheim (Switzerland) was the first to mention the immunoenhancing properties of mistletoe, 

suggesting its use as an adjutant therapy in cancer treatment. 

Therapy of cancer with a Viscum extract has been carried out in Europe for over six decades in 

thousands of patients. Extracts from the plant are used mainly as injections. 

Currently, there is a number of mistletoe preparations used in many countries against 

different kinds of cancer: 

● 

Iscador and Helixor are licensed medications made from plants growing on different host trees, 

like oak, apple, pine and fir, and administered in different kinds of cancer therapy. Some


● 

● 

Iscador preparations also include metal, for example silver, mercury and copper. Iscador is usually 

given by injection. However, it can also be taken orally. The injection treatment typically 

lasts 14 days with one injection each day. It has been approved for use in Austria, Switzerland 

and West Germany; it apparently is also being used in France, Holland, Eastern Europe, 

Britain and Scandinavia. Proponents of the treatment claim that in 1978 almost 2,000,000 

ampules were sold in countries where Iscador is prescribed and that about 30,000 patients are 

treated with it each year. Iscador is manufactured by the Verein fuer Krebsforschung (Cancer 

Research Association), a nonprofit organization in Arlesheim, Switzerland. 

Iscusin-Viscum preparations contain mistletoe from eight different host-trees and are produced 

according to a particular “rhythmic” procedure and additionally “potentialized.” 

Sterilization is achieved by the addition of oligodynamic silver. The indications given are: 

precancerous conditions, postoperative tumor prevention, operable tumors, and inoperable 

tumors. Each of the eight preparations (according to host-tree) has its own list of indications. 

Iscucin is supposed to be injected close to the tumor between 5 and 7 p.m.; the 

dosage and the frequency depend on body temperature. However, no preclinical studies 

have been published on iscucin. In the clinical field, only individual case histories are available, 

four of which have minimal documentation, and results that can be explained without 

iscucin. Iscucin is produced and distributed by Wala-Heilmittel GmbH, Eckwalden. 

Isorel is an aqueous extract from whole shoots of mistletoe, the subspecies fir (Isorel A), 

apple (Isorel M) and pine (Isorel P) in each case. The preparation is injected hypodermically. 

It is usually applied for the medicative treatment of malignant tumors, postoperative and 

recidivation and prophylaxis of metastases, malignant illness of the hemopoietic system and 

defined precancerous stages. Isorel A is used principally for the treatment of male patients, 

while Isorel M is the respective preparation for female patients. Isorel is produced and 

distributed by Novipharm, Austria. 

However, mistletoe preparations are not approved by the US Food and Drug Administration. 

Precautions: It is generally recommended that treatment be stopped during menstrual period 

and pregnancy. According to a report of the Swiss Cancer League, fermented Iscador products 

contain large numbers of both dead and live bacteria and some yeast. 

Home-made mistletoe preparations can be very poisonous. Reported minor side-effects (for 

Isorel) include a small increase in temperature of 1–1.5C which disappear after 1–2 days. 

For Helixor, if the dosage is increased too rapidly, temperature rises of 1–1.5C and headache may 

occur. Several clinical studies of the fermented form of Iscador have noted that patients experience 

moderate fever (a rise of 2.3–2.4C) on the day of the injections. Local reactions around the 

injection site, temporary headaches and chills are also associated with the fever. It is recommended 

to wait for the normalization of the temperature before a new injection is administered. 

In the case of hyperthyroidism, it is recommended to start with low doses and increase gradually. 

Indicative dosage and application: 

● 

● 

In all 11 melanoma cell lines tested: lectins isolated from V. album showed an antiproliferative 

effect at concentrations of 1–10ngml 1 , viscotoxin’s antiproliferative effect rises at 

concentrations of 0.5–1gml 1 and alkaloids’ antiproliferative effect begin at 10gml 1 

(Yoon et al., 1998). 

Lectins ML I, ML II and ML III, at concentrations from 0.02 to 20pgml 1 , were able to 

enhance the secretion of the cytokines tumor necrosis factor (TNF) , interleukin (IL)-1 , 

IL-1 and IL-6 by human monocytes (Ziska, 1978).


Documented target cancers: 

● 

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Viscumin, a galactoside-binding lectin, is a powerful inflammatory mediator able to 

stimulate the immune system (Heiny and Benth, 1994). 

A purified lectin (MLI) from V. album has immunomodulating effects in activating 

monocytes/macrophages for inflammatory responses (Metzner et al., 1987). 

Viscum album L. extracts have been shown to provide a DNA stabilizing effect 

(Woynarowski et al., 1980). 

Since Iscador stimulates the production of the natural killer cells, it can be applied in order to 

stabilize the number of T4 cells and thus the clinical condition of HIV positive persons. 

Laboratory tests suggested that the progress of the HIV infection was inhibited (Rentea et al., 

1981; Schink et al., 1992). 

Iscador has an increased action against breast cancer cells and colon cancer cells 

(Heiny et al., 1994). 

In most patients (but healthy individuals, as well) the quality of life increased remarkably. 

Water-soluble polysaccharides of V. album exert a radioprotective effect, which could be a 

valuable complement to radiotherapy of cancer. 

Iscador therapy proved to be clinically and immunologically effective and well tolerated in 

immuno-compromised children with recurrent upper respiratory infections, due to the 

Chernobyl accident (Lukyanova et al., 1992). 

When whole mistletoe preparations are employed, the effect is host tree-specific. 



● 

● 

The Chinese herb V. alniformosanae is the source of a conditioned medium (CM), 

designated as 572-CMF-, which is capable of stimulating mononuclear cells. This 

CM has the capacity to induce the promyelocytic cell line HL-60 to differentiate into 

morphologically and functionally mature monocytoid cells. Investigations have 

shown that 572-CM did not contain IFN-r, TNF, IL-1 and IL-2 (Chen et al., 1992). 

Hexanoic acid extracts of Viscum cruciatum Sieber parasitic on Crataegus monogyna 

Jacq. (I), C. monogyna Jacq. parasitized with V. cruciatum Sieber (II), and C. monogyna 

Jacq. Non-parasitized (III), and of a triterpenes enriched fractions isolated from I, II 

and III (CFI, CFII, CFIII, respectively) demonstrated significant cytotoxic activity 

against cultured larynx cancer cells (HEp-2 cells) (Gomez et al., 1997). 


● 

A galactose-specific lectin from Viscum album (VAA) was found to induce the 

aggregation of human platelets in a dose- and sugar-dependent manner. Small


● 

● 

● 

● 

● 

● 

● 

non-aggregating concentrations of VAA primed the response of platelets to 

known aggregants (ADP, arachidonic acid, thrombin, ristocetin and A23187). 

VAA-induced platelet aggregation was completely reversible by the addition of 

the sugar inhibitor lactose and the platelets from disrupted aggregates maintained 

the response to other aggregants. The lectin-induced aggregation of washed 

platelets was more resistant to metabolic inhibitors than thrombin- or arachidonic 

acid-dependent cell interaction (Büssing and Schietzel, 1999). 

Partially and highly purified lectins from V. album cause a dose-dependent decrease 

of viability of human leukemia cell cultures, MOLT-4, after 72h treatment. 

The LC50 of the partially purified lectin was 27.8ngml 1 , of the highly purified 

lectin 1.3ngml 1 . Compared to the highly purified lectin a 140-fold higher protein 

concentration of an aqueous mistletoe drug was required to obtain similar cytotoxic 

effects on MOLT-4 cells. The cytotoxicity of the highly purified lectin was preferentially 

inhibited by D-galactose and lactose, cytotoxicity of the mistletoe drug and 

the partially purified lectin were preferentially inhibited by lactose and 

N-acetyl-D-galactosamine (GalNAc) (Olsnes et al., 1982). 

Two lectin fractions with almost the same cytotoxic activity on MOLT-4 cells but 

with different carbohydrate affinities were isolated by affinity chromatography from 

the mistletoe drug: mistletoe lectin I with an affinity to D-galactose and GalNAc and 

mistletoe lectin II with an affinity to GalNAc. The lectin fractions and the mistletoe 

drug inhibited protein synthesis of MOLT-4 cells stronger than DNA synthesis 

(Olsnes et al., 1982). 

Application of an aqueous extract from Viscum album coloratum, a Korean mistletoe 

significantly inhibited lung metastasis of tumor metastasis produced by highly 

metastatic murine tumor cells, B16-BL6 melanoma, colon 26-M3.1 carcinoma and 

L5178Y-ML25 lymphoma cells in mice. The antimetastatic effect resulted from the 

suppression of tumor growth and the inhibition of tumor-induced angiogenesis by 

inducing TNF-alpha (Yoon et al., 1998). 

A peptide isolated from the V. album extract (Iscador) stimulated macrophages in vitro 

and in vivo and activated macrophages were found to have cytotoxic activity towards 

L-929 fibroblasts (Swiss Society for Oncology, 2001). 

Iscador Pini, an extract derived from V. album L. grown on pines and containing a 

non-lectin associated antigen, strongly induced proliferation of peripheral blood 

mononuclear cells (Cammarata and Cajelli, 1967). 

Polysaccharides are possibly involved in the pharmacological effects of V. album 

extracts, which are used in cancer therapy. The main polysaccharide of the green parts 

of Viscum is a highly esterified galacturonan whereas in Viscum ‘berries’ a complex 

arabinogalactan is predominant and interacting with the galactose-specific lectin 

(ML I) (Stein, 1999). 

Water-soluble polysaccharides of V. album were shown to exert a radioprotective effect 

which was a function of both the radiation dose and the drug dose and time of its 

injection. The maximum radioprotective efficacy of polysaccharides was observed 

after their injection 15min before irradiation (Stein, 1999).


Antitumor activity 

● 

● 

● 

● 

● 

● 

The Korean mistletoe extract possesses antitumor activity in vivo and in vitro. 

Antiproliferative activities have been attributed to Viscum album C, Viscum album Qu 

and Viscum album M (trade name Iscador) on melanoma cell lines. Viscum album C contains 

viscotoxin, alkaloids and lectins. Viscum album Qu was extracted by Medac 

(Germany). Viscum album M is a preparation by the Institute Hiscia (Switzerland). 

The antiproliferative effect of the extracts on 11 melanoma cell lines obtained 

through the EORTC-MCG were tested in monolayer proliferation tests. In most of 

the melanoma cell lines tested, there was a significant antiproliferative effect of 

V. album C at a concentration of 100gml 1 , whereas V. album M showed an antiproliferative 

effect at 1,000gml 1 . The lectins isolated from V. album C, when compared 

with each other showed almost in all 11 melanoma cell lines tested a similar 

antiproliferative effect. It was seen at concentrations of 1–10 ng ml 1 . The 

antiproliferative effect of viscotoxin rises at concentrations of 0.5–1gml 1 , whereas 

the antiproliferative effect of alkaloids begins at 10gml 1 (Yoon et al., 1998). 

Iscador inhibited 20-methylcholanthrene-induced carcinogenesis in mice. 

Intraperitoneal administration of Iscador (1mgdose 1 ) twice weekly for 15 weeks 

could completely inhibit 20-methylcholanthrene-induced sarcoma in mice and protect 

these animals from tumour-induced death. Iscador was found to be effective even 

at lowered doses. After administration of 0.166, 0.0166 and 0.00166mgdose 1 , 67, 

50 and 17% of animals, respectively, did not develop sarcoma (Kuttan et al., 1997). 

Patients with advanced breast cancer who were treated parenterally with Iscador 

showed an improvement in repair, possibly due to a stimulation of repair enzymes by 

lymphokines or cytokines secreted by activated leukocytes or an alteration in the 

susceptibility to exogenic agents resulting in less damage (Kovacs et al., 1991). 

Macrophages from mice treated with V. album extract were shown to be active in 

inhibiting the proliferation of tumor cells in culture. These activated macrophages 

have now been shown to protect mice from dying of progressive tumors when 

injected intraperitoneally into the animals. Prophylactic as well as multiple treatments 

with macrophages activated with V. album extract seemed more effective than 

a single treatment. Thus, in addition to a direct cytotoxic effect of V. album extract, 

the activation of macrophages may contribute to the overall antitumor activity of the 

drug (Kuttan, 1993). 

Iscador was found to be cytotoxic to animal tumor cells such as Dalton’s lymphoma 

ascites cells (DLA cells) and Ehrlich ascites cells in vitro and inhibited the growth of 

lung fibroblasts (LB cells), Chinese hamster ovary cells (CHO cells) and human 

nasopharyngeal carcinoma cells (KB cells) at very low concentrations. Moreover, 

administration of Iscador was found to reduce ascites tumors and solid tumors 

produced by DLA cells and Ehrlich ascites cells. The effect of the drug could be seen 

when the drug was given either simultaneously, after tumor development or when 

given prophylactically, indicating a mechanism of action very different from other 

chemotherapeutic drugs. Iscador was not found to be cytotoxic to lymphocytes 

(Luther et al., 1977). 

The ML-I lectin from V. album has been shown to increase the number and cytotoxic 

activity of natural killer cells and to induce antitumor activity in animal models. The


● 

same lectin inhibits cell growth and induces apoptosis (programmed cell death) in 

several cell types (Janssen et al., 1993). 

In mice, an increased number of plaque-forming cells to sheep red blood cells (SRBC) 

followed the injection of Isorel (Novipharm, Austria) together with SRBC. Further, 

survival time of a foreign skin graft was shortened if Isorel was applied at the correct 

time. Finally, suppressed immune reactivity in tumorous mice recovered following 

Isorel injection. Isorel was further shown to be cytotoxic to tumor cells in vitro. Its 

application to tumor-bearing mice could prolong their life but without any therapeutic 

effect. However, a combination of local irradiation and Isorel was very effective: following 

43Gy of local irradiation to a transplanted methylcholanthrene-induced 

fibrosarcoma (volume about 240mm 3 ) growing in syngeneic CBA/HZgr mice, the 

tumor disappeared in about 25% of the animals; the addition of Isorel increased the 

incidence of cured animals to over 65%. The combined action of Isorel, influencing 

tumor viability on the one hand and the host’s immune reactivity on the other, seems 

to be favorable for its antitumor action in vivo (Pouckova et al., 1986). 

Anti-leukemic activity 

● 

● 

Mistletoe lectin I from V. album applied in vitro for 1h in appropriate doses, caused 

irreversible inhibition of leukemic L1210 cell proliferation. The toxin appeared to be 

cytotoxic to normal bone marrow progenitor cells, as well as observed to the P-388 

and L1210 leukemia cells. 

Iscador was found to reduce the leukocytopenia produced by radiation and cyclophosphamide 

treatment in animals. Weight loss due to radiation was considerable 

whereas weight loss due to cyclophosphamide was not altered. Hemoglobin levels 

also were not affected, indicating that treatment with the extract reduces lymphocytopenia 

and hence could be used along with chemotherapy and radiation therapy 

(Kutten et al., 1993). 

Other medical effects 

● 

● 

The 5-bromo-2-deoxyuridine-induced sister chromatid exchange (SCE) frequency of 

amniotic fluid cells (AFC) remained stable after the addition of a therapeutical concentration 

of V. album (Iscador P) but decreased significantly after administration of 

high drug doses. As the proliferation index remained stable, even at extremely high 

drug concentrations, this effect could not be ascribed to a reduction of proliferation. 

No indications of cytogenetic damage or effects of mutagenicity were seen after the 

addition of the preparation. In addition, increasing concentrations of V. album 

L. extracts were shown to significantly reduce SCE frequency of phytohemagglutinin 

(PHA)-stimulated peripheral blood mononuclear cells (PBMC) of healthy individuals 

(Bussing et al., 1995). 

The three mistletoe lectins. ML I, ML II and ML III, at concentrations from 

0.02 to 20pgml 1 (100–10,000-fold lower than those showing toxic effects) were 

able to enhance the secretion of the cytokines tumor necrosis factor (TNF) alpha, 

interleukin (IL)-1 alpha, IL-1 beta and IL-6 by human monocytes several-fold over


● 

● 

control values were observed. The immunoactivating concentrations by the three 

lectins were found different for each donor. At toxic concentrations, the amounts of 

IL-1 alpha, IL-1 beta and to a less extent of TNF alpha in monocytes supernatants 

were particularly high (Ziska, 1998). 

The mistletoe lectin ML-A inactivates rat liver ribosomes by cleaving a N-glycosidic 

bond at A-4324 of 28S rRNA in the ribosomes, as it is characteristic of the common 

ribosome-inactivating proteins (RIPs) (Citores et al., 1993). 

During a phase I/II study to determine the effect of V. album (Iscador) in HIV infection, 

40 HIV-positive patients (with CD4-lymphocyte count200) were injected with 

0.01 mg up to 10mg subcutaneously twice a week over a period of 18 weeks. The 

extract was well tolerated and suggested to have anti-HIV activities (Gorter, 1994). 

References 

Barney, C.W., Hawksworth, F.G. and Geils, B.W. (1998) Hosts of Viscum album. Eur. J. For. Path. 28, 187–208. 

Büssing, A. (2000) Mistletoe: The genus Viscum. Harwood Academic Publishers. 

Büssing, A., Schaller, G. and Pfuller, U. (1998) Generation of reactive oxygen intermediates (ROI) by the 

thionins from Viscum album L. Anticancer Res. 18, 4291–6. 

Büssing, A. and Schietzel, M. (1999) Apoptosis-inducing properties of Viscum album L. Extracts from 

different host trees, correlate with their content of toxic Mistletoe lectins. Anticancer Res. 19, 23–8. 

CA (Anonymous) (1983) Unproven methods of cancer management: Iscador. CA: a Cancer J. Clinicians, 33, 

186–8. 

Cammarata, P.L. and Cajelli, E. (1967) Free amino acid content of Viscum album L. berries parasitizing the 

Pinus silvestris L. and Pinus nigra Arnold var. austriaca. Boll. Chim. Farm. Aug. 106(8), 521–6. 

Chen, P.M., Hsiao, K.I., Su, J.L., Liu, J. and Yang, L.L. (1992) Study of the activities of Chinese 

herb Viscum alniformosanae Part II: The components of conditioned medium produced by Viscum 

alniformosanae-stimulated mononuclear cells. Am. J. Chin. Med. 20(3–4), 307–12. 

Fink, J.M. (1988) Third Opinion: An International Directory to Alternative Therapy Centers for the Treatment and 

Prevention of Cancer and Other Degenerative Diseases. Second edn. Garden City Park, New York: Avery 

Publishing Group Inc., p.137. 

Franz, H. (1986) Mistletoe lectins and their A and B chains. Oncology 43(1), 23–34. 

Grieve, M. (1994) A Modern herbal. Edited and introduced by Mrs. C.F. Leyel, Tiger books international, 

London. 

Gomez, M.A, Saenz, M.T., Garcia, M.D., Ahumada, M.C. and De La Puerta, R. (1997) Cytostatic activity 

against Hep-2 cells of methanol extracts from Viscum cruciatum Sieber parasitic on Crataegus monogyna 

Jacq. and two isolated principles. Phytother. Res. 11, 240–2. 

Gorter, R. (1994) The European Mistletoe (Viscum album): new studies show significant results for AIDS 

and immune system problems. Institute for Oncological and Immunological Research. 

Hauser, S. and Kast, A. (2001) Iscusin – preparations for pre- and postoperative treatment of malignant 

tumours. (BCCA Cancer Information Centre search file 701). 

Hauser, S.P. (1993) Unproven methods in cancer treatment. Curr. Opinion Oncol. 5, 646–54. 

Heiny, B.M. and Benth, J. (1994) Mistletoe extract standardized for the galactoside-specific lectin (ML-1) 

induces B-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res. 14, 1339–42. 

Janssen, O., Scheffler, A., Kabelitz, D. (1993) In vitro effects of mistletoe extracts and mistletoe lectins. 

Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). 

Arzneimittelforschung 43(11), 1221–7. 

Kovacs, E., Hajto, T. and Hostanska, K. (1991) Improvement of DNA repair in lymphocytes of breast cancer 

patients treated with Viscum album extract (Iscador). Eur. J. Cancer 27(12), 1672–6. 

Kuttan, G., Menon, L.G., Antony, S. and Kuttan, R. (1997) Anticarcinogenic and antimetastatic activity 

of Iscador. Anticancer Drugs Apr. 8(Suppl 1), S15–16.


Lukyanova, M., Chernyshov, P., Omelchenko, I., Slukvin, I., Pochinok, V., Antipkin, G., Voichenko, V., 

Heusser, P. and Schneiderman, G. (1992) Research on immune-suppressed children following the 

Chernobyl accident. Mistletoe effective for Chernobyl children. Ukrainian Institute for Pediatrics, Lukas 

Klinik, Switzerland. 

Luther, P., Franz, H., Haustein, B. and Bergmann, K.C. (1977) Isolation and characterization of mistletoe 

extracts (Viscum album L.). II. Effect of agglutinating and cytotoxic fractions on mouse ascites tumor 

cells. Acta Biol Med Ger 36(1), 119–25. 

Metzner, G., Franz, H., Kindt, A., Schumann, I. and Fahlbusch, B. (1987) Effects of lectin I from 

mistletoe (ML I) and its isolated A and B chains on human mononuclear cells: mitogenic activity and 

lymphokine release. Pharmazie May 42(5), 337–40. 

Mueller, A.E. and Anderer, A.F. (1990) A Viscum album oligosaccharide activating human natural cytotoxicity 

is an interferon inducer. Cancer Immunol Immunother. 32, 221–7. 

Olsnes, S., Stirpe, F., Sandvig, K. and Pihl, A. (1982) Isolation and characterization of viscumin, a toxic 

lectin from Viscum album L. (Mistletoe). J. Biol. Chem. 257(22), 13263–70. 

Ontario Breast Cancer Information Exchange Project (1994) Guide to unconventional cancer therapies. 

First edn. Ontario Breast Cancer Information Exchange Project, Toronto. 76–79. 

Rentea, R., Lyon, E. and Hunter, R. (1981) Biologic properties of iscador: a Viscum album preparation I. 

Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following 

X-irradiation. Lab. Invest. Jan. 44(1), 43–8. 

Samuelsson, G. (1992) Drugs of Natural Origin – A Textbook of Pharmacognosy. Third revised, enlarged 

and translated edition. Swedish Pharmaceutical Press. 

Schink, M., Moser, D. and Mechelke, F. (1992) Two-dimensional isolectin patterns of the lectins from 

Viscum album L. (mistletoe). Naturwissenschaften Feb. 79(2), 80–1. 

Stein, M.G., Edlund, U., Pfuller, U., Bussing, A. and Schietzel, M. (1999) Influence of polysaccharides from 

Viscum album L. on human lymphocytes, monocytes and granulocytes in vitro. Anticancer Res. 19, 3907–14. 

Sweeney, E.C., Tonevitsky, A.G., Palmer, R.A., Niwa, H., Pfueller, U., Eck, J., Lentzen, H., Agapov, I.I. and 

Kirpichnikov, M.P. (1998) Mistletoe lectin I forms a double trefoil structure. FEBS Lett. 431(3), 367–70. 

Swiss Society for Oncology. Iscador. (2001) (BCCA Cancer Information Centre search file 701). 

Swiss Society for Oncology, Swiss Cancer League, Study Group on Unproven Methods in Oncology. 

Helixor-mistletoe preparations for treatment of cancer. Document UICC UMS010. (BCCA Cancer 

Information Centre search file 701). 

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U.S. Government Printing Office 1990 Sept. pp. 81–86. 

Werner, M., Zanker, K.S. and Nikolai, G. (1998) Stimulation of T-cell locomotion in an in vitro assay by 

various Viscum album L. preparations (Iscador). Int. J. Immunotherapy XIV(3), 135–42. 

Wagner, H., Jordan, E. and Feil, B. (1986) Studies on the standardization of mistletoe preparations. 

Oncology 43(1), 16–22. 

Wilson, B.R. (1985). Cancer Quackery Primer. Dallas, Oregon. 

Yoon, T.J., Yoo, Y.C., Kang, T.B., Baek, Y.J., Huh, C.S., Song, S.K., Lee, K.H., Azuma, I. and Kim, J.B. 

(1998) Prophylactic effect of Korean mistletoe (Viscum album coloratum) extract on tumor metastasis is 

mediated by enhancement of NK cell activity. Int. J. Immunopharmacol 20(4–5), 163–72. 

Ziska, P., Franz, H. and Kindt, A. (1978) The lectin from viscum album L. purification by biospecific 

affinity chromatography. Experientia, 34(1), 123–4. 

Useful addresses 

Verein fuer Krebsforschung, 01141617012323. 

Prof. Dr Robert Gorter, 

Institute for Oncological and Immunological Research, 

011493039763420 (Fax: 3422). 

NOVIPHARM 

A-9210 Portschach Klagenfurter Str 164, Austria. 

Tel.: 0427227510, Fax: 042723119.


Taxus baccata (Yew) 

Antineoplastic agent 

(Taxaceae and Coniferae) 

Location: Europe, North Africa and Western Asia. The important clinical efficacy of taxol has 

led to the drug supply crisis. As a result, NCI has developed plans to avert similar supply crisis 

in the future by initiating exploratory research projects for large-scale production. 


Stem: a tree 1.2–1.5m high, forming with age a very trunk covered with red-brown, peeling bark 

and topped with a rounded or wide-spreading head of branches. 

Leaves: spirally attached to twigs, but by twisting of the stalks brought more or less into two 

opposed ranks, dark, glossy, almost black-green above, grey, pale-green or yellowish beneath, 

15–45cm long, 2–3cm wide. 

Flowers: unisexual, with the sexes invariably on different trees, produced in spring from the leaf axils 

of the proceeding summer’s twigs. Male, a globose cluster of stamens; female, an ovule surrounded 

by small bracts, the so-called fruit bright red, sometimes yellow, juicy and encloses the seed. 

Biology: Can be propagated by seed or cuttings. Seeds may require warm and cold stratification. 

Mature woodcuttings taken in winter can be rooted under mist. 

Tradition: No tree is more associated with the history and legends of Great Britain. Before 

Christianity, it was a sacred tree favored by the Druids, who built their temples near these trees – 

a custom followed by the early christians. The association of the tree with places of worship still 

prevails. The wood was formerly much valued in archery for the making of long bows. The wood 

is said to resist the action of water and is very hard. 

Part used: stem segments, needles 1–2cm long, and roots. 

Active ingredients: 

● Taxane diterpenes, among them paclitaxel (earlier known as taxol), cephalomannine. 

● Key precursors: baccatin III, 10-desacetylbaccatin III, 9-dihydrobaccatin III, 

13-Acetyl-9-dihydrobaccatin III, baccatin VI. 

● Related compounds, such as taxotere. 

Figure 3.3 Taxus.


Particular value: Taxol research is being carried out on ovarian cancer, breast cancer, colon and 

gastric cancers, arthritis, Alzheimer’s, as an aid in coronary and heart procedures and as an 

antiviral agent. The uses of yew in any form for any medical or health reason should only do after 

consulting a health care professional. 

The status of taxus application in cancer therapy: Taxol (containing paclitaxel) is an anticancer 

drug, it was originally isolated from the Pacific Yew tree in the early 1960s, was recently 

approved by the Food and Drug Administration for use against ovarian cancer and has also shown 

activity against breast, lung and other cancers. This drug was also registered in Poland in 1996. 

In 1958 the US NCI initiates a program to screen 35,000 plants species for anticancer 

activity. In 1963, Drs Monroe Wall and M.C. Wani of Research Triangle Institute, 

North Carolina subsequently find that an extract or the bark of Pacific yew tree has antitumor 

activity. Since that time its use as an anticancer drug has become well established (Cragg, 1998). 

Human trials started in 1983. Despite a few deaths caused by unforeseen allergic reactions 

due to the form in which the drug was administered great promise was shown for women with 

previously incurable ovarian cancer. This led the NCI to issue a contract with Bristol Myers- 

Squibb (BMS), a pharmaceutical company based in the United States, for the clinical development 

of taxol (Rowinsky et al., 1990). 

Intense research on finding alternatives to taxol extracted from the bark of the Pacific yew is 

ongoing. Taxol has been chemically synthesized and semisynthetic versions have been developed 

using needles and twigs from other yew species grown in agricultural settings. This is reducing 

the pressure on natural stands of Pacific yew but bark is still being used for taxol production 

(Cragg et al., 1993). 

Precautions: 

● Poisonous. Many cases of poisoning amongst cattle have resulted from eating parts of it. 

The fruit and seeds seem to be the most poisonous parts of the tree. 

● In the treatment of cancer: reduction in white and red blood cells counts and infection. 

Other common side effects include hair loss, nausea and vomiting, joint and muscle pain, 

nerve pain, numbness in the extremities and diarrhea. Severe hypersensitivity can also 

occur, demonstrated by symptoms of shortness of breath, low blood pressure and rash. The 

likelihood of these reactions is lowered by the use of several kinds of medications that are 

given before the taxol infusion (NCI). 

Indicative dosage and application: the doses of taxol given to most patients are 

● 110mgm 2 in 22% 

● 135mgm 2 in 48% 

● 170mgm 2 in 22%. 

These doses are significantly lower, because of limited hematopoietic tolerance, than those 

previously demonstrated to be safe in minimally pre-treated or untreated patients 

(200–250 mg m 2 ). 

Documented target cancers: 

● Activity against the P-388, P-1534 and L-1210 murine leukemia models. 

● Strong activity against the B16 melanoma system. 

● Cytotoxic activity against KB cell culture system, Walker 256 carcinosarcoma, sarcoma 180 

and Lewis lung tumors. 

● Significant activity against several human tumor xenograft systems, including the MX-1 

mammary tumor.


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● 

Introduced to all ovarian cancer patients (meeting defined disease criteria). 

Responses in patients with metastatic breast cancer and in patients with other forms of advanced 

malignancy including lung cancer, cancer of the head and neck region and lymphomas. 



● 

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The antitumorous properties of paclitaxel are based on the ability to bind and to 

stabilize microtubules and block cell replication in the late G 2 –M phase of the cell 

cycle. In 1979 it was demonstrated that taxol affects the tubulin–microtubule equilibrium: 

it decreases both the critical concentration of tubulin (to almost 0–1mgml 1 ) and the 

induction time for polymerization, either in the presence or absence of GTP, MAPs and 

magnesium. Taken in conjunction with observations showing that taxol promotes the 

end-to-end joining of microtubules, these results point to a rather complex mechanism 

of action for taxol that is not yet completely understood (Cragg, 1998). 

Early studies with HeLa cells and BALB/c mouse fibroblasts treated with low 

concentrations of taxol (0.25moll 1 ), which produce minimal inhibition of DNA, 

RNA and protein synthesis, demonstrated that taxol blocks cell cycle traverse in the 

mitotic phases. Recently, taxol has been demonstrated to prevent transition from the 

G 0 phase to the S phase in fibroblasts during stimulation of DNA synthesis by 

growth factors and to delay traverse of sensitive leukemia cells in nonmitotic phases 

of the cell cycle. These findings indicate that the integrity of microtubules may be 

critical in the transmission of proliferative signals from cell-surface receptors to the 

nucleus. Proposed explanations that at least in part account for taxol’s inhibitory 

effects in nonmitotic phases include disruption of tubulin in the cell membrane 

and/or direct inhibition of the disassembly of the interphase cytoskeleton, which may 

upset many vital cell functions such as locomotion, intracellular transport and 

transmission of proliferative transmembrane signals. 


● 

● 

The plum yews (Cephalotaxus harringtonia Family: Cephalotaxaceae (plum yew family)) 

are similar to, and closely related to, the yews, family Taxaceae. Common Names: 

Japanese plum yew, Harrington plum yew, cow-tail pine, plum yew. 

The plum yews are evergreen, coniferous shrubs or small trees with flat, needle-like 

leaves arranged in two ranks on the green twigs and fleshy, plum-like seeds borne only 

on female plants. Japanese plum yew is a shrub or small tree, but most cultivars are 

quite a bit smaller. Japanese plum yew is native to Japan, Korea and eastern China, 

where it grows in the forest understory. Japanese plum yew has the potential to be a 

very useful landscape plant in the southern US. It is more tolerant of heat than the true 

yews (Taxus). It is produces cephalomannine a promising agent for cancer therapy. 

Taxus brevifolia can be regarded as the first source of taxol. It is common on the 

Olympic Peninsula in Washington and on Vancouver Island in British Columbia. 

The taxol supply needs for preclinical and early clinical studies were easily met by 

bark collections in Oregon between 1976 and 1985, from the bark of the tree. In 

1988 it was demonstrated that the precursor, 10-desacetylbaccatin III, isolated from 

the needles of the tree, can be converted to taxol and related active agents by a


● 

● 

● 

● 

relatively simple semisynthetic procedure, and alternative, more efficient processes 

for this conversion have recently been reported (Helfferich et al., 1993). 

The taxol content of fresh needles of 35 different Taxus cultivars from different 

locations within the US has been analyzed. At least six contain amounts comparable 

to or higher than those found in the dried bark of T. brevifolia. These observations 

have resulted in the initiation of a study of the nursery cultivar, Taxusmedia Hicksii, 

as a potential renewable large-scale source of taxol (Furmanova et al., 1997). 

NCI and Program Resources, in collaboration with various organizations are 

undertaking analytical surveys of needles of a number of Taxus species. They include 

T. baccata from the Black Sea-Caucasus region of Georgia and Ukraine, and 

T. cuspidata from Siberian regions of Russia; T. canadensis from the Gaspe Peninsula 

of Quebec; T. globosa from Mexico, T. sumatriensis from the Philippines and various 

Taxus species from the US. In a number of samples, the taxol content of the needles 

is comparable to that of the dried bark of T. brevifolia (NCI, Cragg et al., 1993). 

Pestalotiopsis microspora (an endophytic fungus) was isolated from the inner bark of a 

small limb of Himalayan yew, T. wallachiana, which has been shown to produce taxol 

in mycelial culture. Fungal taxol was evaluated in the standard 26 cancer cell line test 

and for its ability, when compared to authentic taxol, to inhibit cell division. The fungal 

compound found to be identical to authentic taxol (methods used: NMR, UV 

absorption and electrospray mass spectroscopy). It showed a pattern of activity comparable 

to that produced by standard authentic taxanes in the 26 cancer cell line test. 

In addition, its ability to induce mitotic arrest at a concentration of 37ngml 1 , 

consistent with a tubulin-stabilizing mode of action. The discovery that fungi make 

taxol increasingly adds to the possibility that horizontal gene transfer may have 

occurred between Taxus spp. and its corresponding endophytic organisms. This 

demonstration supports the idea that certain endophytic microbes of Taxus spp. may 

make and tolerate taxol in order to better compete and survive in association with 

these trees. Since Taxus spp. grow in places that are generally damp and shaded certain 

plant-pathogenic fungi (water molds) also prefer this niche (Strobel et al., 1996). 

Taxus marei Hu ex Liu is a native Taiwan species sparsely distributed in mountainous 

terrain. Many are giant trees with a diameter at breast height greater than 100cm and 

an estimated age of more than 1,000 years. Taxol concentration in the needles of these 

trees and selected superior trees with respect to high taxol and 10-desacetyl baccatin III 

concentrations. It was found that rooted cutting (steckling) ramets of these trees also 

exhibited high taxol concentrations in mature needles, confirming that taxol yield is 

a heritable trait. Young needles from vegetatively propagated elite yew trees can serve 

as a renewable and economic tissue source for increasing taxol production. 

Micropropagation of mature Taxus marei was achieved using bud explants derived 

from approximately 1,000-year-old field grown trees. It might be a very useful tool to 

use for the mass propagation of superior yew trees and the production of high-quality 

(orthotropic) plantlets for nursery operation (Chang, 2001). 


● 

Taxol has been shown to inhibit steroidogenesis in human Y-1 adrenocortical tumors 

and in MLTC-1 Leydig tumors by decreasing the intracellular transport of cholesterol


● 

to cholesterol side-chain cleavage enzymes. This effect appears to be related to 

perturbations in microtubule dynamics (Nicolaou et al., 1994). 

Taxol has also been shown to inhibit specific functions in many nonmalignant tissues, 

which may be mediated through microtubule disruption. For example, in human 

neutrophils, taxol inhibits relevant morphological and biochemical processes, including 

chemotaxis, migration, cell spreading, polarization, generation of hydrogen peroxide 

and killing of phagocytosed microorganisms. Taxol also antagonizes the effects 

of microtubule-disrupting drugs on lymphocyte function and adenosine 3,5-cyclic 

monophosphate metabolism and inhibits the proliferation of stimulated human lymphocytes, 

but blast transformation is not affected during lymphocyte activation. 

Taxol has also been found to mimic the effects of endotoxic bacterial lipopolysaccharide 

on macrophages, resulting in a rapid decrement of receptors for tumor factor- 

and TNF- release. This finding suggests that an intracellular target affected by taxol 

may be involved in the actions of lipopolysacccharide on macrophages and other cells. 

Interestingly, taxol inhibits chorioretinal fibroblast proliferation and contractility in 

an in vitro model of proliferative vitreoretinopathy, a fact that may be relevant to the 

treatment of traction retinal detachment and proliferative vitreoretinopathy. Taxol 

inhibits, also, the secretory functions of many specialized cells. Examples include 

insulin secretion in isolated rat islets of Langerhans, protein secretion in rat hepatocytes 

and the nicotinic receptor-stimulated release of catecholamines from chromaffin 

cells of the adrenal medulla (Nicolaou et al., 1994). 


● 

● 

● 

Taxotere is a highly promising analog of taxol that has been synthesized. It promotes the 

assembly and stability of microtubules with potency approximately twice that of taxol. 

Recently, taxol and taxotere have been shown to compete for the same binding site. 

While most of the effects of taxotere mirror those of taxol, it appears that the 

microtubules formed by taxotere induction are structurally different from those formed 

by taxol induction. Taxotere is currently produced by attaching a synthetic sidechain to 

10-desacetyl baccatin III, which is readily available from the European yew T. baccata, 

in yields approaching 1kg from 3.000kg of needles (Hirasuna et al., 1996). 

Cell culture has already been used to produce 14 C labeled taxol from 14 C sodium 

acetate. The USDA (United States Department of Agriculture) has received a patent 

for the production of taxol from cultured callus cells of T. brevifolia. They have 

licensed this process to Phyton Catalytic, who estimate that they will begin 

commercial production soon. The advantage of this system is that the major secretion 

product of the cells is taxol, which reduces the purification to an ether extraction 

of the medium. ESCA genetics has also announced technology for producing 

high levels of taxol in plant cell cultures, and they project large-scaled production in 

the near future. Additionally, callus cultures of T. cuspidata and T. canadensis have 

been sustained in a taxol-producing system for over two months. A fungus indigenous 

to T. brevifolia, that produces small amounts of taxol has recently been isolated 

and cultured (Helfferich et al., 1993). 

As a target for chemical synthesis, taxol presents a plethora of potential problems. 

Perhaps most obvious is the challenge presented by the central B ring, an


eight-membered carbocycle. Such rings are notoriously difficult to form because of 

both entropic and enthalpic factors. The normally high transannular strain of an 

eight-membered ring is further increased in this case by the presence of the geminal 

dimethyl groups, which project into the interior of the B ring. Then the trans-fused 

C ring with its angular methyl group and another ring (A ring), which is a 1,3-C3 

bridge, must be introduced. The A ring includes a somewhat problematic bridgehead 

alkene formally forbidden in a six-membered ring by Bredt’s rule. If assembling the 

carbon skeleton alone is not a daunting enough task, one should consider the high 

degree of oxygenation that must be introduced in a manner which allows the differential 

protection of five alkoxy groups in a minimum of three orthogonal classes. 

Additionally, some of the functionality is quite sensitive to environmental conditions. 

The oxetane ring, for example, will open under acidic or nucleophilic conditions, 

and the 7-hydroxyl group, if left unprotected, will epimerize under 

basic conditions. Despite the many attempts to synthesize taxol, the molecule still 

remains inaccessible by total synthesis (Nicolaou et al., 1994). 

● Taxol is supplied as a sterile solution of 6mgml 1 in 5ml ampoules (30mg 

per ampoule). Because of taxol’s aqueous insolubility, it is formulated in 50% cremophor 

EL and 50% dehydrated alcohol. The contents of the ampoule must be 

diluted further in either 0.9% sodium chloride or 5% dextrose. During early phase I 

and II studies, taxol was diluted to final concentrations of 0.003–0.60mgml 1 . 

These concentrations were demonstrated to be stable for 24 and 3h, respectively, in 

early stability studies. This short stability period required the administration of large 

volumes of fluids and/or drug preparation at frequent intervals for patients receiving 

higher doses. In recent studies, concentrations of 0.3–1.2mgml 1 in either 5% 

dextrose or normal saline solution have demonstrated both chemical and physical 

stability for at least 12h (Rowinsky et al., 1990). 

● Taxol and its relatives are emerging as yet another class of naturally occurring 

substances, like the enediyne antitumor antibiotics and the macrocyclic 

immunophilin ligands, that combine novel molecular architecture, important 

biological activity and fascinating mode of action. 

References 

Cragg, G.M. (1998) Paclitaxel (Taxol ): a success story with valuable lessons for Natural Product Drug 

discovery and development. John Wiley & Sons, Inc., New York. 

Cragg, G.M., Schepartz, S.A., Suffness, M. and Grever, M.R. (1993) The taxol supply crisis. New NCI 

policies for handling the large-scale production of novel natural product anticancer and Anti-HIV 

agents. J. Nat. Prod. 56(10), 1657–68. 

Chang, S.H., Ho, C.K., Chen, Z.Z. and Tsay, J.Y. (2001) Micropropagation of Taxus mairei from mature 

trees. Plant Cell Rep. 20, 496–502. 

Furmanowa, M., Glowniak, K., Syklowska-Baranek, K., Zgorka, G. and Jozefczyk, A. (1997) Effect of picloram 

and methyl jasmonate on growth and taxane accumulation in callus culture of Taxus media var. 

Hatfieldii. Plant Cell, Tissue Organ Culture 49, 75–79. 

Grieve M. (1994) A Modern Herbal. Edited and introduced by Mrs C.F. Leyel, Tiger books international, 

London.


Helfferich, C. (1993) Taxol Revisited Article, Alaska Science Forum, 1126. 

Hirasuna, T.J., Pestchanker, L.J., Srinivasan, V. and Shuler, M.L. (1996) Taxol production in suspension 

cultures of Taxus baccata. Plant Cell, Tissue Organ Culture 44, 95–102. 

Ketchum, R.E.B. and Gibson, D.M. (1996) Pactitaxel production in suspension cell cultures of Taxus. 


Ketchum, R.E.B., Gibson, D.M. and Greenspan Gallo, L. (1995) Media optimization for maximum 

biomass production in cell cultures of pacific yew. Plant Cell, Tissue Organ Culture, 42, 185–193. 

Luo, J.P., Mu Q. and Gu, Y.-H. (1999) Protoplast culture and paclitaxel production by Taxus yunnanensis. 


Nicolaou, K.C., Dai, W.M. and Guy, R.K. (1994) Chemistry and Biology of Taxol Angew. Chem. Int. Ed. 

Engl. 33, 15–44. 

Rowinsky, E.K., Cazenave, L.A. and Donehower, R.C. (1990) Taxol: a novel investigational 

antimicrotubule agent. Review. J. Natnl Cancer Inst., 82(15), 1247–1259. 

Samuelsson, G. (1992) Drugs of Natural Origin – A textbook of Pharmacognosy. Third revised, enlarged and 

translated edition. Swedish Pharmaceutical Press. 

Strobel, G., Yang, X., Sears, J., Kramer, R., Sidhu, R.S. and Hess, W.M. (1996) Taxol from Pestalotiopsis 

microspora, an endophytic fungus of Taxus wallachiana. Microbiology 142, 435–440. 

Sho-saiko-to, Juzen-taiho-to 

Sho-saiko-to (SST) and Juzen-taiho-to ( JTT) are not plants but Japanese modified Chinese 

herbal medicines, or Kampo. Juzen-taiho-to was formulated by Taiping Hui-Min Ju (Public 

Welfare Pharmacy Bureau) in Chinese Song Dynasty in AD 1200. It is prepared by extracting a 

mixture of ten medical herbs (Rehmannia glutinosa, Paeonia lactiflora, Liqusticum wallichii, 

Angelica sinesis, Glycyrrhiza uralensis, Poria cocos, Atractylodes macrocephala, Panax ginseng. 

Astragalus membranaceus and Cinnamomum cassia) that tone the blood and vital energy, and 

strengthen health and immunity. (Aburada et al., 1983). This potent and popular prescription 

has traditionally been used against anemia, anorexia, extreme exhaustion, fatigue, kidney and 

spleen insufficiency and general weakness, particularly after illness. TT is the most effective biological 

response modifier among 116 Chinese herbal formulates (Hisha et al., 1997). Animal 

models and clinical studies have revealed that it demonstrates extremely low toxicity (LD 50 

15gkg 1 of murine), self-regulatory and synergistic actions of its components in 

immunomodulatory and immunopotentiating effects (by stimulating hemopoietic factors and 

interleukins production in association with NK cells, etc.), potentiates therapeutic activity in 

chemotherapy (mitomycin, cisplatin, cyclophosphamide and fluorouracil) and radiotherapy, 

inhibits the recurrence of malignancies, prolongs survival, as well as ameliorate and/or prevents 

adverse toxicities (GI disturbances such as anorexia, nausea, vomiting, hematotoxicity, immunosuppression, 

leukopenia, thrombocytopenia, anemia and nephropathy, etc.) of many anticancer 

drugs (Horie et al., 1994; Ikehara et al., 1992; Ohnishi et al., 1998). 

Liver metastasis: the effect of the medicine was assayed after the inoculation of a liver-metastatic 

variant (L5) of murine colon 26 carcinoma cells into the portal vein. (Ohnishi et al., 1998). 

Oral administration of JTT for 7 days before tumor inoculation resulted in dose-dependent inhibition 

of liver tumor colonies and significant enhancement of survival rate as compared with 

the untreated control, without side effects. JTT significantly inhibited the experimental liver 

metastasis of colon 26-L5 cells in mice pretreated with anti-asialo GM1 serum and untreated 

normal mice, whereas it did not inhibit metastasis in 2-chloroadenosine-pretreated mice or T-celldeficient 

nude mice. Oral administration of Juzen-taiho-to activated peritoneal exudate 

macrophages (PEM) to become cytostatic against the tumor cells. These results show that oral


administration of Juzen-taiho-to inhibited liver metastasis of colon 26-L5 cells, possibly through 

a mechanism mediated by the activation of macrophages and/or T-cells in the host immune system. 

Thus, Juzen-taiho-to may be efficacious for the prevention of cancer metastasis. 

Both SST and JTT suppressed the activities of thymidylate synthetase and thymidine kinase 

involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively, in mammary 

tumors of SHN mice with the reduction of serum prolactin level. These results indicate that 

SST and JTT may have the antitumor effects on mammary tumors (Sakamoto et al., 1994). 

Juzen-taiho-to also improves the general condition of cancer patients receiving chemotherapy 

and radiation therapy. Oral administration of TJ-48 accelerates recovery from hemopoietic 

injury induced by radiation and the anticancer drug mitomycin C. The effects are found to be 

due to its stimulation of spleen colony-forming units. It has been suggested that the administration 

of TJ-48 should be of benefit to patients receiving chemotherapy, radiation therapy or 

bone marrow transplantation. 

In combination with an anticancer drug UFT (5-fluorouracil derivative), it prevented the 

body weight loss and the induction of the colonic cancer in rats treated with a chemical carcinogen 

1,2-dimethylhydrazine (DMH), and suppressed markedly the activity of thymidylate 

synthetase (TS) involved in the de novo pathway of pyrimidine synthesis in colonic cancer 

induced by DMH (Sakamoto et al., 1991). 

The combination of TJ-48 and mitomycin C (MMC) produced significantly longer survival 

in p-388 tumor-bearing mice than MMC alone, and TJ-48 decreased the diverse effects of MMC 

such as leukopenia, thrombopenia and weight loss. 

Immunostimulation: In mice, TJ-48 augmented antibody production and activated 

macrophage by oral administration of TJ-48, but reduced the MMC-induced immunosuppression 

in mice. TJ-48 showed a mitogenic activity in splenocytes but not in thymocytes, and an 

anti-complementary activity was also observed. Anti-complementary activity and mitogenic 

activity were both observed in high-molecular polysaccharide fraction but not in low-molecular 

weight fraction (Satomi et al., 1989). Of several polysaccharide fractions in TJ-48, only pectic 

polysaccharide fraction (F-5-2) showed potent mitogenic activity. F-5-2 was also shown to have 

the highest anti-complementary activity. However, the polygalacturonan region is essential for 

the expression of the mitogenic activity, but that the contribution of polygalacturonan region 

to the anti-complementary activity is less. F-5–2 activates complement via alternative 

complement pathway and induces the proliferation of B cells but does not differentiate those 

cells from antibody producing cells. 

Contribution to the prevention of the lethal and marked side effects of recombinant human 

TNF (rhTNF) and lipopolysaccharide (LPS) without impairing their antitumor activity. These 

drugs are thought to decrease the oxygen radicals and stabilize the cell membranes, with a deep 

relation to the arachidonic cascade. The release of prostaglandins and leukotriene B4 was suppressed 

by pretreatment with Shosaiko-to (Yano et al., 1994). Thromboxane B2 was transiently 

increased, followed by suppression. After pretreatment with Hochu-ekki-to or Juzen-taiho-to, 

suppression of leukotriene B4 could not be observed. The release of prostaglandin D2 was suppressed 

in mice pretreated with SST, JTT or Ogon (Scutellariae Radix) but it increased following 

pretreatment with Hochu-ekki-to. Chemicals that could prevent the lethality of rhTNF and LPS 

also revealed suppression of prostaglandins, leukotriene B4 and thromboxane B2. In general, 

drugs that prevented the lethality of rhTNF and LPS without impairing the antitumor activity 

could inhibit the release of leukotriene B4 and/or prostaglandin D2 (Sugiyama et al., 1995). 

rhTNF could activate the arachidonic cascade in combination with LPS. The lethality of rhTNF


and LPS could be prevented by pretreatment with Japanese modified traditional Chinese 

medicines and the crude drug, Ogon. 

In BDF1-mice which were implanted with P-388 leukemic cells, JTX prolonged 

significantly the average survival days of MMC-treated group. In tumor-free BDF1-mice, JTX 

improved the leukopenia and the body weight loss which were caused by MMC. Additionally, 

JTX delayed the appearance of deaths by lethal doses of MMC. These results indicate that JTX 

enhances the antitumor activity of MMC and lessens the adverse effects of it. JTX may be useful 

for patients undertaking MMC treatment. 

TJ-48 has the capacity to accelerate recovery from hematopoietic injury induced by radiation 

and the anticancer drug MMC. The effects are found to be due to its stimulation of spleen 

colony-forming unit (CFU-S) counts on day 14. 

Compound isolation: n-Hexane extract from TJ-48 shows a significant immunostimulatory 

activity. The extract is further fractionated by silica gel chromatography and HPLC in order to 

identify its active components. 1H-NMR and GC-EI-MS indicate that the active fraction is 

composed of free fatty acids (oleic acid and linolenic acid). When 27 kinds of free fatty acids 

(commercially available) are tested using the HSC proliferating assay, oleic acid, elaidic acid and 

linolenic acid are found to have potent activity. The administration of oleic acid to MMC-treated 

mice enhances CFU-S counts on days 8 and 14 to twice the control group. These findings 

strongly suggest that fatty acids contained in TJ-48 actively promote the proliferation of HSCs. 

Although many mechanisms seem to be involved in the stimulation of HSC proliferation, we 

speculate that at least one of the signals is mediated by stromal cells, rather than any direct 

interaction with the HSCs. 

The inhibitory effect of JTT on progressive growth of a mouse fibrosarcoma is partly 

associated with prevention of gelatin sponge-elicited progressive growth, probably mediated 

by endogenous factors including antioxidant substances, in addition to the augmentation of 

host-mediated antitumor activity (Ohnishi et al., 1996). 

Juzen-taiho-to could be an effective drug for protecting against the side effects 

(nephrotoxicity, immunosuppression, hepatic toxicity and gastrointestinal toxicity) induced by 

carboplatin in the clinic as well as by cisplatin. 

Sodium L-malate, C 4 H 4 Na 2 O 5 , was found to exhibit protective effects against both 

nephrotoxicity (ED 50 : 0.4mgkg 1 , p.o.) and bone marrow toxicity (ED 50 : 1.8mg/kg 1 , p.o.), 

without reducing the antitumor activity of cis-diamminedichloroplatinum (II) (CDDP) 

(Sugiyama et al., 1994). These findings indicate that Angelicae Radix and its constituent sodium 

L-malate could provide significant protection against CDDP-induced nephrotoxicity and bone 

marrow toxicity without reducing the antitumor activity. 

Water-soluble related compounds of the herbal medicine SST dose-dependently inhibited the 

proliferation of a human hepatocellular carcinoma cell line (KIM-1) and a cholangiocarcinoma 

cell line (KMC-1). Fifty percent effective doses on day 3 of exposure to SST were 

353.5 / 32.4 gml 1 for KIM-1 and 236.3/26.5gml 1 for KMC-1. However, 

almost no suppressive effects were detected in normal human peripheral blood lymphocytes or 

normal rat hepatocytes (Hano et al., 1994). Sho-saiko-to suppressed the proliferation of the carcinoma 

cell lines significantly more strongly than did each of its major related compounds, that 

is, saikosaponin a, c and d, ginsenoside Rb1 and Rg1, glycyrrhizin, baicalin, baicalein and 

wogonin, or another herbal medicine, JTT (P0.05 or 0.005). Because such related compounds 

are barely soluble in water, there could be synergistic or additive effects of the related 

compounds in SST. Morphological, DNA, and cell cycle analyses revealed two possible modes of


action of SST to suppress the proliferation of carcinoma cells: (a) it induces apoptosis in the early 

period of exposure; and (b) it induces arrest at the G 0 /G 1 phase in the late period of exposure. 

The effect of Shi-Quan-Da-Bu-Tang (TJ-48) on hepatocarcinogenesis induced by 

N-nitrosomorpholine (NNM) was investigated in male Sprague–Dawley rats. (Tatsuta et al., 

1994). Rats were given drinking water containing NNM for 8 weeks, and also from the start of 

the experiment, regular chow pellets containing 2.0% or 4.0% TJ-48 until the end of the 

experiment. Preneoplastic and neoplastic lesions staining for the placental type of 

glutathione-S-transferase (GST-P) or -glutamyl transpeptidase (GGT) were examined histochemically. 

In week 15, quantitative histological analysis showed that prolonged administration 

of either 2.0% or 4.0% TJ-48 in the diet significantly reduced the size, volume and/or number 

of GST-P-positive and GGT-positive hepatic lesions. This treatment also caused a significant 

increase in the proportion of interleukin-2 receptor-positive lymphocytes among the lymphocytes 

infiltrating the tumors as well as a significant decrease in the labeling index of preneoplastic 

lesions. These findings indicate that TJ-48 inhibits the growth of hepatic enzyme-altered 

lesions, and suggests that its effect may be in part due to activation of the immune system. 

References 

Aburada, M., Takeda, S., Ito, E., Nakamura, M. and Hosoya, E. (1983) Protective effects of juzentaihoto, 

dried decoctum of 10 Chinese herbs mixture, upon the adverse effects of mitomycin C in mice. 

J. Pharmacobiodyn 6(12), 1000–4. 

Hisha, H., Yamada, H., Sakurai, M.H., Kiyohara, H., Li, Y., Yu, C., Takemoto, N., Kawamura, H., 

Yamaura, K., Shinohara, S., Komatsu, Y., Aburada, M. and Ikehara, S. (1997) Isolation and identification 

of hematopoietic stem cell-stimulating substances from Kampo ( Japanese herbal) medicine, 

Juzen-taiho-to. Blood 90(3), 1022–30. 

Horie, Y., Kato, K., Kameoka, S., Hamano, K. (1994) Bu ji (hozai) for treatment of postoperative gastric 

cancer patients. Am. J. Chin. Med. 22, (3–4), 309–19. 

Horii, A., Kyo, M., Asakawa, M., Yasumoto, R. and Maekawa, M. (1991) Multidisciplinary treatment for 

bladder carcinoma–biological response modifiers and kampo medicines. Urol Int. 471, 108–12. 

Ikehara, S., Kawamura, H., Komatsu, Y., Yamada, H., Hisha, H., Yasumizu, R., Ohnishi-Inoue, Y., Kiyohara, H., 

Hirano, M. and Aburada, M. (1992) Effects of medicinal plants on hemopoietic cells. Adv. Exp. Med. Biol. 

319, 319–30. 

Onishi, Y., Yamaura, T., Tauchi, K., Sakamoto, T., Tsukada, K., Nunome, S., Komatsu, Y. and Saiki, I. 

(1998) Expression of the anti-metastatic effect induced by Juzen-taiho-to is based on the content of 

Shimotsu-to constituents. Biol. Pharm. Bull. 21(7), 761–5. 

Ohnishi, Y., Fujii, H., Hayakawa, Y., Sakukawa, R., Yamaura, T., Sakamoto, T., Tsukada, K., Fujimaki, M., 

Nunome, S., Komatsu, Y. and Saiki, I. (1998) Oral administration of a Kampo ( Japanese herbal) medicine 

Juzen-taiho-to inhibits liver metastasis of colon 26-L5 carcinoma cells. Jpn. J. Cancer Res. 89(2), 

206–13. 

Ohnishi, Y., Fujii, H., Kimura, F., Mishima, T., Murata, J., Tazawa, K., Fujimaki, M., Okada, F., 

Hosokawa, M. and Saiki, I. (1996) Inhibitory effect of a traditional Chinese medicine, Juzen-taiho-to, 

on progressive growth of weakly malignant clone cells derived from murine fibrosarcoma. Jpn. J. Cancer 

Res. 87(10), 1039–44. 

Sakamoto, S., Furuichi, R., Matsuda, M., Kudo, H., Suzuki, S., Sugiura, Y., Kuwa, K., Tajima, M., 

Matsubara, M. and Namiki, H. (1994) Effects of Chinese herbal medicines on DNA-synthesizing 

enzyme activities in mammary tumors of mice. Am. J. Chin. Med. 22(1), 43–50. 

Sakamoto, S., Kudo, H., Kuwa, K., Suzuki, S., Kato, T., Kawasaki, T., Nakayama, T., Kasahara, N. and 

Okamoto, R. (1991) Anticancer effects of a Chinese herbal medicine, juzen-taiho-to, in combination


with or without 5-fluorouracil derivative on DNA-synthesizing enzymes in 1,2-dimethylhydrazine 

induced colonic cancer in rats. Am. J. Chin. Med. 19(3–4), 233–41. 

Satomi, N., Sakurai, A., Iimura, F., Haranaka, R. and Haranaka, K. (1989) Japanese modified traditional 

Chinese medicines as preventive drugs of the side effects induced by tumor necrosis factor and 

lipopolysaccharide. Mol. Biother. 1(3), 155–62. 

Sugiyama, K., Ueda, H. and Ichio, Y. (1995) Protective effect of juzen-taiho-to against carboplatininduced 

toxic side effects in mice. Biol. Pharm. Bull. 18(4), 544–8. 

Sugiyama, K., Ueda, H., Ichio, Y. and Yokota, M. (1995) Improvement of cisplatin toxicity and lethality 

by juzen-taiho-to in mice. Biol. Pharm. Bull. 18(1), 53–8. 

Sugiyama, K., Ueda, H., Suhara, Y., Kajima, Y., Ichio, Y. and Yokota, M. (1994) Protective effect 

of sodium L-malate, an active constituent isolated from Angelicae radix, on 

cis-diamminedichloroplatinum(II)-induced toxic side effect. Chem. Pharm. Bull. (Tokyo) 42(12), 

2565–8. 

Tatsuta, M., Iishi, H., Baba, M., Nakaizumi, A. and Uehara, H. (1994) Inhibition by shi-quan-da-bu-tang 

(TJ-48) of experimental hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats. 

Eur. J. Cancer 30(1), 74–8. 

Yamada, H. (1989) Chemical characterization and biological activity of the immunologically active 

substances in Juzen-taiho-to. Gan To Kagaku Ryoho 16(4 Pt 2-2), 1500–5. 

Yano, H., Mizoguchi, A., Fukuda, K., Haramaki, M., Ogasawara, S., Momosaki, S. and Kojiro, M. (1994) 

The herbal medicine sho-saiko-to inhibits proliferation of cancer cell lines by inducing apoptosis and 

arrest at the G0/G1 phase. Cancer Res. 54(2), 448–54. 

Zee-Cheng, R.K. (1992) Shi-quan-da-bu-tang (ten significant tonic decoction), SQT. A potent Chinese 

biological response modifier in cancer immunotherapy, potentiation and detoxification of anticancer 

drugs. Methods Find Exp. Clin. Pharmacol. 14(9), 725–36. 

3.2.2. Promising candidates for the future: plant species with 

a laboratory-proven potential 

Acronychia oblongifolia (Acronychia) (Rutaceae) 

Cytotoxic 

Location: In all types of rainforest. 


Stem: 12m high. 

Leaves: 4–12cm long and emit a pleasant smell when crushed. Oil dots are visible and numerous, 

and the leaf blade is very glossy. 

Flowers: they are produced on the bare stems and behind the foliage. 

Parts used: bark, stem. 


● 

● 

Flavonols: 5,3-dihydroxy-3,6,7,8,4-pentamethoxyflavone, 5-hydroxy-3,6,7,8,3,4-hexamethoxyflavone, 

digicitrin, 3-O-demethyldigicitrin, 3,5,3-trihydroxy-6,7,8,4-tetramethoxyflavone 

and 3,5-dihydroxy-6,7,8,3,4-pentamethoxyflavone. 

Alkaloids: 1,2,3-trimethoxy-10-methyl-acridone, 1,3,4-trimethoxy-10-methyl-acridone, des-Nmethyl 

acronycine, normelicopine and noracronycine. 


● 

● 

human nasopharyngeal carcinoma 

tubulin inhibitor.


Figure 3.4 Acronychia sp. 



● Acronychia porteri contains various flavonols (see above) which showed activity against 

(KB) human nasopharyngeal carcinoma cells (IC 50 0.04gml 1 ) and inhibited tubulin 

assembly into microtubules (IC 50 12M) (Lichius et al., 1994). 

● Acronychia pedunculata: The bark contains acrovestone and bauerenol, two crystalline 

substances (Wu et al., 1989; Zhu et al., 1989). 

● Acronychia baueri (Rutaceae): the bark contains the alkaloids, 1,2,3-trimethoxy-10- 

methyl-acridone, 1,3,4-trimethoxy-10-methyl-acridone, des-N-methyl acronycine, normelicopine 

and noracronycine (Svoboda et al., 1966). 

● Acronychia laurifolia BL: contains acronylin, a phenolic compound (Biswas et al., 1970). 

● Acronychia haplophylla: This plant contains the alkaloids acrophylline and acrophyllidine 

(Lahey et al., 1968). 

References 

Biswas, G.K. and Chatterjee, A. (1970) Isolation and structure of acronylin: a new phenolic compound 

from Acronychia laurifolia BL. Chem. Ind. 16(20), 654–5. 

Chowrashi, B.K., Mukherjea, B. and Sikder, S. (1976) Some central effects of Acronychia laurifolia Linn 

(letter). Indian J. Physiol. Pharmacol. 20(4), 250–1. 

Funayama, S. and Cordell, G.A. (1984) Chemistry of acronycine IV. Minor constituents of acronine and the 

phytochemistry of the genus Acronychia. J. Nat. Prod. 47(2), 285–91. 

Lahey, F.N. and McCamish, M. (1968) Acrophylline and acrophyllidine. Two new alkaloids from Acronychia 

haplophylla. Tetrahedron Lett., 12, 1525–7.


Lichius, J.J., Thoison, O., Montagnac, A., Pais, M., Gueritte-Voegelein, F., Sevenet, T., Cosson, J.P. and 

Hadi, A.H. (1994) Antimitotic and cytotoxic flavonols from Zieridium pseudobtusifolium and Acronychia 

porteri. J. Nat. Prod., 57(7), 1012–6. 

Svoboda, G.H., Poore, G.A., Simpson, P.J. and Boder, G.B. (1966) Alkaloids of Acronychia Baueri Schott I. 

Isolation of the alkaloids and a study of the antitumor and other biological properties of acronycine. 

J. Pharm. Sci., 55(8), 758–68. 

Wu, T.S., Wang, M.L., Jong, T.T., McPhail, A.T., McPhail, D.R. and Lee, K.H. (1989) X-ray crystal 

structure of acrovestone, a cytotoxic principle from Acronychia pedunculata. J. Nat. Prod., 52(6), 1284–9. 

Zhou, F.X. and Min, Z.D. (1989) Studies on the chemical constituents of Acronychia pedunculata (L.) Mig. 

Chung Kuo Chung Yao Tsa Chih. 14(2), 30–1, 62. 

Agrimonia pilosa (Agrimony) (Rosaceae) 


Cytotoxic 

Location: Of Chinese origin, it is found in most places – on hedge-banks, meadows, open woods 

and roadsides – though not in the far north. 

Appearance 

Stem: erect and cylindrical, hairy, 50–150cm high, mostly unbranched. 

Root: long, woody and black. 

Leaves: 7.7–20cm long, pinnate with to other leaflets. 

Flowers: small, yellow, on terminal spikes, emitting an apricot-like odor. Fruits bear hairy spines. 

Fruit deeply grooved. 

In bloom: June–September. 

Tradition: One of the most famous “magic” herbs, it has been used against wounds of various causes 

and for the prevention and cure of liver disorders. The Chinese A. pilosa is known as xian he cao. 

Part used: Root 

Active ingredients: agrimoniin (tannin), unidentified components of methanolic extract. 

Particular value: Its use presents a relatively low risk of side effects. 

Precautions: Avoid use in case of constipation. 

Indicative dosage and application: agrimoniin: intraperitoneal injection with 10mgkg 1 . 


● 

● 

● 

Agrimoniin is capable of inducing interleukin-1. 

The methanol extract from roots of the plant helps to prolong the life span of mammary 

carcinoma-bearing mice while inhibiting tumor growth. 

Is cytotoxic to tumor cells, normal cells are far less affected. 



● 

An antimutagenic activity against benzo[a]pyrene (B[a]P) was marked in the 

presence of A. pilosa extracts (boiled for 2h in a water bath) whereas that against 1,6- 

dinitropyrene (1,6-diNP) and 3,9-dinitrofluoranthene (3,9-diNF) varied from 20%


● 

to 86%. The observed differences in inhibition might be due to the inactivation of 

metabolic enzymes (Horikawa et al., 1994). 

A significant amount of interleukin-1 (IL-1) beta in the culture supernatant of the 

human peripheral blood mononuclear cells was stimulated with agrimoniin 

(Miyamoto, 1988). Agrimoniin induced IL-1 beta secretion dose- and timedependently 

(Murayama, 1992). The adherent peritoneal exudate cells from mice 

intraperitoneally injected with agrimoniin (10mgkg 1 ) also secreted IL-1 four days 

later. These results suggested that agrimoniin is a novel cytokine inducer. 


● 

To evaluate the antitumor activity of A. pilosa, the effects of the methanol extract 

from roots of the plant (AP-M) on several transplantable rodent tumors were investigated. 

AP-M inhibited the growth of S-180 solid type tumors (Miyamoto, 1987). 

On the other hand, the prolongation of life span induced by AP-M on S-180 ascites 

type tumor-bearing mice was markedly minimized or abolished by the pretreatment 

with cyclophosphamide. AP-M showed considerably strong cytotoxicity on MM-2 

cells in vitro, but the effect was diminished to one-tenth by the addition of serum to 

the culture. Against the host animals, the peripheral white blood cells in mice were 

significantly increased from 2 to 5 days after the i.p. injection of AP-M. On day 4 

after the injection of AP-M, the peritoneal exudate cells, which possessed the cytotoxic 

activity on MM-2 cells in vitro, were also increased to about 5-fold relative to 

those in the non-treated control. The spleen of the mice was enlarged, and the spleen 

cells possessed the capacity to uptake 3H-thymidine. However, AP-M did not show 

direct migration activity like other mitogens against spleen cells from non-treated 

mice (Miyamoto, 1987). These results indicate that the roots of A. pilosa contain 

some antitumor constituents, and possible mechanisms of the antitumor activity may 

include host-mediated actions and direct cytotoxicity. 

References 

Horikawa, K., Mohri, T., Tanaka, Y. and Tokiwa, H. (1994) Moderate inhibition of mutagenicity and carcinogenicity 

of benzo[a]pyrene, 1,6-dinitropyrene and 3,9-dinitrofluoranthene by Chinese medicinal 

herbs. Mutagenesis 9(6), 523–6. 

Kimura, Y., Takido, M. and Yamanouchi, S. (1968) Studies on the standardization of crude drugs. XI. 

Constituents of Agrimonia pilosa var. japonica Yakugaku Zasshi 88(10), 1355–7. 

Koshiura, R., Miyamoto, K., Ikeya, Y. and Taguchi, H. (1985) Antitumor activity of methanol extract 

from roots of Agrimonia pilosa Ledeb. Jpn. J. Pharmacol. 38(1), 9–16. 

Min, B.S., Kim, Y.H., Tomiyama, M., Nakamura, N., Miyashiro, H., Otake, T. and Hattori, M. (2001) 

Inhibitory effects of Korean plants on HIV-1 activities. Phytother. Res. 15(6), 481–6. 

Murayama, T., Kishi, N., Koshiura, R., Takagi, K., Furukawa, T. and Miyamoto, K. (1992) Agrimoniin, 

an antitumor tannin of Agrimonia pilosa Ledeb., induces interleukin-1. Anticancer Res. 12(5), 1471–4. 

Miyamoto, K., Kishi, N. and Koshiura, R. (1987) Antitumor effect of agrimoniin, a tannin of Agrimonia 

pilosa Ledeb., on transplantable rodent tumors. Jpn. J. Pharmacol. 43(2), 187–95. 

Miyamoto, K., Kishi, N., Murayama, T., Furukawa, T. and Koshiura, R. (1988) Induction of cytotoxicity 

of peritoneal exudate cells by agrimoniin, a novel immunomodulatory tannin of Agrimonia pilosa Ledeb. 

Cancer Immunol. Immunother. 27(1), 59–620.


Pei, Y.H., Li, X., Zhu, T.R. and Wu, L.J. (1990) Studies on the structure of a new flavanonol glucoside of 

the root-sprouts of Agrimonia pilosa Ledeb Yao Xue Xue Bao 5(4), 267–70. 

Angelica archangelica L. (Angelica) (Umbelifereae) 

Cytotoxic 

Location: Of Syria origin, native in cold and moist places in Scotland, and in countries further 

north (Lapland, Iceland). It can be easily found, as it is largely cultivated in some places. 


Stem: stout, fluted, 1.3–2m high and hollow. 

Root: long, spindle-shaped, thick and fleshy with large heavy specimens. 

Leaves: bright green, composed of numerous small leaflets, divided into three principal groups 

each of which is subdivided into three lesser groups. Edges are finely toothed or serrated. 

Flowers: small and numerous, yellowish or greenish, grouped into large, globular umbels. 

In bloom: July. 

Tradition: It was well known for its protection against contagion, for purifying the blood and 

for curing every conceivable malady, such as poisons, agues and all infectious maladies. 

Part used: root, leaves, seeds. 


● 

● 

● 

Pyranocoumarins: decursin, archangelici, and 8(S),9(R)-9-angeloyloxy-8,9-dihydrooroselol. 

Chalcones: 4-hydroxyderricin, xanthoangelol and ashitaba-chalcone. 

Polysaccharide: uronic acid. 

Precautions: Should not be given to patients who have tendency towards diabetes, because it 

increases sugar in the urine. 

Documented target cancers: Skin cancer (mouse), Ehrlich tumors (mouse), and the stimulation 

of the uptake of tritiated thymidine into murine and human spleen cells. 

Figure 3.5 Angelica archangelica.




● 

● 

Pyranocoumarins decursin is cytotoxic against various human cancer cell lines, possibly 

due to protein kinase C activation. Relatively low cytotoxicity against normal 

fibroblasts. 

Polysaccharide: cytotoxic, immunostimulating. 


● 

● 

● 

● 

● 

Angelica gigas: roots contain the cytotoxic pyranocoumarin decursin (also found in 

A. decursiva) Fr. et Sav. (Ahn et al., 1996). 

Angelica sinensis: the rhizome contains a low molecular weight (3kd) polysaccharide 

composed partly of uronic acid. It shows strong antitumor activity on Ehrlich Ascites 

tumor-bearing mice. It also exhibits immunostimulating activities, both in vitro and 

in vivo (Choy et al., 1994). 

Angelica keiskei: roots contain two angular furanocoumarins, archangelicin 

and 8(S),9(R)-9-angeloyloxy-8,9-dihydrooroselol as well as three chalcones, 

4-hydroxyderricin, xanthoangelol and ashitaba-chalcone which can suppress 12-O-tetradecanoylphorbol-13-acetate 

(TPA)-stimulated 32 P i -incorporation into phospholipids of 

cultured cells. In addition, 4-hydroxyderricin and xanthoangelol have antitumorpromoting 

activity in mouse skin carcinogenesis induced by 7,12- 

dimethylbenz[a]anthracene (DMBA) plus TPA, possibly due to the modulation of 

calmodulin involved systems (Okuyama et al., 1991). 

Angelica acutiloba is one of the main components of the oriental Kampo-prescription, 

Shi-un-kou (in which other two constituents are Lithospermum erythrorhizon and 

Macrotomia euchroma). The drug exhibits inhibitory activity on Epstein–Barr virus activation 

and skin tumor formation in mice. Roots contain an immunostimulating polysaccharide 

(AIP) consisting of uronic acid, hexose and peptide (Kumazawa et al., 1982). 

Angelica radix is another oriental herb whose administration in mice is associated 

with an increased production of the TNF, possibly through stimulation of the reticuloendothelial 

system (RES) (Haranaka et al., 1985). 

References 

Ahn, K.S., Sim, W.S. and Kim, I.H., (1996) Decursin: a cytotoxic agent and protein kinase C activator 

from the root of Angelica gigas. Planta Med. 62(1), 7–9. 

Choy, Y.M., Leung, K.N., Cho, C.S., Wong, C.K. and Pang, P.K. (1994) Immunopharmacological studies 

of low molecular weight polysaccharide from Angelica sinensis. Am. J. Chin. Med. 22(2), 137–45. 

Haranaka, K., Satomi, N., Sakurai, A., Haranaka, R., Okada, N. and Kobayashi, M. (1985) Antitumor 

activities and tumor necrosis factor producibility of traditional Chinese medicines and crude drugs. 

Cancer Immunol. Immunother. 20(1), 1–5.


Konoshima, T., Kozuka, M., Tokuda, H. and Tanabe, M. (1989) Anti-tumor promoting activities and 

inhibitory effects on Epstein–Barr virus activation of Shi-un-kou and its constituents Yakugaku Zasshi. 

109(11), 843–6. 

Kumazawa, Y., Mizunoe, K. and Otsuka, Y. (1982) Immunostimulating polysaccharide separated from hot 

water extract of Angelica acutiloba Kitagawa (Yamato tohki). Immunology 47(1), 75–83. 

Okuyama, T., Takata, M., Takayasu, J., Hasegawa, T., Tokuda, H., Nishino, A., Nishino, H. and Iwashima, A. 

(1991) Anti-tumor-promotion by principles obtained from Angelica keiskei. Planta Med. 57(3), 242–6. 

Annona cherimola (Annona) (Annonaceae) 

Cytotoxic 

Location: Central America (Ecuador, Colombia and Bolivia) 


Stem: 5–10m high, erect, low brunched. 

Leaves: briefly deciduous, alternate, 2-ranked, with minutely hairy petioles 0.8–1.5cm long, 

ovate to elliptic or ovate-lanceolate. 

Flowers: fragrant, solitary or in groups of 2 or 3, on short hairy stalks along the branches, 3 outer 

greenish petals and 3 smaller, inner pinkish petals. 

In bloom: Spring, summer, autumn, winter. 

Part used: fruit. 

Active ingredients: Annonaceous acetogenins (lactones), alkaloids. 

Figure 3.6 Annona sp.



● 

● 

● 

Prostate adenocarinoma 

pancreatic carcinoma cell line (human) 

sarcoma. 



● Annona muricata: leaves contain two Annonaceous acetogenins, muricoreacin and 

murihexocin C., showing significant cytotoxicities among human tumor cell lines 

with selectivities to the prostate adenocarinoma (PC-3) and pancreatic carcinoma 

(PACA-2) cell lines (Kim et al., 1998). 

● Annona senegalensis is used against sarcomas (Durodola et al., 1975a,b). 

● Annona purpurea contains alkaloids (Sonnet et al., 1971). 

● Annona reticulata: seeds contain the cytotoxic gamma-lactone acetogenin, 

cis-/trans-isomurisolenin, along with annoreticuin, annoreticuin-9-one, bullatacin, 

squamocin, cis-/trans-bullatacinone and cis-/trans-murisolinone (Chang, 1998). 


● 

● 

The bark of A. squamosa yielded three new mono-tetrahydrofuran (THF) ring 

acetogenins, each bearing two flanking hydroxyls and a carbonyl group at the C-9 

position. These compounds were isolated using the brine shrimp lethality assay as a 

guide for the bioactivity-directed fractionation. (2,4-cis and trans)-Mosinone A is a 

mixture of ketolactone compounds bearing a threo/trans/threo ring relationship and 

a double bond two methylene units away from the flanking hydroxyl. The other two 

new acetogenins differ in their stereochemistries around the THF ring; mosin B has a 

threo/trans/erythro configuration across the ring, and mosin C possesses a threo/cis/threo 

relative stereochemistry. Also found was annoreticuin-9-one, a known acetogenin that 

bears a threo/trans/threo ring configuration and a C-9 carbonyl and is new to this 

species. The structures were elucidated based on spectroscopic and chemical methods. 

Compounds 1–4 all showed selective cytotoxic activity against the human pancreatic 

tumor cell line, PACA-2, with potency 10–100 times that of Adriamycin 

(Hopp et al., 1997). 

Activity-guided fractionation of the stem bark of A. senegalensis gave four bioactive 

ent-kaurenoids. Compound 2 showed selective and significant cytotoxicity for MCF- 

7 (breast cancer) cells (ED 50 1.0gml 1 ), and 3 and 4 exhibited cytotoxic selectivity 

for PC-3 (prostate cancer) cells but with weaker potencies (ED 50 17–18gml 1 ). 

The structure of the new compound, 3, was deduced from spectral evidence (Fatope 

et al., 1996). 

● The bark extracts of A. squamosa yielded a new bioactive acetogenin, squamotacin (1), 

and the known compound, molvizarin, which is new to this species. Compound 1 is


● 

● 

● 

● 

identical to the potent acetogenin, bullatacin, except that the adjacent bis- THF rings 

and their flanking hydroxyls are shifted two carbons toward the -lactone ring. 

Compound 1 showed cytotoxic activity selectively for the human prostate tumor cell 

line (PC-3), with a potency of over 100 million times that of Adriamycin (Hopp 

et al., 1997). 

Bioactivity-directed fractionation of the seeds of A. muricata L. (Annonaceae) 

resulted in the isolation of five new compounds: cis-annonacin, cis-annonacin-10-one, 

cis-goniothalamicin, arianacin and javoricin. Three of these) are among the first cis 

mono-THF ring acetogenins to be reported. NMR analyses of published model synthetic 

compounds, prepared cyclized formal acetals, and prepared Mosher ester 

derivatives permitted the determinations of absolute stereochemistries. Bioassays of 

the pure compounds, in the brine shrimp test, for the inhibition of crown gall 

tumors, and in a panel of human solid tumor cell lines for cytotoxicity, evaluated 

relative potencies. Compound 1 was selectively cytotoxic to colon adenocarcinoma 

cells (HT-29) in which it was 10,000 times the potency of adriamycin (Rieser 

et al., 1996). 

In a continuing activity-directed search for new antitumor compounds, using brine 

shrimp lethality test (BST), mixtures of three additional pairs of bis-THF ketolactone 

acetogenins were isolated from the ethanol extract of the bark of A. bullata Rich. 

(Annonaceae). Compared with (2,4-cis and trans)-bullatacinone, these new compounds 

each have one more aliphatic OH group at a different position on the hydrocarbon 

chain and thus, were named (2,4-cis and trans)-10-hydroxybullatacinone (1 and 2), 

(2,4-cis and trans)-12-hydroxybullatacinone (3 and 4), and (2,4-cis and trans)-29-hydroxybullatacinone. 

These mixtures all showed potent activities in the BST and exhibited 

cytotoxicities comparable to those of adriamycin against human solid tumor cells in 

culture with selectivities exhibited especially toward the breast cancer cell line 

(MCF-7) (Gu et al., 1993). 

From A. bullata, three more pairs of new ketolactone Annonaceous acetogenins were 

isolated by bioactivity-directed isolation. They are hydroxylated adjacent bis-THF 

acetogenins and are named (2,4-cis and trans)-32-hydroxybullatacinone (1 and 2), (2,4- 

cis and trans)-31-hydroxybullatacinone (3 and 4), and (2,4-cis and trans)-30-hydroxybullatacinone. 

The structures were elucidated by analysis of the 1 H- and 13 C-NMR 

spectra of 1–6 and their acetates and the MS of their tri-trimethylsilyl (TMSi) derivatives 

as compared with bullatacinone. This is the first time that Annonaceous acetogenins 

with OH groups at successive positions near the end of the aliphatic chain have been 

reported. All of the new compounds showed potent activities in the BST and against 

human solid tumor cells in culture, with selectivities exhibited especially toward the 

colon cancer cell line (HT-29) (Gu et al., 1994). 

Structural work and chemical studies are reported for several cytotoxic agents from 

the plants Annona densicoma, Annona reticulata, Claopodium crispifolium, Polytrichum 

obioense, and Psorospermum febrifugum. Studies are also reported based on 

development of a mammalian cell culture benzo[a]pyrene metabolism assay for the 

detection of potential anticarcinogenic agents from natural products (Cassady et al., 

1990).

References 


Cassady, J.M., Baird, W.M. and Chang, C.J. (1990) Natural products as a source of potential cancer 

chemotherapeutic and chemopreventive agents. J. Nat. Prod. 53(1), 23–41. 

Chang, F.R., Chen, J.L., Chiu, H.F., Wu, M.J. and Wu, Y.C. (1998) Acetogenins from seeds of Annona 

reticulata. Phytochemistry 47(6), 1057–61. 

Durodola, J.I. (1975a) Viability and transplantability of developed tumour cells treated in vitro with 

antitumour agent C/M2 isolated from a herbal cancer remedy – of Annona senegalensis. Planta Med. 28(4), 

359–62. 

Durodola, J.I. (1975b) Antitumour effects against sarcoma 180 ascites of fractions of Annona senegalensis. 

Planta Med. 28(1), 32–6. 

Fatope, M.O., Audu, O.T., Takeda, Y., Zeng, L., Shi, G., Shimada, H. and McLaughlin, J.L. (1996) 

Bioactive ent-kaurene diterpenoids from Annona senegalensis. J. Nat. Prod. 59(3), 301–3. 

Gu, Z.M., Fang, X.P., Hui, Y.H. and McLaughlin, J.L. (1994) 10-, 12-, and 29-hydroxybullatacinones: 

new cytotoxic Annonaceous acetogenins from Annona bullata Rich (Annonaceae). Nat. Toxins. 2(2), 

49–55. 

Gu, Z.M., Fang, X.P., Miesbauer, L.R, Smith, D.L. and McLaughlin, J.L. (1993) 30-, 31-, and 

32-hydroxybullatacinones: bioactive terminally hydroxylated annonaceous acetogenins from Annona 

bullata. J. Nat. Prod. 56(6), 870–6. 

Hopp, D.C., Zeng, L., Gu, Z.M., Kozlowski, J.F. and McLaughlin, J.L. (1997) Novel mono-tetrahydrofuran 

ring acetogenins, from the bark of Annona squamosa, showing cytotoxic selectivities for the human 

pancreatic carcinoma cell line, PACA-2. J. Nat. Prod. 60(6), 581–6. 

Hopp, D.C., Zeng, L., Gu, Z. and McLaughlin, J.L. (1996) Squamotacin: an annonaceous acetogenin with 

cytotoxic selectivity for the human prostate tumor cell line (PC-3). J. Nat. Prod. 59(2), 97–9. 

Kim, G.S., Zeng, L., Alali, F., Rogers, L.L., Wu, F.E., Sastrodihardjo, S. and McLaughlin, J.L. (1998) 

Muricoreacin and murihexocin C, mono-tetrahydrofuran acetogenins, from the leaves of Annona 

muricata. Phytochemistry 49(2), 565–71. 

Rieser, M.J., Gu, Z.M., Fang, X.P., Zeng, L., Wood, K.V. and McLaughlin, J.L. (1996) Five novel monotetrahydrofuran 

ring acetogenins from the seeds of Annona muricata. J. Nat. Prod. 59(2), 100–8. 

Sonnet, P.E. and Jacobson, M. (1971) Tumor inhibitors. II. Cytotoxic alkaloids from Annona purpurea. 

J. Pharm. Sci. 60(8), 1254–6. 

Brucea antidysenterica (Brucea) 

(Simaroubaceae) (Figure 3.7) 

Location: China, Japan. 

Part used: stem. 


Cytotoxic 

● Cytotoxic: Bruceoside C, bruceanic acid A and its methyl ester 2 (new), bruceanic acid B, C and D. 

● Quassinoid glucosides: bruceosides D, E and F, bruceantinoside C and yadanziosides G and N, 

bruceanic acids. 

● Alkaloids: 1,11-dimethoxycanthin-6-one, 11-hydroxycanthin-6-one and canthin-6-one. 

Indicative dosage and application: Tested in human carcinoma cells at: 

● 

● 

250gml 1 showed 42% growth inhibition. 

500gml 1 showed 56% growth inhibition.


Figure 3.7 Brucea. 

The 50% of the results are visible after the first 7h. 

Documented target cancers: Leukemia and non-small-cell lung, colon, CNS, melanoma and 

ovarian cancer. 

● 

● 

● 

● 

Bruceanic acid D is cytotoxic against P-388 lymphocytic leukemia cells. 

Bruceanic acid A against KB and TE 671 tumor cells, brain metastasis, in lung cancer with 

radiotherapy. 

Bruceoside C is used against KB, A-549, RPMI and TE-671 tumor cells. 

The three above-mentioned alkaloids are cytotoxic and are used as anti-leukemic alkaloids. 



● 

● 

The fruit of Brucea javanica contains quassinoid glucosides, which show selective cytotoxicity 

in the leukemia and non-small cell lung, colon, CNS, melanoma and ovarian 

cancer, cell lines with logGI 50 values ranging from 4.14 to 5.72. A fruitderived 

emulsion inhibited human squamous cell carcinoma cells. At a dose of 

250 gml 1 at 96h after drug exposure, it showed 42% growth inhibition, and at 

500gml 1 inhibited 56% of the cell growth. The effect of more than 50% of the 

growth inhibition was evident at more than 7h after drug exposure. In the analysis 

of the mechanism of the drug using a flow cytometry, the arrest in G 1 phase of cell 

cycle was found during incubation of cancer cells with drug (Fukamiya et al., 1992). 

The 10% Brucea javanica emulsion has synergetic with radiotherapy in treating brain 

metastasis in lung cancer. Median survival (15 months) of the patients treated was 

prolonged for 50% (Wang, 1992).


● 

In addition, the venous emulsion of BJOE had strong action against the elevation of 

intracranial pressure produced by SNP (P 0.01) while oral emulsion had mild 

action against it, which was similar to the clinical observation exhibiting improvement 

of clinical manifestations after application of BJOE on intracranial hypertension 

caused by brain metastasis from lung cancer (Wang, 1992; Lu et al., 1994). 


● 

● 

The stem of Brucea antidysenterica contains bruceanic acid A and its methyl ester 2, as 

well as the bruceanic acids B, C, and D. It also contains three cytotoxic, quassinoid 

glycosides, bruceantinoside C and the yadanziosides G and N (Toyota et al., 1990). 

These species also contains three cytotoxic anti-leukemic alkaloids, 1,11-dimethoxycanthin-6-one, 

11-hydroxycanthin-6-one and canthin-6-one. 

References 

Fukamiya, N., Okano, M., Miyamoto, M., Tagahara, K. and Lee, K.H. (1992) Antitumor agents, 127. 

Bruceoside C, a new cytotoxic quassinoid glucoside, and related compounds from Brucea javanica. J. Nat. 

Prod. 55(4), 468–75. 

Fukamiya, N., Okano, M., Aratani, T., Negoro, K., McPhail, A.T., Ju-ichi, M. and Lee, K.H. (1986) 

Antitumor agents, 79. Cytotoxic anti-leukemic alkaloids from Brucea antidysenterica. J. Nat. Prod. 49(3), 

428–34. 

Fukamiya, N., Okano, M., Tagahara, K., Aratani, T., Muramoto, Y. and Lee, K.H. (1987) Antitumor 

agents, 90. Bruceantinoside C, a new cytotoxic quassinoid glycoside from Brucea antidysenterica. J. Nat. 

Prod. 50(6), 1075–9. 

Kupchan, S.M., Britton, R.W., Ziegler, M.F. and Sigel, C.W. (1973) Bruceantin, a new potent antileukemic 

simaroubolide from Brucea antidysenterica. J. Org. Chem. 38(1), 178–9. 

Lu, J.B., Shu, S.Y. and Cai, J.Q. (1994) Experimental study on effect of Brucea javanica oil emulsion on rabbit 

intracranial pressure. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 14(10), 610–1. 

Ohnishi, S., Fukamiya, N., Okano, M., Tagahara, K. and Lee, K.H. (1995) Bruceosides D, E, and F, three 

new cytotoxic quassinoid glucosides from Brucea javanica. J. Nat. Prod. 58(7), 1032–8. 

Okano, M., Lee, K.H. and Hall, I.H. (1981) Antitumor agents. 39. Bruceantinoside-A and -B, novel antileukemic 

quassinoid glucosides from Brucea antidysenterica. J. Nat. Prod. 44(4), 470–4. 

Phillipson, J.D. and Darwish, F.A. (1981) Bruceolides from Filjian Brucea javanica. Planta Med. 41(3), 

209–20. 

Phillipson, J.D. and Darwish, A. (1979) TLX-5 lymphoma cells in rapid screening for cytotoxicity in 

Brucea extracts. Planta Med. 35(4), 308–15. 

Sakaki, T., Yoshimura, S., Tsuyuki, T., Takahashi, T. and Honda, T. (1986) Yadanzioside P, a new antileukemic 

quassinoid glycoside from Brucea javanica (L.) Merr with the 3-O-(beta-Dglucopyranosyl)bruceantin 

structure. Chem. Pharm. Bull. (Tokyo) 34(10), 4447–50. 

Toyota, T., Fukamiya, N., Okano, M., Tagahara, K., Chang, J.J. and Lee, K.H. (1990) Antitumor agents, 

118. The isolation and characterization of bruceanic acid A, its methyl ester, and the new bruceanic acids 

B, C, and D, from Brucea antidysenterica. J. Nat. Prod. 53(6), 1526–32. 

Wang, Z.Q. (1992) Combined therapy of brain metastasis in lung cancer. Chung Kuo Chung Hsi I Chieh Ho 

Tsa Chih. 12(10), 609–10. 

Xuan, Y.B., Yasuda, S., Shimada, K., Nagai, S. and Ishihama, H. (1994) Growth inhibition of the emulsion 

from to Brucea javanica cultured human carcinoma cells. Gan To Kagaku Ryoho. 21(14), 2421–5.


Bursera simaruba (Bursera) 

Cytotoxic 

(Burseraceae) 

Antitumor 

Location: Central and northern South America. 


Stem: 6–17m high, with reddish bark that reveal a smooth and sinuous gray underbark, thick 

trunk, large irregular branches. 

Leaves: 10–28cm long with 3–7 oval or elliptic leaflets, each 2,5–5cm long. 

Flowers: small, inconspicuous, with 3–5 greenish petals, blooming in elongate racemes. 

In bloom: Winter. 

Part used: stem, leaves. 

Active ingredients (lignans): deoxypodophyllotoxin, beta-peltatin methyl ether, picro-beta-peltatin methyl 

ether and dehydro-beta-peltatin methyl ether. 


● lymphocytic leukemia, human epidermoid carcinoma of the nasopharynx. 

● Lignans: deoxypodophyllotoxin (KB, PS test systems), 5- desmethoxydeoxypodophyllotoxin 

(morelensin) (KB test system). 

● Sapelins A and B: PS system. 



● 

The stem of Bursera permollis contains four cytotoxic lignans: deoxypodophyllotoxin, 

beta-peltatin methyl ether, picro-beta-peltatin methyl ether and dehydro-betapeltatin 

methyl ether (Wickramaratne et al., 1995). Deoxypodophyllotoxin and 

another lignan, 5-desmethoxydeoxypodophyllotoxin, were also isolated from the 

Figure 3.8 Bursera.


● 

● 

● 

dried exudate of B. morelensis ( Jolad et al., 1977b), B. microphylla also contains 

deoxypodophyllotoxin (Bianchi et al., 1968). 

The leaves of B. klugii contain non-polar substances, such as sapelins A and B, which 

showed activity against two test systems, the P-388 lymphocytic leukemia (3PS) and 

the human epidermoid carcinoma of the nasopharynx (9KB) ( Jolad et al., 1977a). 

The isolation and identification from Burseraceae are reported. 

The existence of lignans with antitumor activity in B. schlechtendalii has been reported 

(McDoniel et al., 1972). 

References 

Bianchi, E., Caldwell, M.E. and Cole, J.R. (1968) Antitumor agents from Bursera microphylla (Burseraceae) I. 

Isolation and characterization of deoxypodophyllotoxin. J. Pharm. Sci. 57(4), 696–7. 

Jolad, S.D., Wiedhopf, R.M. and Cole, J.R. (1977a) Cytotoxic agents from Bursera klugii (Burseraceae) I: 

isolation of sapelins A and B. J. Pharm. Sci. 66(6), 889–90. 

Jolad, S.D., Wiedhopf, R.M. and Cole, J.R. (1977b) Cytotoxic agents from Bursera morelensis (Burseraceae): 

deoxypodophyllotoxin and a new lignan, 5-desmethoxydeoxypodophyllotoxin. J. Pharm. Sci. 66(6), 892–3. 

McDoniel, P.B. and Cole, J.R. (1972) Antitumor activity of Bursera schlechtendalii (Burseraceae): isolation 

and structure determination of two new lignans. J. Pharm. Sci. 61(12), 1992–4. 

Wickramaratne, D.B., Mar, W., Chai, H., Castillo, J.J., Farnsworth, N.R., Soejarto, D.D., Cordell, G.A., 

Pezzuto, J.M. and Kinghorn, A.D. (1995) Cytotoxic constituents of Bursera permollis. Planta Med. 61(1), 

80–1. 

Cassia acutifolia (Cassia, Senna) (Leguminosae) 

Cytotoxic 

Location: Egypt, Nubia, Arabia and Sennar. 

Appearance 

Stem: erect, smooth, pale green with long spreading branches, 0.70m high. 

Leaves: bearing leaflets in four or five pairs, 1inch long, lanceolate or obovate, brittle, grayishgreen, 

of a faint, peculiar odor and mucilaginous, sweetish taste. 

Flowers: small, yellow. 

Parts used: dried leaflets, pods. 

Active ingredients (Bitetrahydroanthracene derivative): torosaol-III, Pyranosides, Polysaccharides, 

Piperidine. 

Documented target cancers: KB cells, solid Sarcoma-180 (mice). 


It has been found that contains Related compounds that are cytotoxic and DNA damaging. 


● Cassia torosa Cav.: The flowers contain torosaol-III, physcion, 5,7-physcionanthronephyscion, 

5,7-biphyscion, torosanin-9,10-quinone, 5,7-dihydroxy-chromone, naringenin and


● 

● 

chrysoeriol. Dimeric tetrahydroanthracenes exhibited cytotoxic activity against KB cells 

in the tissue culture (Kitanaka et al., 1994). 

Cassia angustifolia L.: The leaves contain water-soluble polysaccharides, including 

L-rhamnose, L-arabinose, D-galactose, D-galacturonic acid and derivatives thereof, exhibiting 

activity against the solid Sarcoma-180 in CD1 mice (Muller et al., 1987). 

Cassia leptophylla contains the DNA-damaging compound piperidine. 

References 

Kitanaka, S. and Takido, M. (1994) Bitetrahydroanthracenes from flowers of Cassia torosa Cav. Chem. 

Pharm. Bull. (Tokyo) 42(12), 2588–90. 

Kwon, B.M., Lee, S.H., Choi, S.U., Park, S.H., Lee, C.O., Cho, Y.K., Sung, N.D. and Bok, S.H. (1998) 

Synthesis and in vitro cytotoxicity of cinnamaldehydes to human solid tumor cells. Arch. Pharm. Res. 

21(2), 147–52. 

Lee, C.W., Hong, D.H., Han, S.B., Park, S.H., Kim, H.K., Kwon, B.M. and Kim, H.M. (1999) 

Inhibition of human tumor growth by 2-hydroxy- and 2-benzoyloxycinnamaldehydes. Planta Med. 

65(3), 263–6. 

Messana, I., Ferrari, F., Cavalcanti, M.S. and Morace, G. (1991) An anthraquinone and three 

naphthopyrone derivatives from Cassia pudibunda. Phytochemistry 30(2), 708–10. 

Muller, B.M., Kraus, J. and Franz, G. (1989) Chemical structure and biological activity of water-soluble 

polysaccharides from Cassia angustifolia leaves. Planta Med. 55(6), 536–9. 

Chelidonium majus L. (Chelodonium, Celandine) Immunomodulatory 

(Papaveraceae) 

Location: found by old walls, on waste ground and in hedges, nearly always in the neighborhood 

of human habitations. 

Appearance 

Stem: slender, round and slightly hairy, 0.5–1m high, much branched. 

Root: thick, fleshy. 

Leaves: yellowish-green, much paler, almost grayish below, graceful in form and slightly hairy, 

15–30cm long, 5–7.5cm wide, deeply divided as far as the central rib, so as to form usually two 

pairs of opposite leaflets with rounded teeth edges. 

Flowers: arranged at the ends of the stems in loose umbels. 

In bloom: summer. 

Tradition: It was used as a drug plant since the Middle Ages and Dioscorides and Pliny mention 

it. It was used to take away specks from the eye and to stop incipient suffusions. It is useful, also, 

as alterative, diuretic, purgative, in jaundice, eczema and scrofulous diseases. 

Part used: the whole herb. 

Active ingredients (Alkaloids): chelidonine and its semisynthetic compound; Tris(2-([5bS- 

(5ba,6b,12ba)])-5b,6,7,12b,13,14-Hexahydro-13-methyl )([1,3]-benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i] 

phenanthridinium-6-ol-Ethaneaminyl ) Phosphinesulfide 6HCl (Ukrain).


Particular value: Although Ukrain, of high concentrations is cytostatic for malignant cells and 

may suppress the growth of cancer, is not cytostatic of normal concentrations. 


● 

● 

Every second day in a dose of 10mg per injection. Each patient receives 300mg of the drug 

(30 injections). 

In lung cancer it is used in an intravenous injection every three days. One course consisted 

of 10 applications of 10mg each. 

Documented target cancers: It has been reported that the herb extract of Chelidonium majus 

showed preventive effects on glandular stomach tumor development in rats treated with 

N-methyl-N-nitro-N nitrosoguanidine (MNNG) and hypertonic sodium chloride. The incidence 

of forestomach neoplastic lesions (papillomas and squamous cell carcinomas) also showed a tendency 

to decrease with the herbal extract treatment (Bruller, 1992). 



● 

Ukrain, is a semi-synthetic thiophosphoric acid compound of alkaloid chelidonine 

isolated from Chelidonium majus L. Its full chemical name is Tris(2-([5bS- 

(5ba,6b,12ba)])-5b,6,7,12b,13,14-Hexahydro-13-methyl]([1,3]-benzodioxolo[5,6-c]- 

1,3-dioxolo[4,5-i]phenanthridinium-6-ol-Ethaneaminyl) Phosphinesulfide 6HCl. Ukrain 

causes a regression of tumors and metastases in many oncological patients. More than 

400 documented patients with various carcinomas in different stages of development 

have been treated with Ukrain. J.W. Nowicky produced Ukrain for the first time in 

1978. (Austrian Patent No. 354644, Vienna, January 25, 1980.) Ukrain can be 

immunologically effective in lung cancer patients and can improve human cellular 

response (Nowicky et al., 1991). 


● Ukrain was applied as an i.v. injection every three days on nine men (aged 42–68 

years, mean 57 years) with histologically proven lung cancer, previously untreated. 

One course consisted of 10 applications of 10mg each. The treatment was generally 

well tolerated. The results showed an increase in the proportion of total T-cells, and 

a significant decrease in the percentage of T-suppressor cells. There were no signs of 

activation of NK, T-helper and B-cells. The restoration of cellular immunity was 

accompanied by an improvement in the clinical course of the disease. This effect was 

particularly pronounced in patients who responded to further chemotherapy. 

Objective tumor regression was seen in 44.4% of treated patients. Four out of nine 

patients (44.4%) died of progressive disease during the course of this study 

(Staniszewski et al., 1992).


● 

● 

● 

Thirty-six stage III cancer patients were treated with Ukrain. The drug was injected 

intravenously every second day in a dose of 10mg per injection. Each patient received 

300mg of the drug (30 injections). The cytostatic effect of Ukrain was monitored clinically 

and by ultrasonography (USG) and computer tomography (CT), as well as by 

determination of CEA and CA-125 in the sera of patients with rectal and ovarian cancers, 

respectively. The influence of Ukrain on immune parameters was evaluated by 

monoclonal antibodies (MAb) to CD2, CD4, CD8 and CD22. The influence of Ukrain 

on immune parameters in cancer patients was matched with its effect on these parameters 

in 20 healthy volunteer controls. The results obtained indicate that Ukrain, in a 

concentration not cytostatic in normal cells, is cytostatic for malignant ones, may 

suppress the growth of cancer. The compound also has immunoregulatory properties, 

regulating the T lymphocyte subsets (Steinacker et al., 1996). 

The effect of Ukrain on the growth of Balb/c syngenic mammary adenocarcinoma was 

assessed. Intravenous, but not subcutaneous or intraperitoneal, administration of this 

drug was found to be effective in delaying tumor growth in an actual therapeutic protocol 

initiated five days after tumor implantation. No untoward side effects were 

observed using these in vivo treatment modalities. Ukrain’s in vivo effects against the 

development of mammary tumors may be due, at least in part, to its ability to restore 

macrophage cytolytic function. 

Ukrain is an effective biological response modifier augmenting, by up to 48-fold, 

the lytic activity of splenic lymphocytes obtained from alloimmunized mice. The 

lytic activities of IL-2-treated spleen cells and peritoneal exudate lymphocytes were 

also significantly increased by the addition of Ukrain to the cell mediated lysis 

(CML) assay medium. The highest Ukrain-induced enhancement of splenic lymphocytolytic 

activity in vitro was found to occur at day 18 after alloimmunization 

was dose-dependent and specific for the immunizing P815 tumor cells. Since 

Ukrain was present only during the CML assays, its mode of action is thought to 

be via direct activation of the effector cells’ lytic mechanism(s). The effect of 

Ukrain on the growth of Balb/c syngenic mammary adenocarcinoma was also evaluated. 

Intravenous, but not subcutaneous or intraperitoneal, administration of this 

drug was found to be effective in delaying tumor growth in an actual therapeutic 

protocol initiated five days after tumor implantation. No deleterious side effects 

were observed using these in vivo treatment modalities. The role of macrophages in 

the observed retardation of tumor development was investigated, using PEM in 

cytotoxicity assays. Previous studies showed that PEM of mammary tumor-bearing 

mice lose their capacity to kill a variety of tumor target cells including the in vitro 

cultured homologous tumour cells (DA-3). Pretreatment of PEM from normal 

mice with 2.5 M Ukrain for 24h, followed by stimulation with either IFN- or 

with LPS plus IFN- enhanced their cytotoxic activity. Treatment of PEM from 

tumour-bearing mice with 2.5 M Ukrain and LPS results in a reversal of their 

defective cytotoxic response against DA-3 target cells. Furthermore, Ukrain alone, 

in the absence of a secondary signal, induced the activation of tumoricidal function 

of PEM from tumor-bearing, but not from normal, mice. These data indicate that 

Ukrain’s in vivo effects against the development of mammary tumors may be due, 

at least in part, to its ability to restore macrophage cytolytic function (Sotomayor 

et al., 1992).



● 

For the treatment of AIDS patients with Kaposi’s sarcoma, Ukrain was injected i.v. 

in the dose of 5mg every other day for a total of 10 injections. During treatment the 

Kaposi’s sarcoma lesions diminished in size, showed decoloration and no lesion 

appeared in the 30-day interval after the beginning of treatment. Both patients tolerated 

Ukrain well and showed an improved immunohematological status: an 

increase in total leukocytes, T-lymphocytes and T-suppressor numbers. In one case 

T-helper lymphocytes were also increased (Voltchek et al., 1996). 

References 

Bruller, W. (1992) Studies concerning the effect of Ukrain in vivo and in vitro. Drugs Exp. Clin. Res. 

18, 13–6. 

Ciebiada, I., Korczak, E., Nowicky, J.W. and Denys, A. (1996a) Estimation of direct influence of Ukrain 

preparation on influenza viruses and the bacteria E. coli and S. aureus. Drugs Exp. Clin. Res. 22(3–5), 

219–23. 

Ciebiada, I., Korczak, E., Nowicky, J.W. and Denys, A. (1996b) Does the Ukrain preparation protect mice 

against lethal doses of bacteria Drugs Exp. Clin. Res. 22(3–5), 207–11. 

Ebermann, R., Alth, G., Kreitner, M. and Kubin, A. (1996) Natural products derived from plants as 

potential drugs for the photodynamic destruction of tumor cells. J. Photochem., Photobiol. B. 36(2), 95–7. 

Kim, D.J., Ahn, B., Han, B.S. and Tsuda, H. (1997) Potential preventive effects of Chelidonium majis 

L. (Papaveraceae) herb extract on glandular stomach tumor development in rats treated with 

N-methyl-N-nitro-N nitrosoguanidine (MNNG) and hypertonic sodium chloride. Cancer Lett. 

112(2), 203–8. 

Liepins, A. and Nowicky, J.W. (1996) Modulation of immune effector cell cytolytic activity and tumour 

growth inhibition in vivo by Ukrain (NSC 631570). Drugs Exp. Clin. Res. 22(3–5), 103–13. 

Liepins, A. and Nowicky, J.W. (1992) Activation of spleen cell lytic activity by the alkaloid thiophosphoric 

acid derivative: Ukrain. Int. J. Immunopharmacol. 14(8), 1437–42. 

Lohninger, A. and Hamler, F. (1992) Chelidonium majus L. (Ukrain) in the treatment of cancer patients. 

Drugs Exp. Clin. Res. 18, 73–7. 

Malaveille, C., Friesen, M., Camus, A.M., Garren, L., Hautefeuille, A., Bereziat, J.C., Ghadirian, P., 

Day, N.E. and Bartsch, H. (1982) Mutagens produced by the pyrolysis of opium and its alkaloids as possible 

risk factors in cancer of the bladder and oesophagus. Carcinogenesis 3(5), 577–85. 

Nowicky, J.W., Manolakis, G., Meijer, D., Vatanasapt, V. and Brzosko, W.J. (1992) Ukrain both as an anticancer 

and immunoregulatory agent. Drugs Exp. Clin. Res. 18, 51–4. 

Nowicky, J.W., Staniszewski, A., Zbroja-Sontag, W., Slesak, B., Nowicky, W. and Hiesmayr, W. (1991) 

Evaluation of thiophosphoric acid alkaloid derivatives from Chelidonium majus L. (“Ukrain”) as an 

immunostimulant in patients with various carcinomas. Drugs Exp. Clin. Res. 17(2), 139–43. 

Ranadive, K.J., Gothoskar, S.V. and Tezabwala, B.U. (1973) Testing carcinogenicity of contaminants in 

edible oils. II. Argemone oil in mustard oil. Indian J. Med. Res. 61(3), 428–34. 

Ranadive, K.J., Gothoskar, S.V. and Tezabwala, B.U. (1972) Carcinogenicity of contaminants in indigenous 

edible oils. Int. J. Cancer. 10(3), 652–66. 

Shi, G.Z. (1992) Blockage of Glyrrhiza uralensis and Chelidonium majus in MNNG induced cancer and 

mutagenesis. Chung Hua Yu Fang I Hsueh Tsa Chih. 26(3), 165–7. 

Sotomayor, E.M., Rao, K., Lopez, D.M. and Liepins, A. (1992) Enhancement of macrophage tumouricidal 

activity by the alkaloid derivative Ukrain. In vitro and in vivo studies. Drugs Exp. Clin. Res. 18, 

5–11.


Slesak, B., Nowicky, J.W. and Harlozinska, A. (1992) In vitro effects of Chelidonium majus L. alkaloid thiophosphoric 

acid conjugates (Ukrain) on the phenotype of normal human lymphocytes. Drugs Exp. Clin. 

Res. 18, 17–21. 

Staniszewski, A., Slesak, B., Kolodziej, J., Harlozinska-Szmyrka, A. and Nowicky, J.W. (1992) 

Lymphocyte subsets in patients with lung cancer treated with thiophosphoric acid alkaloid derivatives 

from Chelidonium majus L. (Ukrain). Drugs Exp. Clin. Res. 18, 63–7. 

Steinacker, J., Kroiss, T., Korsh, O.B. and Melnyk, A. (1996) Ukrain therapy in a frontal anaplastic grade 

III astrocytoma (case report). Drugs Exp. Clin. Res. 22(3–5), 275–7. 

Voltchek, I.V., Liepins, A., Nowicky, J.W. and Brzosko, W.J. (1996) Potential therapeutic efficacy of 

Ukrain (NSC 631570) in AIDS patients with Kaposi’s sarcoma. Drugs Exp. Clin. Res. 22(3–5), 283–6. 

Xian, M.S., Hayashi, K., Lu, J.P. and Awai, M. (1989) Efficacy of traditional Chinese herbs on squamous 

cell carcinoma of the esophagus: histopathologic analysis of 240 cases. Acta Med. Okayama. 43(6), 

345–51. 

Cinnamomum camphora (Cinnamomum, Cytotoxic Immunomodulator 

Camphor tree) (Lauraceae) 

Location: East Asia. It can be found in most sub-tropical countries, as it can be cultivated successfully 

there. 


Stem: 20–40m, many branched, evergreen. 

Leaves: evergreen with oval oblong blades. 

Flowers: white, small and clustered. 

In bloom: Spring. 

Tradition: Chinese use the camphor oil exudes in the process of extracting camphor for many 

centuries. It was mentioned by Marko Polo in the thirteenth century and Camoens in 1571, who 

called it the “balsam of disease”. Very useful in complaints of stomach and bowels, in spasmodic 

cholera and flatulent colic. 

Part used: gum. 

Active ingredients (Cinnamaldehydes): 2-Hydroxycinnamaldehyde (HCA) and 2-benzoxy-cinnamaldehyde 

(BCA). 

Precautions: In large doses it is very poisonous. Should be used cautiously in certain heart 

disease. 

Documented target cancers: Human cancer cells lines, SW-620 human tumor xenograft. 



● The species are cytotoxic (the key functional group of the cinnamaldehyde-related 

compounds in the antitumor activity is the propenal group) (Ling and Liu, 1996). 

● Immunomodulation is effected due to the inhibition of farnesyl protein transferase. 

RAS activation, which is accompanied with its farnesylation, has been known to be


Figure 3.9 Cinnamomum camphora. 

important in immune cell activation as well as in carcinogenesis. Extracts inhibit the 

lymphoproliferation and induce a T-cell differentiation through the blockade of early 

steps in signaling pathway leading to cell growth. 


● 

Cinnamomum cassia Blume (Lauraceae): the bark contains 2-hydroxycinnamaldehyde 

which reacts with benzoyl chloride in order to give 2-benzoyloxycinnamaldehyde


(Lee et al., 1999). Both compounds strongly inhibited in vitro growth of 29 kinds of 

human cancer cells and in vivo growth of SW-620 human tumor xenograft without 

the loss of body weight in nude mice. 


● 

Two kinds of cinnamaldehyde derivative, HCA and BCA, were studied for their 

immunomodulatory effects. These compounds were screened as anticancer drug 

candidates from stem bark of Cinnamomum cassia for their inhibitory effect on activity 

(Lee et al., 1999). Treatment of these cinnamaldehydes to mouse splenocyte cultures 

induced suppression of lymphoproliferation following both Con A and LPS 

stimulation in a dose-dependent manner. A dose of 1M of HCA and BCA inhibited 

the Con A-stimulated proliferation by 69% and 60%, and the LPS-induced 

proliferation by 29% and 21%, respectively. However, the proliferation induced by 

PMA plus ionomycin was affected by neither HCA nor BCA treatment. Decreased 

levels of antibody production by HCA or BCA treatment were observed in both 

SRBC-immunized mice and LPS-stimulated splenocyte cultures. The exposure of 

thymocytes to HCA or BCA for 48h accelerated T-cell differentiation from CD4 and 

CD8 double positive cells to CD4 or CD8 single positive cells. The inhibitory effect 

of cinnamaldehyde on lymphoproliferation was specific to the early phase of cell 

activation, showing the strongest inhibition of Con A- or LPS-stimulated proliferation 

when added concomitantly with the mitogens. In addition, the treatment of 

HCA and BCA to splenocyte cultures attenuated the Con A-triggered progression of 

cell cycle at G 1 phase with no inhibition of S–G 2 /M phase transition. Although 

cinnamaldehyde treatment had no effect on the IL-2 production by splenocyte cultures 

stimulated with Con A, it inhibited markedly and dose-dependently the 

expression of IL-2R and IFN-. Taken together, the results in this study suggest 

both HCA and BCA. 

References 

Balachandran, B. and Sivaramkrishnan, V.M. (1995) Induction of tumours by Indian dietary constituents. 

Indian J. Cancer 32(3), 104–9. 

Chen, C.H., Yang, S.W. and Shen, Y.C. (1995) New steroid acids from Antrodia cinnamomea, a fungal 

parasite of Cinnamomum micranthum. J. Nat. Prod. 58(11), 1655–61. 

Choi, J., Lee, K.T., Ka, H., Jung, W.T., Jung, H.J. and Park, H.J. (2001) Constituents of the essential oil 

of the Cinnamomum cassia stem bark and the biological properties. Arch Pharm Res. 24(5), 418–23. 

Haranaka, R., Hasegawa, R., Nakagawa, S., Sakurai, A., Satomi, N. and Haranaka, K. (1988) Antitumor 

activity of combination therapy with traditional Chinese medicine and OK432 or MMC. J. Biol. 

Response. Mod. 7(1), 77–90. 

Haranaka, K. Satomi, N., Sakurai, A., Haranaka, R., Okada, N. and Kobayashi, M. (1985) Antitumor 

activities and tumor necrosis factor producibility of traditional Chinese medicines and crude drugs. 

Cancer Immunol. Immunother. 20(1), 1–5. 

Ikawati, Z., Wahyuono, S. and Maeyama, K. (2001) Screening of several Indonesian medicinal plants for 

their inhibitory effect on histamine release from RBL-2H3 cells. J. Ethnopharmacol. 75(2–3), 249–56. 

Kwon, B.M., Lee, S.H., Choi, S.U., Park, S.H., Lee, C.O., Cho, Y.K., Sung, N.D. and Bok, S.H. (1998) 

Synthesis and in vitro cytotoxicity of cinnamaldehydes to human solid tumor cells. Arch. Pharm. Res. 

21(2), 147–52.


Lee, C.W., Hong, D.H., Han, S.B., Park, S.H., Kim, H.K., Kwon, B.M. and Kim, H.M. (1999) Inhibition 

of human tumor growth by 2-hydroxy- and 2-benzoyloxycinnamaldehydes. Planta Med. 65(3), 263–6. 

Ling, J. and Liu, W.Y. (1996) Cytotoxicity of two new ribosome-inactivating proteins, cinnamomin and 

camphorin, to carcinoma cells. Cell Biochem. Funct. 14(3), 157–61. 

Mihail, R.C. (1992) Oral leukoplakia caused by cinnamon food allergy. J. Otolaryngol. 21(5), 366–7. 

Sakamoto, S., Yoshino, H., Shirahata, Y., Shimodairo, K. and Okamoto, R. (1992) Pharmacotherapeutic 

effects of kuei-chih-fu-ling-wan (keishi-bukuryo-gan) on human uterine myomas. Am. J. Chin. Med. 

20(3–4), 313–7. 

Sedghizadeh, P.P. and Allen, C.M. (2002) White plaque of the lateral tongue. J. Contemp. Dent. Pract. 15, 

3(3), 46–50. 

Westra, W.H., McMurray, J.S., Califano, J., Flint, P.W. and Corio, R.L. (1998) Squamous cell carcinoma 

of the tongue associated with cinnamon gum use: a case report. Head Neck 20(5), 430–3. 



drugs. Methods Find Exp. Clin. Pharmacol. 14(9), 725–36. Review. 

Chrysanthemum 

See in Glycyrriza under Further details. 

Colchicum autumnale (Meadow saffron) (Liliaceae) 

Cytotoxic 

Synonyms: Autumn Crocus, Naked Ladies. 

Location: In Southern and Central Europe, in meadows and deciduous woods. 

Appearance 

Root: scaly corm, up to 7cm. 

Leaves: basal, linear-lanceolate, up to 40cm long. 

Flowers: long-tubed purple or white, directly emerging from the underground corm. They share 

a resemblance to the flowers of Crocus sativus, but they possess 6 anthers. 

Fruit: oval capsule. 

In bloom: August–October. 

Tradition: Considered to be the Hermodactyls of the Arabians, it has been used against rheumatism 

and gout. 

Part used: Root, seeds. 

Active ingredients: colchicine (alkaloid) and related compounds, such as thiocolchicine and thioketones. 

Particular value: It is used as anti-rheumatic, cathartic, emetic. 

Precautions: Extremely poisonous. Colchicine acts upon all secretive organs, such as the bowels 

and kidneys. 


● Colchicine and several of its analogues show good antitumor effect in mice infected with 

P388 lymphocytic leukemia (Kupchan et al., 1973). 

● High antitubulin effects of derivatives of 3-demethylthiocolchicine, methylthio ethers of 

natural colchicinoids and thioketones derived from thiocolchicine (Muzaffar et al., 1990). 

● Treatment of esophageal cancer with colchamine (Vitkin, 1969).




● 

● 

Colchicum autumnale: It is also, considered to have cytostatic effects bibliography. 

Colchicine can cause induction of chromosome (loss and gain): The fruit fly Drosophila 

melanogaster is one of the standard systems used for mutagen screening. The 

colchicine-containing drugs Colchicum-Dispert and Colchysat Burger were fed at 

extremely low concentrations (1:300000 and 1:50 000 respectively) to Drosophila 

females. Among their offspring a remarkably high frequency of aneuploid individuals 

(XO and XXY flies) were found. These aneuploids correspond karyotypically to the 

human Ullrich-Turner (XO) and Klinefelter’s (XXY) syndromes and result from 

chromosome loss (XO) and chromosome gain (XXY). The maximum aneuploidy frequency 

observed after colchicine feeding was 24 times the control value. Depending 

on their size the aneuploidy frequencies are as great as those obtained by X-rayirradiation 

with some hundred or some thousand R (Traut and Sommer, 1976). 


● 

Esterification of the phenolic group in 3-demethylthiocolchicine and exchange of the 

N-acetyl group with other N-acyl groups or a N-carbalkoxy group afforded many 

compounds which showed superior activity over the parent drug as inhibitors of tubulin 

polymerization and of the growth of L1210 murine leukemia cells in culture 

(Muzaffar et al., 1990). A comparison of naturally occurring colchicum alkaloids with 

thio isosters, obtained by replacing the OMe group at C(10) with a SCH3 group, 

showed the thio ethers to be invariably more potent in these assays. The comparison 

included 3-demethylthiodemecolcine prepared from 3-demethylthiocolchicine by 

partial synthesis. Thiation of thiocolchicine with Lawesson’s reagent afforded novel 

thiotropolones which exhibited high antitubulin activity. Their structures are fully 

secured by spectral data. Colchicine and several of its analogues show good antitumor 

effect in mice infected with P388 lymphocytic leukemia, and all of them show high 

affinity for tubulin and inhibit tubulin polymerization at low concentration (Muzaffar 

et al., 1990). Consequently, antitubulin assays with this class of compounds can serve 

as valuable prescreens for the initial evaluation of potential antitumor drugs. 


● 

Colchicum speciosum: It concerns as a tumor inhibitor, with anti-leukemic activity 

(Kupchan et al., 1973). 

References 

Brncic, N., Viskovic, I., Peric, R., Dirlic, A., Vitezic, D. and Cuculic, D. (2001) Accidental plant poisoning 

with Colchicum autumnale: report of two cases. Croat. Med. J. 42(6), 673–5. 

Danel, V.C., Wiart, J.F., Hardy, G.A., Vincent, F.H. and Houdret, N.M. (2001) Self-poisoning with 

Colchicum autumnale L. flowers. J. Toxicol. Clin. Toxicol. 39(4), 409–11. 

Haupt, H. (1996) Toxic and less toxic plants 29 Kinderkrankenschwester 15(9), 337–8.


Klintschar, M., Beham-Schmidt, C., Radner, H., Henning, G. and Roll, P. (1999) Colchicine poisoning by 

accidental ingestion of meadow saffron (Colchicum autumnale): pathological and medicolegal aspects. 

Forensic. Sci. Int. 20, 106, (3), 191–200. 

Kupchan, S.M., Britton, R.W., Chiang, C.K., NoyanAlpan, N. and Ziegler, M.F. (1973) Tumor inhibitors. 

88. The antileukemia principles of Colchicum speciosum. Lloydia, 36(3), 338–40. 

Lindholm, P., Gullbo, J., Claeson P., Goransson, U., Johansson, S., Backlund, A., Larsson, R. and Bohlin, L. 

(2002) Selective cytotoxicity evaluation in anticancer drug screening of fractionated plant extracts. J. Biomol. 

Screen. 7(4), 333–40. 

Muzaffar, A., Brossi, A., Lin, C.M. and Hamel, E. (1990) Antitubulin effects of derivatives of 

3-demethylthiocolchicine, methylthio ethers of natural colchicinoids, and thioketones derived from 

thiocolchicine. Comparison with colchicinoids. J. Med. Chem. 33(2), 567–71. 

Rueffer, M. and Zenk, M.H. (1998) Microsome-mediated transformation of O-methylandrocymbine to 

demecolcine and colchicine. FEBS Lett. 30, 438 (1–2), 111–3. 

Schrader, A., Schulz, O., Volker, H. and Puls, H. (2001) Recent plant poisoning in ruminants of northern 

and eastern Germany. Communication from the practice for the practice Berl Munch Tierarztl Wochenschr. 

114(5–6), 218–21. 

Traut, H. and Sommer, U. (1976) The induction of chromosome loss and gain by colchicines. MMW Munch 

Med. Wochenscr. 3, 118, (36), 1113–6. 

Van and Os, F.H. (1970) Plants with cytostatic effect Farmaco. Science 25(6), 455–83. Review. 

Vitkin, B.S. (1969) Treatment of esophageal cancer with colchamine. Vopr. Onkol. 15(11), 90–2. 

Weinberger, A. and Pinkhas, J. (1980) The history of colchicine. Korot 7(11–12), 760. 

Yamada, M., Kobayashi, Y., Furuoka, H. and Matsui, T. (2000) Comparison of enterotoxicity between 

autumn crocus (Colchicum autumnale L.) and colchicine in the guinea pig and mouse: enterotoxicity in 

the guinea pig differs from that in the mouse. J. Vet. Med. Sci. 62(8), 809–13. 

Yamada, M., Matsui, T., Kobayashi, Y., Furuoka, H., Haritani, M., Kobayashi, M. and Nakagawa, M. 

(1999) Supplementary report on experimental autumn crocus (Colchicum autumnale L.) poisoning in cattle: 

morphological evidence of apoptosis. J. Vet. Med. Sci. 61(7), 823–5. 

Yamada, M., Nakagawa, M., Haritani, M., Kobayashi, M., Furuoka, H. and Matsui, T. (1998) 

Histopathological study of experimental acute poisoning of cattle by autumn crocus (Colchicum 

autumnale L.). J. Vet. Med. Sci. 60(8), 949–52. 

Crocus sativus (Saffron) (Iridaceae) 

Cytotoxic 

Chemopreventive 

Synonyms: Crocus, Saffron Crocus, Krokos (Greek), Zaffer (Arabian). 

Location: Wild forms are found in Italy, Greece, the Balkans, Eastern Asia (mainly Iran). From 

Europe to Asia, it can be found, in meadows or (mostly) in cultivation. 

Appearance 

Root: corm. 

Leaves: short and linear, with a white-pale central nerve, up to 30cm long. 

Flowers: long-tubed pale violet, directly emerging from the underground corm, with 3 yellow 

anthers and red-orange styles, up to 10cm long. 

In bloom: September–November. 

Biology: The plant is perennial, with five forms existing in the wild state. Fruit setting requires 

cross-fertilization. Corms must not be left to grow in the same ground for too long (longer than 

three years). 

Tradition: Already known in ancient times, saffron is referred to as Karkom in the Song of 

Solomon (iv. 14). The luxury yellow dye traditionally derived from the plant has been 

mentioned in various Greek myths, along with its scent and flavor.


Part used: Flower stigmas. 

Active ingredients: crocin, crocetin, picrocrocin and safranal (carotenoids). 

Particular value: It is used as carminative, emmenagogue, diaphoretic for children and for 

chronic hemorrhage of the uterus in adults. 


● 

● 

Oral administration of 200mg/kg 1 body weight of the extract increased the life span of 

S-180, EAC, DLA tumor-bearing mice to 111.0%, 83.5% and 112.5%, respectively. The 

same extract was found to be cytotoxic to P38B, S-180, EAC and DLA tumor cells in vitro 

(potential use of saffron as an anticancer agent). 

Intraperitoneal administration of Nigella sativa (100mg/kg 1 body wt) and oral administration 

of Crocus sativus (100mg/kg 1 body wt) 30 days after subcutaneous administration 

of MCA (745nmol2 days) restricted tumor incidence to 33.3% and 10%, respectively, 

compared with 100% in MCA-treated controls. 


● 

● 

● 

● 

Crocin, safranal and picrocrocin inhibit the growth of human cancer cells in vitro (Escribano 

et al., 1996). 

Saffron extract (dimethyl-crocetin) possesses anticarcinogenic, anti-mutagenic and 

immunomodulating effects: dose-dependent cytotoxic effect to carcinoma, sarcoma and 

leukemia cells in vitro, delayed ascites tumor growth and increased the life span of the 

treated mice compared to untreated controls by 45–120%. In addition, it delayed the onset 

of papilloma growth, decreased incidence of squamous cell carcinoma and soft tissue sarcoma 

in treated mice (Salomi et al., 1991). 

Crocetin has a dose-dependent inhibitory effect on DNA and RNA synthesis in isolated 

nuclei and suppressed the activity of purified RNA polymerase II. Also, crocetin causes a 

dose-dependent inhibition of nucleic acid and protein synthesis (Abdullaev, 1994). (Cell 

lines: HeLa (cervical epitheloid carcinoma), A549 (lung adenocarcinoma) and VA13 (SV-40 

transformed fetal lung fibroblast) cells.) 

Antitumor activity against intraperitoneally transplanted sarcoma-180 (S-180), Ehrlich 

ascites carcinoma (EAC) and Dalton’s lymphoma ascites (DLA) tumors in mice (Nair et al., 

1991). 



● 

● 

Doses inducing 50% cell growth inhibition (LD 50 ) on HeLa cells were 2.3mgml 1 

for an ethanolic extract of saffron dry stigmas, 3mM for crocin, 0.8mM for safranal 

and 3mM for picrocrocin. Crocetin did not show any cytotoxic effect (Escribano 

et al., 1996). 

Cells treated with crocin exhibited wide cytoplasmic vacuole-like areas, reduced 

cytoplasm, cell shrinkage and pyknotic nuclei, suggesting apoptosis induction


● 

(Abdullaev, 1994). Considering its water-solubility and high inhibitory growth 

effect, crocin is the more promising saffron compound to be assayed as a cancer 

therapeutic agent. 

Saffron (dimethyl-crocetin) disrupts DNA–protein interactions for example, 

topoisomerases II, important for cellular DNA synthesis (significant inhibition in the 

synthesis of nucleic acids but not protein synthesis) (Abdullaev, 1994). 


● 

● 

The effects of carotenoids of Crocus sativus L. (saffron) on cell proliferation and 

differentiation of HL-60 cells have been studied and compared with those of all-trans 

retinoic acid. Results demonstrated that the doses inducing 50% inhibition of cell 

growth were 0.12M for all-trans retinoic acid (ATRA) and for carotenoids of saffron 

0.8M for dimethylcrocetin (DMCRT), 2M for crocetin (CRT) and 2M for 

crocins (CRCs). At 5M, all these compounds induced differentiation of HL-60 

cells, at 85% for ATRA, 70% for DMCRT, 50% for CRT and 48% for CRCs. In these 

experiments, leukemic cells were cultured for 5 days in the absence or in the presence 

of up to 5M ATRA or seminatural and natural carotenoids. Since retinoids have a 

potential application as chemopreventive agents in humans, their toxicity as an 

important limiting factor for their use in treatment should be extensively explored. 

The seminatural (DMCRT and CRT) and natural carotenoids (CRCs) of Crocus sativus L. 

are not provitamin A precursors and could therefore be less toxic than retinoids, even 

at high doses (Tarantilis et al., 1994). 

Topical application of Nigella sativa and Crocus sativus extracts (common food spices) 

inhibited two-stage initiation/promotion [dimethylbenz[a]anthracene (DMBA)/ 

croton oil] skin carcinogenesis in mice. A dose of 100mgkg 1 body wt of these 

extracts delayed the onset of papilloma formation and reduced the mean number of 

papillomas per mouse, respectively. The possibility that these extracts could inhibit 

the action of 20-methylcholanthrene (MCA)-induced soft tissue sarcomas was evaluated 

by studying the effect of these extracts on MCA-induced soft tissue sarcomas in 

albino mice (Salomi et al., 1991). 

References 

Abdullaev, F.I. (1994) Inhibitory effect of crocetin on intracellular nucleic acid and protein synthesis in 

malignant cells. Toxicol. Lett. 70, 2, 243–51. 

Escribano, J., Alonso, G.L., Coca-Prados, M. and Fernandez, J.A. (1996) Crocin, safranal and picrocrocin 

from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer Lett. 27, 100, 

(1–2), 23–30. 

Nair, S.C., Kurumboor, S.K. and Hasegawa, J.H. (1995) Saffron chemoprevention in biology and medicine: 

a review. Cancer Biother. 10(4), 257–64. 

Nair, S.C., Pannikar, B. and Panikkar, K.R. (1991) Antitumour activity of saffron (Crocus sativus). Cancer 

Lett. 57(2), 109–14. 

Salomi, M.J., Nair, S.C. and Panikkar, K.R. (1991) Inhibitory effects of Nigella sativa and saffron (Crocus 

sativus) on chemical carcinogenesis in mice. Nutr. Cancer. 16(1), 67–72. 

Tarantilis, P.A., Morjani, H., Polissiou, M. and Manfait, M. (1994) Inhibition of growth and induction of 

differentiation of promyelocytic leukemia (HL-60) by carotenoids from Crocus sativus L. Anticancer Res. 

14(5A), 1913–8.


Dendropanax arboreus (Dendropanax) (Araliaceae) 

Cytotoxic 

Appearance 

Stem: spines absent. 

Root: stilt roots absent. 

Leaves: spiral, not scale-like, simple, trinerved at base, coriaceous, symmetric at the base, 

palmately lobed, smooth margined. 

Flowers: bisexual, stalked, round. 


● Falcarinol, dehydrofalcarinol, diyenne, falcarindiol, dehydrofalcarindiol; and 

● two novel polyacetylenes: dendroarboreols A and B. 



The major compound responsible for the in vitro cytotoxicity was falcarinol. Several other 

known compounds were isolated and found to be cytotoxic, including dehydrofalcarinol, a 

diyenne, falcarindiol and dehydrofalcarindiol. In addition, two novel polyacetylenes, dendroarboreols 

A and B, were isolated and characterized by standard and inverse-detected NMR 

methods (Bernart et al., 1996). 

References 

Arikawa, J., Nogita, T., Murata, Y. and Kawashima, M. (1998) Contact dermatitis due to Dendropanax 

trifidus Makino. Contact Dermatitis 38(5), 291–2. 

Bernart, M.W., Cardellina, J.H., Balaschak, M.S., Alexander, M.R., Shoemaker, R.H. and Boyd, M.R. 

(1996) Cytotoxic falcarinol oxylipins from Dendropanax arboreus. J. Nat. Prod. 59(8), 748–53. 

Huang, J.Y., Liu, C.M., Qi P.L. and Liu, K.M. (1989) Studies on the antiarrhythmic effects of leaves of 

Dendropanax chevalieri (Vig.) Merr. Et Chun Zhongguo Zhong Yao Za Zhi 14(6), 367–70, 384. 

Lans, C., Harper, T., Gearges, K. and Bridgewater, E. (2001) Medicinal and ethnoveterinary remedies of 

hunters in Trinidad. BMC Complement Altern Med. 1(1)10. 

Moriarity, D.M., Huang, J., Yancey, C.A., Zhang, P., Setzer, W.N., Lawton, R.O., Bates, R.B. and Caldera, S. 

(1998) Lupeol is the cytotoxic principle in the leaf extract of Dendropanax cf. querceti. Planta Med. 64(4), 

370–2. 

Oka, K., Saito, F., Yasuhara, T. and Sugimoto, A. (1997) The major allergen of Dendropanax trifidus 

Makino. Contact Dermatitis 36(5), 252–5. 

Oka, K. and Saito, F. (1999) Allergic contact dermatitis from Dendropanax trifidus. Contact Dermatitis 41(6), 

350–1. 

Oka, K., Saito, F., Yasuhara, T. and Sugimoto, A. (1999) The allergens of Dendropanax trifidus Makino and 

Fatsia japonica Decne. et Planch. and evaluation of cross-reactions with other plants of the Araliaceae 

family. Contact Dermatitis 40(4), 209–13. 

Setzer, W.N., Green, T.J., Whitaker, K.W., Moriarity, D.M., Yancey, C.A., Lawton, R.O. and Bates, R.B. 

(1995) A cytotoxic diacetylene from Dendropanax arboreus Planta Med. 61(5), 470–1.


Eriophyllum 

See in Eupatorium under Active ingredients. 

Ervatamia divaricata (Ervatamia) (Apocynaceae) 

Cytotoxic 

Location: Southeast Asia. 

Appearance 

Stem: round, many branches, 0.5–3m. 

Leaves: single, green, the surfaces of which are smooth and with raised veins. The length is 6–15cm 

and its width is 2–4cm. 

Flowers: snow white, 1–5cm diameter, fragrant. The flower stalk protrudes from the leaves and 

bears 1 or 2 flowers. 

Part used: root, steam and leaf. 

Active ingredients: Vinca alkaloids (conophylline). 


● 

● 

● 

Conophylline inhibits the growth of K-ras-NRK cells, but this inhibition is reversible. 

The alkaloid also inhibits the growth of K-ras-NRK and K-ras-NIH3T3 tumors transplanted 

into nude mice. 

On the other hand, it shows no effect on survival of the mice loaded with L1210 leukemia. 


Other species 

● 

● 

Ervatamia heyneana: the whole plant contains unidentified factors with anticancer 

properties (Chitnis et al., 1971). 

Ervatamia microphylla contains conophylline, a vinca alkaloid, isolated from the plant 

(Umezawa et al., 1996). 

References 

Chitnis, M.P., Khandalekar, D.D., Adwankar, M.K. and Sahasrabudhe, M.B. (1971) Anticancer activity of 

the extracts of root, stem & leaf of Ervatamia heyneana. Indian J. Exp. Biol. 9(2), 268–70. 

Johnson, R.K., Chitnis, M.P., Embrey, W.M. and Gregory, E.B. (1978) In vivo characteristics of resistance 

and cross-resistance of an adriamycin-resistant subline of P388 leukemia. Cancer Treat. Rep. 62(10), 

1535–47. 

Umezawa, K., Taniguchi, T., Toi, M., Ohse, T., Tsutsumi, N., Yamamoto, T., Koyano, T. and Ishizuka, M. 

(1996) Growth inhibition of K-ras-expressing tumours by a new vinca alkaloid, conophylline, in nude 

mice. Drugs Exp. Clin. Res. 22(2), 35–40.


Eupatorium cannabinum (Agrimony (Hemp)) (Compositae) 

Synonyms: Holy Rope, St John’s Herb. 

Antitumor 

Location: Common on the banks of rivers, sides of ditches, at the base of cliffs on the seashore, 

and in other damp places in most parts of Britain and Europe. 

Appearance 

Stem: round, growing from 60 to 150cm, with short branches, reddish in color, covered with 

downy hair, woody below. 

Root: woody. 

Leaves: the root-leaves are on long stalks. The stem-leaves have only very short footstalks. All the 

leaves bear distinct, short hairs. 

Flowers: flower heads being arranged in crowded masses of a dull lilac color at the top of the stem 

or branches. Each little composite head consists of about five or six florets. 

In bloom: late in Summer and Autumn. 

Tradition: It has the reputation of being a good wound herb, whether bruised or made into an 

ointment with lard. They used it as a strong purgative and emetic, and for curing dropsy. 

Part used: herb. 


● Sesquiterpene lactones: eupatoriopicrin (EUP) (E. cannabinum), eupaserrin and deacetyleupaserrin 

(E. semiserratum), eupacunin (E. cuneifolium), lactones from E. rotundifolium. 

● -lactones: germacranolides (E. semiserratum and Eriophyllum confertiflorum). 

● Eupatolide (E. formosanum HAY) 

● Flavones: eupatorin and 5-hydroxy-3,4,6,7-tetramethoxyflavone (E. altissimum). 

Particular value: Herbalists recognize its cathartic, diuretic and anti-scorbutic properties and 

consider it a good remedy for purifying the blood. 

Precautions: Cytotoxicity. 


● Growth inhibition of the Lewis lung carcinoma and the F10 26 fibrosarcoma, was found after 

i.v. injection of 20 or 40mgkg 21 EUP (in mice C57B1), at a tumor volume of 500l. 


● Anti-leukemic: eupaserrin and deacetyleupaserrin, germacranolides, flavones. 

● Antitumor: eupatoriopicrin, eupatolide, flavones. 

● Cytotoxic: flavones. 



● 

The sesquiterpene lactone EUP from Eupatorium cannabinum L. has been shown to be 

cytotoxic in a glutathione (GSH)-dependent way, through the induction of DNA 

damage in tumor cells. The amount of EUP, requested to demonstrate DNA damage


● 

● 

after a 24h post-incubation period lay within the concentration range that was effective 

in the clonogenic assay (1–10gml 1 ). Glutathione depletion of the cells to 

about 99%, by use of buthionine sulphoximine (BSO), enhanced the extent of DNA 

damage (Woerdenbag et al., 1989). 

Germacranolides: the ,-unsaturated ester side chain adjacent to the -lactone and 

either a primary or secondary allylic alcohol or both demonstrates an in vivo antileukemic 

activity (Kupchan et al., 1978). 

Flavones showed confirmed activity in the P-388 lymphocytic leukemia assay in 

mice, and the chloroform solubles showed both cytotoxic activity in the 9KB carcinoma 

of the nasopharynx cell culture assay and antitumor activity in the P-388 lymphocytic 

leukemia assay (Dobberstein et al., 1977). 


● 

E. rotundifolium is a native of new England and Virginia. 

References 

Dobberstein, R.H., Tin-wa, M., Fong, H.H., Crane, F.A. and Farnsworth, N.R. (1977) Flavonoid constituents 

from Eupatorium altissimum L. (Compositae). J. Pharm. Sci. 66(4), 600–2. 

Elsasser-Beile, U., Willenbacher, W., Bartsch, H.H., Gallati, H., Schulte Monting, J., von Kleist, S. (1996) 

Cytokine production in leukocyte cultures during therapy with Echinacea extract. J. Clin. Lab. Anal. 

10(6), 441–5. 

Kupchan, S.M., Ashmore, J.W. and Sneden, A.T. (1978) Structure–activity relationships among in vivo 

active germacranolides. J Pharm. Sci. 67(6), 865–7. 

Kupchan, S.M., Fujita, T., Maruyama, M. and Britton, R.W. (1973) The isolation and structural elucidation 

of eupaserrin and deacetyleupaserrin, new anti-leukemic sesquiterpene lactones from Eupatorium 

semiserratum. J. Org. Chem. 38(7), 1260–4. 

Kupchan, S.M., Maruyama, M., Hemingway, R.J., Hemingway, J.C., Shibuya, S., Fujita, T., Cradwick, 

P.D., Hardy, A.D. and Sim, G.A. (1971) Eupacunin, a novel anti-leukemic sesquiterpene lactone from 

Eupatorium cuneifolium. J. Am. Chem. Soc. 93(19), 4914–6. 

Kupchan, S.M., Kelsey, J.E., Maruyama, M., Cassady, J.M., Hemingway, J.C. and Knox, J.R. (1969) 

Tumor inhibitors. XLI. Structural elucidation of tumor-inhibitory sesquiterpene lactones from 

Eupatorium rotundifolium. J. Org. Chem. 34(12), 3876–83. 

Lee, K.H., Huang, H.C., Huang, E.S. and Furukawa, H. (1972) Antitumor agents. II. Eupatolide, a new 

cytotoxic principle from Eupatorium formosanum HAY. J. Pharm. Sci. 61(4), 629–31. 

Woerdenbag, H.J., van der Linde, J.C., Kampinga, H.H., Malingre, T.M. and Konings, A.W. (1989) 

Induction of DNA damage in Ehrlich ascites tumour cells by exposure to eupatoriopicrin. Biochem. 

Pharmacol. 38(14), 2279–83. 

Woerdenbag, H.J., Lemstra, W., Malingre, T.M. and Konings, A.W. (1989) Enhanced cytostatic activity 

of the sesquiterpene lactone eupatoriopicrin by glutathione depletion. B. J. Cancer 59(1), 68–75. 

Fagara macrophylla (Fagara) (Rutaceae) 

Location: Africa. 

Part used: roots. 

Cytotoxic 

Anti-leukemic



● 

● 

Alkaloids: nitidine chloride, 6-oxynitidine, 6-methoxy-5,6-dihydronitidine (Fagara macrophylla). 

Fagaronine (Fine) (Fagara xanthoxyloides). 


● Alkaloids: nitidine chloride and 6-methoxy-5,6-dihydronitine are used at doses of 30–50mgkg 1 . 

● Fagaronine is used at a concentration of 3106moll 1 at day 4. 


● The alkaloids nitidine chloride and 6-methoxy-5,6-dihydronitine are about equipotent in P-388 

mouse leukemia, giving high T/C values of 240–260% (Wall et al., 1987). 

● Fagaronine (Fine) inhibits cell proliferation of human erythroleukemia K562 cells by 50% 

at a concentration of 310 6 moll 1 at day 4 (more informations in Further details) 

(Comoe et al., 1988). 



● 

● 

The known alkaloids nitidine chloride (1), 6-oxynitidine (2) and 6-methoxy-5,6- 

dihydronitidine (3) have been isolated from Fagara macrophylla. Compound 3 was the 

major product and was shown to be an artifact. The alkaloids 1 and 3 have been interconverted 

by treatment of 1 under basic conditions or 3 under acidic conditions. On 

sublimation 1 and 3 formed 8,9-dimethoxy-2,3-methylenedioxybenzo[c]phenanthridine 

which could then be converted to 5,6-dihydronitidine. The alkaloids 1 and 3 are about 

equipotent in P-388 mouse leukemia, giving high T/C values of 240–260% at doses 

of 30–50mgkg 1 . The other compounds were inactive. The structural requirement 

for antitumor activity in the phenanthridine series is the ability to form a C-6 

iminium ion (Wall et al., 1987). 

Fagaronine (Fine) is an anti-leukemic drug extracted from the root of Fagara 

xanthoxyloides Lam. (Rutaceae). Fine inhibits cell proliferation of human erythroleukemia 

K562 cells by 50% at a concentration of 310 6 moll 1 on day 4. It 

stimulates incorporation of labelled macromolecular thymidine on day 1, but 

decreases incorporation on days 2, 3 and 4. Fine induces a cell accumulation in G 2 

and late-S phases (Messmer et al., 1972). 

References 

Comoe, L., Carpentier, Y., Desoize, B. and Jardillier, J.C. (1988) Effect of fagaronine on cell cycle progression 

of human erythroleukemia K562 cells. Leuk. Res. 12(8), 667–72. 

Comoe, L., Kouamouo, J., Jeannesson, P., Desoize, B., Dufour, R., Yapo, E.A. and Jardillier, J.C. (1987) 

Cytotoxic effects of root extracts of Fagara zanthoxyloides Lam. (Rutaceae) on the human erythroleukemia 

K562 cell line. Ann. Pharm. Fr. 45(1),79–86.


Messmer, W.M., Tin-Wa, M., Fong, H.H., Bevelle, C., Farnsworth, N.R., Abraham, D.J. and Trojanek, J. 

(1972) Fagaronine, a new tumor inhibitor isolated from Fagara zanthoxyloides Lam. (Rutaceae). J. Pharm. 

Sci. 61(11), 1858–9. 

Wall, M.E., Wani, M.C. and Taylor, H. (1987) Plant antitumor agents, 27. Isolation, structure, and 

structure activity relationships of alkaloids from Fagara macrophylla. J. Nat. Prod. 50(6), 1095–9. 

Ficus carica L. (Ficus) (Urticaceae) 

Anti-leukemic 

Location: Indigenous to Persia, Asia Minor and Syria, wild in most of the Mediterranean 

countries. 


Stem: 6–7m high. 

Root: free from stagnant water, sheltered from cold. 

Leaves: broad, rough, deciduous, deeply lobed. 

Flowers: concealed within the body of the fruit. 

In bloom: July–August. 

Part used: Seeds, fruit. 

Active ingredients: Lectins (Ficus cunia). 

Documented target cancers: It is used for different types of leukemia (chronic myeloid leukemia, 

acute myeloblastic leukemia, acute lymphoblastic leukemia and chronic lymphocytic leukemia) 

(Agrawal et al., 1990; Guyot et al., 1986). 

Figure 3.10 Ficus carica.




● The seeds of Ficus cunia contain a lectin with a molecular weight of 3300–3500, 

which can agglutinate white blood cells (leukocytes and mononuclear cells) from 

patients with different types of leukemia (as mentioned above) (Ray et al., 1993). 


● 

● 

A lectin, isolated from the seeds of Ficus cunia and purified by affinity chromatography 

on fetuin-Sepharose, was homogeneous in PAGE, GPC, HPLC, and 

immunodiffusion, and had molecular weight of 3200–3500. In SDS-PAGE and 

HPLC in the absence and presence of 2-mercaptoethanol, the lectin gave a single 

band or peak corresponding to M(r) 3300–3500, thus indicating it to be a 

monomer. The lectin agglutinated human erythrocytes regardless of blood group, 

bound to Ehrlich ascites cells and to human rat spermatozoa, and was thermally 

stable; Ca 2 enhanced its activity. The lectin is a metalloprotein that was inactivated 

by dialysis with EDTA followed by acetic acid, but reactivated by the addition 

of Ca 2 . The lectin contained 2.0% of carbohydrates, large proportions of 

acidic amino acids, but little methionine. In hapten-inhibition assays, chitin 

oligosaccharides linked -GlcNAc] and N-acetyl-lactosamine were inhibitors of 

which N,N-tetra-acetylchitotetraose was the most potent. Among the macromolecules 

tested that contain either multiple N-acetyl-lactosamine and/or linked 

-GlcNAc, asialofetuin glycopeptide was the most potent inhibitor. Thus, an N- 

acetyl group and substitution at C-1 of D-GlcN are necessary for binding (Ray et 

al., 1993). 

Semipurified saline extracts of seeds from Crotolaria juncea, Cassia marginata, Ficus 

racemosa, Cicer arietinum (L-532), Gossipium indicum (G-27), Melia composita, Acacia 

lenticularis, Meletia ovalifolia, Acacia catechu and Peltophorum ferrenginium were tested 

for leukoagglutinating activity against whole leukocytes and mononuclear cells from 

patients with chronic myeloid leukemia, acute myeloblastic leukemia, acute 

lymphoblastic leukemia, chronic lymphocytic leukemia, various lymphoproliferative/hematologic 

disorders and normal healthy subjects. In addition, bone marrow 

cells from three patients undergoing diagnostic bone marrow aspiration and activated 

lymphocytes from mixed lymphocyte cultures (MLC) were also tested. All the seed 

extracts agglutinated white blood cells from patients with different types of 

leukemia. But none of them reacted with peripheral blood cells of normal individuals, 

patients with various lymphoproliferative/hematologic disorders or cells from 

MLC. Leukoagglutination of leukemic cells with each of the seed extracts was inhibited 

by simple sugars. Only in one instance, cells from bone marrow of an individual 

who had undergone diagnostic bone marrow aspiration for a non-malignant condition 

were agglutinated. It is felt that purification of these seed extracts may yield 

leukemia-specific lectins (Agrawal et al., 1990).

References 


Agrawal, S. and Agarwal, S.S. (1990) Preliminary observations on leukaemia specific agglutinins from 

seeds. Indian J. Med. Res. 92, 38–42. 

Guyot, M., Durgeat, M. and Morel, E. (1986) Ficulinic acid A and B, two novel cytotoxic straight-chain 

acids from the sponge Ficulina ficus. J. Nat. Prod. 49(2), 307–9. 

Peraza-Sanchez, S.R., Chai, H.B., Shin, Y.G., Santisuk, T., Reutrakul, V., Farnsworth, N.R., Cordell, G.A., 

Pezzuto, J.M. and Kinghorn, A.D. (2002) Constituents of the leaves and twigs of Ficus hispida. Planta 

Med. 68(2), 186–8. 

Ray, S., Ahmed, H., Basu, S. and Chatterjee, B.P. (1993) Purification, characterisation, and carbohydrate 

specificity of the lectin of Ficus cunia. Carbohydr. Res. 7, 242, 247–63. 

Rubnov, S., Kashman, Y., Rabinowitz, R., Schlesinger, M. and Mechoulam, R. (2001) Suppressors of cancer 

cell proliferation from fig (Ficus carica) resin: isolation and structure elucidation. J. Nat. Prod. 64(7), 993–6. 

Simon, P.N., Chaboud, A., Darbour, N., Di Pietro, A., Dumontet, C., Lurel, F., Raynaud J. and Barron, D. 

(2001) Modulation of cancer cell multidrug resistance by an extract of Ficus citrifolia. Anticancer Res. 

21(2A), 1023–7. 

Garcinia hombrioniana (Garcinia) (Guttifereae) 

Location: Riverine and coastal alluvial regions. Malaysia, Brunei. 


Stem: 10m high, numerous branches. 

Leaves: tertiary branches hold much of the leaves. 

Flowers: in clusters of not more than five small flowers. 

Cytotoxic 

Antitumor 

Tradition: Very powerful drastic hydragogue, cathartic, very useful in dropsical conditions. 

Part used: gum resin. 

Active ingredients: Garonolic acids. 

Figure 3.11 Garcinia fruit.


Precautions: Full dose is rarely given alone, as it causes vomiting, nausea and griping. In high 

dose it can cause death. 


● 

Garcinia hunburyi (Gamboge), when steam processed (0.15MPa, 126C for 30min) is cytotoxic 

on K562 tumor cells (Lu et al., 1996). 



● The technology for processing steamed Garcinia hunburyi with high pressure was 

synthetically selected by using orthogonal experimental design, based on the indexes 

of anti-inflammatory, bacteriocidal, antitumour effects and gambagic acid content. 

The result shows that the best way is to steam for 0.5h at 126C (Ye et al., 1996). 


● 

The cytotoxicity of different processed products of Gamboge on K562 tumor cell was 

observed. The result showed that the antitumor action of Garcinia hunburyi processed 

by steaming (0.15MPa, 126C for 30min) was the strongest (Lu et al., 1996). 


● 

However, there is a possibility that the Nigerian cola plant (Garcinia) may be a cause 

of human cancer in countries where kola nuts are widely consumed as stimulants (e.g. 

via chewing), because of their content of primary and secondary amines, and their 

relative methylating potential due to nitrosamide formation (Atawodi et al., 1995). 

References 

Atawodi, S.E., Mende, P., Pfundstein, B., Preussmann, R. and Spiegelhalder, B. (1995) Nitrosatable 

amines and nitrosamide formation in natural stimulants: Cola acuminata, C. nitida and Garcinia cola. Food 

Chem. Toxicol. 33(8), 625–30. 

Lu, Y., Wang, G. and Ye, D. (1996) Comparison of cytotoxicity of different processed products of gamboge 

on K562 tumor cells. Chung Kuo Chung Yao Tsa Chih. 21(2), 90–1, 127. 

Ye, D. and Kong, L. (1996) Selection of technology for processing steamed Garcinia hunburyi with high 

pressure. Chung Kuo Chung Yao Tsa Chih. 21(8), 472–3. 

Glycyrrhiza glabra L. (Glycyrrhiza, Liquorice) (Leguminosae) 

Antitumor 

Location: It can be found in Southeast Europe, Southwest Asia. It is cultured in Spain, Italy, UK 

and USA.


Appearance 

Stem: graceful, with light, spreading, pinnate foliage, presenting an almost feathery appearance 

from a distance. 

Root, double: the one part consisting of a vertical or tap root, often with several branches penetrating 

to a depth of 1–1.5m, the other of horizontal rhizomes or stolons, thrown out of the root 

below the surface of the ground. 

Leaves: leaflets. 

Flowers: from the axils of the leaves spring racemes or spikes of papilionaceous small pale blue, 

violet, yellowish-white or purplish, followed by small pods. 


Tradition: Very common in use in South Italy for stomach disorders, cough and also as a sweeter. 

Part used: root and stolons. 

Active ingredients: Glycyrrhizic acid, glycyrrhetinic acid, flavonoids, triterpenoids. 


● 

● 

Prevention, skin cancer, leukemia. 

Some triterpenoids from Glycyrrhiza spp. were effective against adriamycin (ADM)- 

resistant P-388 leukemia cells (P-388/ADM), which were resistant to multiple anticancer 

drugs (Hasegawa et al., 1995). 



● 

Glycyrrhiza uralensis is one of the main related compounds of Hua-sheng-ping 

(Chrysanthemum morifolium, Glycyrrhiza uralensis, Panax notoginseng), which has many 

medicinal uses (Yu, 1993). 


● 

Glycyrrhizic acid, the active ingredients in licorice, and its metabolite carbenoxolone are 

members of short-chain dehydrogenase reductase (SDR) enzymes. The SDR family 

includes over 50 proteins from human, mammalian, insect and bacterial sources 

(Duax et al., 1997). 


● 

Glycyrrhiza uralensis: Extracts have strong antimutagenic properties, indicated for 

syndromes such as Spleen–Stomach Asthenic Cold and has been proved to be an effective 

prescription for precancerous lesions. An important component is glycyrrhetinic 

acid, which can protect rapid DNA damage and decrease the unscheduled DNA 

synthesis induced by benzo(alpha)pyrene (Chen et al., 1994).


● 

Glycyrrhizae inflata: Extracts contain 6 flavonoids with significant antioxidant effects, 

showing anti-promoting effects on two-stage carcinogenesis in mouse skin induced 

by DMBA plus croton oil. The TPA enhanced 32P i -incorporation into phospholipid 

fraction in HeLa cells was inhibited, and the micronuclei in mouse bone marrow cells 

induced by cytoxan were also depressed (Agarwal et al., 1991). 

References 

Agarwal, R., Wang, Z.Y. and Mukhtar, H. (1991) Inhibition of mouse skin tumor-initiating activity of 

DMBA by chronic oral feeding of glycyrrhizin in drinking water. Nutr. Cancer 15(3–4), 187–93. 

Biglieri, E.G. (1995) My engagement with steroids: a review. Steroids 60(1), 52–8. 

Chen, X. and Han, R. (1995) Effect of glycyrrhetinic acid on DNA damage and unscheduled DNA 

synthesis induced by benzo(alpha)pyrene. Chin. Med. Sci J. 10(1), 16–9. 

Chen, X.G. and Han, R. (1994) Effect of glycyrrhetinic acid on DNA damage and unscheduled DNA 

synthesis induced by benzo (a) pyrene. Yao Hsueh Hsueh Pao. 29(10), 725–9. 

Duax, W.L. and Ghosh, D. (1997) Structure and function of steroid dehydrogenases involved in hypertension, 

fertility, and cancer. Steroids 62(1), 95–100. 

Fu, N., Liu, Z. and Zhang, R. (1995) Anti-promoting and anti-mutagenic actions of G9315. Chung Kuo I 

Hsueh Ko Hsueh Yuan Hsueh Pao 17(5), 349–52. 

Hasegawa, H., Sung, J.H., Matsumiya, S., Uchiyama, M., Inouye, Y., Kasai, R., Yamasaki, K. (1995) 

Reversal of daunomycin and vinblastine resistance in multidrug-resistant P388 leukemia in vitro 

through enhanced cytotoxicity by triterpenoids. Planta Med. 61(5), 409–13. 

Horn, B. (1986) Rarities in family practice. Consequences for education and continuing education. Schweiz 

Rundsch. Med. Prax. 75(44), 1323–7. 

Liu, X.R., Han, W.Q. and Sun, D.R. (1992) Treatment of intestinal metaplasia and atypical hyperplasia of 

gastric mucosa with xiao wei yan powder. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 12(10), 602–3, 580. 

Montanari, G., Zanaletti, F., Quadrelli, G.C., Di Battista, F., Ongis, G.A., Fraschini, A., Zinzalini, G. and 

Abbiati, C. (1988) Arterial hypertension with hypokalemia. Minerva Med. 79(3), 209–14. 

Shackleton, C.H. (1993) Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension 

research. J. Steroid Biochem. Mol. Biol. 45(1–3), 127–40. 

Shi, G.Z. (1992) Blockage of Glycyrrhiza uralensis and Chelidonium majus in MNNG induced cancer and 

mutagenesis. Chung Hua Yu Fang I Hsueh Tsa Chih. 26(3), 165–7. 

Takahashi, K., Yoshino, K., Shirai, T., Nishigaki, A., Araki, Y. and Kitao, M. (1988) Effect of a traditional 

herbal medicine (shakuyaku-kanzo-to) on testosterone secretion in patients with polycystic ovary 

syndrome detected by ultrasound. Nippon Sanka Fujinka Gakkai Zasshi. 40(6), 789–92. 

Yamashiki, M., Nishimura, A., Huang, X.X., Nobori, T., Sakaguchi, S. and Suzuki, H. (1997) Effects of 

the Japanese herbal medicine “Sho-saiko-to” (TJ-9) on in vitro interleukin-10 production by peripheral 

blood mononuclear cells of patients with chronic hepatitis C. Hepatology 25(6), 1390–7. 

Yu, X.Y. (1993) A prospective clinical study on reversion of 200 precancerous patients with huasheng-ping. 

Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 13(3), 147–9. 

Wang, Z.Y., Agarwal, R., Khan, W.A. and Mukhtar, H. (1992) Protection against benzo[a]pyrene- and 

N-nitrosodiethylamine-induced lung and forestomach tumorigenesis in A/J mice by water extracts of 

green tea and licorice. Carcinogenesis 13(8), 1491–4. 

White, P.C., Mune, T. and Agarwal, A.K. (1997) 11 -Hydroxysteroid dehydrogenase and the syndrome 

of apparent mineralocorticoid excess. Endocr Rev. 18(1), 135–56. 

Webb, T.E., Stromberg, P.C., Abou-Issa, H., Curley, R.W. Jr and Moeschberger, M. (1992) Effect of dietary 

soybean and licorice on the male F344 rat: an integrated study of some parameters relevant to cancer 

chemoprevention. Nutr. Cancer 18(3), 215–30.





Goniothalamus sp. (Annonaceae) 

Location: Malaysia, China. 


Cytotoxic 

● Acetogenins: gardnerilins A and B; 

● Styrylpyrone(SPD), goniodiol-7-monoacetate; 

● Acetogenin lactones: goniothalamicin, annonacin. 

Indicative dosage and application: Doses used in rat mammary tumors with good effects were: 

2, 10 and 50mgkg 1 . 

Documented target cancers: Antiestrogen (mice), breast cancer, cytotoxic, 9ASK (astrocytoma) 

and weakly active against 3PS murine leukemia. 



● 

● 

● 

Goniothalamus gardneri: the roots contain the C35 acetogenins gardnerilins A and B 

(Chen et al., 1998). 

Goniothalamus amuyon, and other Goniothalamus species contain the styrylpyrone, 

goniodiol-7-monoacetate [6R-(7R,8R-dihydro-7-acetoxy-8-hydroxystyryl)-5,6 

-dihydro-2-pyrone] (Wu et al., 1991). 

The stem bark of Goniothalamus giganteus Hook. Thomas contains the -lactone 

goniothalamicin, a tetrahydroxy-mono-tetrahydrofuran fatty acid, along with annonacin. 


● 

The estrogen antagonism: agonism ratio for SPD is much higher than Tamoxifen, 

which is indicative of the breast cancer antitumor activity as seen in compounds such 

as MER-25. Pretreatment assessment on 1mgkg 1 BW SPD and Tam showed that 

SPD is not a very good, estrogen antagonist compared to Tam, as it was unable to 

revert the estrogenicity effect of estradiol benzoate (EB) on immature rat uterine 

weight. Antitumor activity assessment for SPD exhibited significant tumor growth 

retardation in DMBA-induced rat mammary tumors at all doses employed (2, 10 and 

50mgkg 1 ) compared to the controls. This compound was found to be more potent 

than Tam (2 and 10mgkg 1 ) and displayed greater potency at a dose of 10mgkg 1 . 

It caused complete remission of 33.3% of tumors but failed to prevent onset of new 

tumors. However, SPD administration at 2mgkg 1 caused 16.7% complete


remission and partial remission. It also prevented the onset of new tumors throughout 

the experiment (Hawariah and Stanslas, 1998). 


● 

● 

Goniodiol-7-monoacetate showed potent (ED 50 values less than 0.1gml 1 ) cytotoxicities 

against KB, P-388, RPMI, and TE671 tumor cells (Wu et al., 1991). 

Goniothalamicin is cytotoxic and insecticidal and inhibits the formation of crown gall 

tumors on potato discs. Annonacin, the only other reported mono-tetrahydrofuran 

acetogenin, was also isolated, which is active against 9ASK (astrocytoma) and weakly 

active against 3PS murine leukemia (Alkofahi et al., 1988). 

References 

Alkofahi, A., Rupprecht, J.K., Smith, D.L., Chang, C.J. and McLaughlin, J.L. (1988) Goniothalamicin 

and annonacin: bioactive acetogenins from Goniothalamus giganteus (Annonaceae). Experientia 44(1), 

83–5. 

Chen, Y., Jiang, Z., Chen, R.R. and Yu, D.Q. (1998) Two linear acetogenins from Goniothalamus gardneri. 

Phytochemistry 49(5), 1317–21. 

Hawariah, A. and Stanslas, J. (1998) Antagonistic effects of styrylpyrone derivative (SPD) on 7,12- 

dimethylbenzanthracene-induced rat mammary tumors. In Vivo 12(4), 403–10. 

Wu, Y.C., Duh, C.Y., Chang, F.R., Chang, G.Y., Wang, S.K., Chang, J.J., McPhail, D.R., McPhail, A.T. 

and Lee, K.H. (1991) The crystal structure and cytotoxicity of goniodiol-7-monoacetate from 

Goniothalamus amuyon. J. Nat. Prod. 54(4), 1077–81. 

Gossypium herbaceum L. (GOSSYPIUM, Cotton root) 

(Malvaceae) 

Cytotoxic 

Location: Asia Minor, cultivated in USA. and Egypt, Mediterranean, India. 


Stem: 0.5–2m high, branching stems. 

Root: the root bark consists of thin flexible bands covered with a brownie yellow. periderm, odor 

not strong, tastes slightly acid. 

Leaves: palmate, hairy, green, lobes lanceolate and acute. 

Flowers: yellow with a purple spot in the center. 

In bloom: August–September. 

Tradition: One of the well-known Chinese medicine used as an anticancer crude drug. 

Part used: bark of root. 

Active ingredients: Catechin. 

Indicative dosage and application: It is used as crude extract, mixed with other herbs, usually 

oral intake. 

Documented target cancers: Murine B16 melanoma and L1210 lymphoma cells.


Figure 3.12 Gossypium herbaceum. 



● Gossypium indicum has a moderate antimutagenic activity against benzo[a]pyrene. Its 

aqueous–alcoholic extracts from unripe cotton balls are well known for their antitumor 

activity. The hydrophilic fractions contain certain amounts of catechin and its derivatives, 

which are responsible for the antitumor activities of the herb (Choi et al., 1998). 

References 

Choi, J.J., Yoon, K.N., Lee, S.K., Lee, Y.H., Park, J.H., Kim, W.Y., Kim, J.K. and Kim, W.K. (1998) 

Antitumor activity of the aqueous-alcoholic extracts from unripe cotton ball of Gossypium indicum. Arch 

Pharm. Res. 21(3), 266–72. 

Hoffmann, K., Kaspar, K., Gambichler, T. and Altmeyer, P. (2000) In vitro and in vivo determination of the 

UV protection factor for lightweight cotton and viscose summer fabrics: a preliminary study. J. Am. 

Acad. Dermatol. 43(6), 1009–16. 

Lee, H. and Lin, J.Y. (1988) Antimutagenic activity of extracts from anticancer drugs in Chinese medicine. 

Mutat. Res. 204(2), 229–34. 

MacFarlane, D. and Goldberg, L.H. (1999) Use of the cotton-tipped applicator in lower eyelid surgery. 

Dermatol Surg. 25(4), 326–7. 

Hannoa chlorantha (Hannoa) (Simaroubaceae) 

Anti-leukemic 

Location: Africa. 

Tradition: Hannoa chlorantha and Hannoa klaineana (Simaroubaceae) are used in traditional 

medicine of Central African countries against fevers and malaria.


Part used: stem bark, root bark. 


Quassinoids (15-desacetylundulatone), 14-hydroxychaparrinone, chaparrinone 15-O--Dglucopyranosyl-21-hydroxy-glaucarubolone 

was found to be more toxic while 6--tigloyloxyglaucarubol 

and 21-hydroxyglaucarubolone was found inactive. 

Documented target cancers: P-388 cells mouse lymphocytic leukemia, colon 38 adenocarcinoma. 



● Hannoa chlorantha and Hannoa klaineana: Apart from their documented antimalaria 

activity, stem bark extracts from H. klaineana and H. chlorantha are also cytotoxic 

against P-388 cells mouse lymphocytic leukemia cells. This activity is due to the 

presence of 14-hydroxychaparrinone (and, in a lesser degree, chaparrinone) from H. 

klaineana (Francois et al., 1998). In addition, the quassinoid 15-desacetylundulatone 

isolated from the root bark of Hannoa klaineana, was found active against P-388 and 

colon 38 adenocarcinoma, while 15-O--D-glucopyranosyl-21-hydroxyglaucarubolone 

were found to be more toxic while 6--tigloyloxy-glaucarubol and 

21-hydroxyglaucarubolone were found inactive (Francois et al., 1998). 

References 

Francois, G., Diakanamwa, C., Timperman, G., Bringmann, G., Steenackers, T., Atassi, G., Van Looveren, 

M., Holenz, J., Tassin, J.P., Assi, L.A., Vanhaelen-Fastre, R. and Vanhaelen, M. (1998) Antimalarial and 

cytotoxic potential of four quassinoids from Hannoa chlorantha and Hannoa klaineana, and their 

structure–activity relationships. Int. J. Parasitol. 28(4), 635–40. 

Lumonadio, L., Atassi, G., Vanhaelen, M. and Vanhaelen-Fastre, R. (1991) Antitumor activity of quassinoids 

from Hannoa klaineana. J. Ethnopharmacol. 31(1), 59–65. 

Polonsky, J. and Bourguignon-Zylber, N. (1965) Study of the bitter constituents of the fruit of Hannoa 

klaineana (Simarubaceae): chaparrinone and klaineanone Bull. Soc. Chim. Fr. 10, 2793–9. 

Helenium microcephalum (Sneezeweed) (Compositae) 

Cytotoxic 

Other common names: smallhead sneezeweed, red and gold sneezeweed. 

Location: Of North America origin, it is found in mountain meadows and moist places. It can 

be easily cultivated. 

Appearance 

Stem: stout, 20–90cm high. 

Leaves: alternate, lance-shaped, up to 2–2.5cm long. 

Flowers: yellow-orange flowerheads. 

In bloom: June–September or generally during the warm season of the year.


Biology: Helenium is a perennial plant, growing well on moist but well drained soil and requiring 

full sun. It can be easily propagated by seed and by dividing clumps every 3–4 years. 

Tradition: Species of the genus Helenium are long valued daisy-like ornamentals used in cutting 

and butterfly gardens for late summer color (‘Helen’s Flower’). 

Part used: Whole plant. 


Helenalin (a sesquiterpene lactone), microhelenin-E (1) and -F (2) (nor-pseudoguaianolides). 

Precautions 

The plant and related species (such as H. hoopesii) are very poisonous. Helenalin has a documented 

acute toxicity. Reported effects on liver, kidney and lung include depression, appetite 

loss, weak irregular pulse, weakness, stiffness, nasal discharge, bloat, “spewing sickness”, vomiting, 

foaming at the mouth, coughing, green nasal discharge, diarrhea, and photosensitization. 

Death may occur rapidly, 4–24h of ingestion, or over a longer period in chronic cases. 


● 

● 

The oral median lethal dose of helenalin for 5 mammalian species is between 85 and 

105 mgkg 1 . 

In a study, they used a single i.p. dose of helenalin in male mice 43mgkg 1 and they continue 

for the next three days with i.p. injection of 25mg helenalinkg 1 . 


● 

● 

Helenalin, a sesquiterpene lactone found in species of the plant genus Helenium, inhibits the 

proliferation of cancer cells. 

Microlenin acetate, a dimeric sesquiterpene lactone, has a significant anti-leukemic activity. 


Antitumour activity 

● 

Helenalin causes a marked potentiation of the increases in intracellular free Ca 2 concentration 

([Ca 2 ] i ) produced by mitogens such as vasopressin, bradykinin, and 

platelet-derived growth factor in Swiss mouse 3T3 fibroblasts. Removing external 

Ca 2 partly attenuated the increased [Ca 2 ] i responses caused by helenalin. The 

increased [Ca 2 ] i responses occurred at concentrations of helenalin that inhibited cell 

proliferation. At higher concentrations, helenalin inhibited the [Ca 2 ] i responses. No 

change in resting [Ca 2 ] i was caused by helenalin even at high concentrations. Other 

helenalin analogues also increased the [Ca 2 ] i response (Powis et al., 1994). Helenalin 

did not inhibit protein kinase C (PKC) and PKC appeared to play a minor role in the 

effects of helenalin on [Ca 2 ] i responses in intact cells. Studies with saponinpermeabilized 

HT-29 human colon carcinosarcoma cells indicated that helenalin


caused an increased accumulation of Ca 2 into nonmitochondrial stores and that the 

potentiating effect of helenalin on mitogen-stimulated [Ca 2 ] i responses was due in 

part to an increase in the inositol-(1,4,5)-trisphosphate-mediated release of Ca 2 

from these stores. 


● 

● 

● 

Two new nor-pseudoguaianolides, microhelenin-E (1) and -F (2), were isolated from 

Texas Helenium microcephalum and their structures elucidated on the basis of physicochemical 

data and spectral evidence (Kasai et al., 1982). Microhelenin-E demonstrated 

significant in vitro and in vivo cytotoxic and anti-leukemic activities against 

KB tissue cell culture (ED 50 1.38gml 1 ) P-388 lymphocytic leukemia growth 

in BDF1 male mice (T/C-166% at 8mgkg 1 per day), respectively. 

The antitumor sesquiterpene lactones microhelenins-A, B and C, microlenin acetate 

and plenolin were isolated from Helenium microcephalum. The structures and stereochemistry 

of these lactones were determined by physical methods as well as by chemical 

transformations and correlations (Lee et al., 1976). Microlenin acetate is probably 

the first novel dimeric sesquiterpene lactone demonstrated to have significant antileukemic 

activity. 

The known compound isohelenalin and a new anti-leukemic sesquiterpene lactone, 

isohelenol were isolated from Helenium microcephalum (Sims et al., 1979). 

Cytotoxic activity 

● Studies with smallhead sneezeweed indicated that helenalin, is the only significant 

toxic constituent present. The oral median lethal dose of helenalin for 5 mammalian 

species was between 85 and 105mgkg 1 . 

● The acute toxicity of helenalin was examined in male BDF1 mice. The 14-day LD 50 

for a single ip dose of helenalin in male mice was 43mgkg 1 . A single i.p. injection 

of 25mgkg 1 helenalin increased serum alanine aminotransferase (ALT), lactate 

dehydrogenase (LDH), urea nitrogen (BUN), and sorbitol dehydrogenase within 6h 

of treatment (Chapman et al., 1988). Multiple helenalin exposures, i.p. injection of 

25mgkg 1 for 3 days, increased differential polymorphonuclear leukocyte counts 

and decreased lymphocyte counts. Serum ALT, BUN and cholesterol levels were also 

increased by multiple helenalin exposures at 25mgkg 1 per day. Helenalin significantly 

reduced liver, thymus and spleen relative weights and histologic evaluation 

revealed substantial effects of multiple helenalin exposures on lymphocytes of the 

thymus, spleen and mesenteric lymph nodes. No helenalin-induced histologic 

changes were observed in the liver or kidney. Multiple helenalin exposures 

(25 mg kg 1 per day) significantly inhibited hepatic microsomal enzyme activities 

(aminopyrine demethylase and aniline hydroxylase) and decreased microsomal 

cytochromes P-450 and b5 contents. Three concurrent days of diethyl maleate 

(DEM) pretreatment (3.7mmolkg 1 , 0.5h before helenalin treatment) significantly 

increased the toxicity of helenalin exposure. These results indicate that the hepatic 

microsomal drug metabolizing system and lymphoid organs are particularly


● 

vulnerable to the effects of helenalin. In addition, helenalin toxicity is increased by 

DEM pretreatments, which have been shown to decrease GSH concentrations. 

Helenalin (25mgkg 1 ) administered to immature male ICR mice caused a rapid 

decrease in hepatic GSH levels and was lethally toxic to greater than 60% of the 

animals within 6 days. L-2 Oxothiazolidine 4-carboxylate (OTC), a compound that 

elevates cellular GSH levels, administered to ice 6 or 12h before helenalin protected 

against hepatic GSH depletion and the lethal toxicity of these toxins. OTC administered 

at the same time as the sesquiterpene lactones was not protective, suggesting 

that the critical events against which GSH is protective occur within the first 6h. In 

primary rat hepatocyte cultures, helenalin (4–16M) caused a rapid lethal injury as 

determined by the release of lactate dehydrogenase. Cotreatment of cultures with 

N-acetylcysteine at high concentrations (4mM) afforded significant protection 

against lethal injury by both toxins (Merrill et al., 1988). In contrast, BCNU, which 

inhibits glutathione reductase, or diethylmaleate, which depletes hepatocellular 

GSH, potentiated the hepatotoxicity of helenalin in monolayer rat hepatocytes. These 

studies suggest that the in vivo and in vitro toxicity of helenalin is strongly dependent 

on hepatic GSH levels, which helenalin rapidly depletes at very low concentrations. 

References 

Kasai, R., Shingu, T., Wu, R.Y., Hall, I.H. and Lee, K.H. (1982) Antitumor agents 57. The isolation and 

structural elucidation of microhelenin-E, a new anti-leukemic nor-pseudoguaianolide, and microhelenin- 

F from Helenium microcephalum. J. Nat. Prod. 45(3), 317–20. 

Lee, K.H., Imakura, Y. and Sims, D., (1976) Antitumor agents XVII; Structure and stereochemistry of 

microhelenin-A, a new antitumor sesquiterpene lactone from Helenium microcephalum. J. Pharm. Sci. 65(9), 

1410–2. 

Merrill, J.C., Kim, H.L., Safe, S., Murray, C.A. and Hayes, M.A. (1988) Role of glutathione in the toxicity 

of the sesquiterpene lactones hymenoxon and helenalin. J. Toxicol. Environ. Health 23(2), 159–69. 

Sims, D., Lee, K.H. and Wu, R.Y. (1979) Antitumor agents 37. The isolation and structural elucidation 

of isohelenol, a new anti-leukemic sesquiterpene lactone, and isohelenalin from Helenium microcephalum. 

J. Nat. Prod. 42(3), 282–6. 

Hypericum perforatum L. (Hypericum (St John’s Wort)) 

(Hypericaceae) 

Location: Britain and throughout Europe and Asia. 


Stem: 0.3–1m high, erect, branching in the upper part. 

Leaves: pale green, sessile, and oblong, with pellucid dots or oil glands. 

Flowers: bright cheery yellow in terminal corymb. 

In bloom: June–August. 

Cytotoxic 

Tradition: Its name has been connected with many ancient superstitions. It was used as aromatic, 

astringent, resolvent, expectorant and nervine. 

Parts used: herb tops, flowers.


Figure 3.13 Hypericum perforatum. 

Active ingredients: Aromatic polycyclic diones (pseudohypericin and hypericin). 

Documented target cancers: Photodynamic cancer therapy, human cancer cell lines (breast, 

colon, lung, melanoma), antiretroviral. 



● 

Pseudohypericin and hypericin, the major photosensitizing constituents of Hypericum 

perforatum, have been proposed as a photosensitizer for photodynamic cancer therapy 

(Vandenbogaerde et al., 1988). The presence of foetal calf serum (FCS) or albumin 

extensively inhibits the photocytotoxic effect of pseudohypericin against A431 tumor 

cells, and is associated with a large decrease in cellular uptake of the compound. 

These results suggest that pseudohypericin, in contrast to hypericin, interacts 

strongly with constituents of FCS, lowering its interaction with cells. Since pseudohypericin 

is two to three times more abundant in Hypericum than hypericin and the 

bioavailabilities of pseudohypericin and hypericin after oral administration are similar, 

these results suggest that hypericin, and not pseudohypericin, is likely to be the 

constituent responsible for hypericism. Moreover, the dramatic decrease of 

photosensitizing activity of pseudohypericin in the presence of serum may restrict its 

applicability in clinical situations.


● 

Hexane extracts of Hypericum drummondii showed significant cytotoxic activity on cultured 

P-388, KB, or human cancer cell lines (breast, colon, lung, melanoma) 

(Jayasuriya et al., 1989). 


● 

Hypericin and pseudohypericin have potent antiretroviral activity and are highly effective 

in preventing viral-induced manifestations that follow infections with a variety of 

retroviruses in vivo and in vitro (Meruelo et al., 1988). Pseudohypericin and hypericin 

probably interfere with viral infection and/or spread by direct inactivation of the virus 

or by preventing virus shedding, budding, or assembly at the cell membrane. These 

compounds have no apparent activity against the transcription, translation, or transport 

of viral proteins to the cell membrane and also no direct effect on the polymerase. 

This property distinguishes their mode of action from that of the major antiretro-virus 

group of nucleoside analogues. Hypericin and pseudohypericin have low in vitro cytotoxic 

activity at concentrations sufficient to produce dramatic antiviral effects in 

murine tissue culture model systems that use radiation leukemia and Friend viruses. 

Administration of these compounds to mice at the low doses sufficient to prevent 

retroviral-induced disease appears devoid of undesirable side effects. This lack of toxicity 

at therapeutic doses extends to humans, as these compounds have been tested in 

patients as antidepressants with apparent salutary effects. These observations suggest 

that pseudohypericin and hypericin could become therapeutic tools against retroviralinduced 

diseases such as acquired immunodeficiency syndrome (AIDS). 

References 

Cott, J. (1995) NCDEU update. Natural product formulations available in europe for psychotropic indications. 

Psychopharmacol Bull. 31(4), 745–51. 

Jayasuriya, H., McChesney, J.D., Swanson, S.M. and Pezzuto, J.M. (1989) Antimicrobial and cytotoxic 

activity of rottlerin-type compounds from Hypericum drummondii. J. Nat. Prod. 52(2), 325–31. 

Muller, W.E. and Rossol, R. (1994) Effects of hypericum extract on the expression of serotonin receptors. 

J Geriatr. Psychiatry Neurol. 71, 63–4. 

Meruelo, D., Lavie, G. and Lavie, D. (1988) Therapeutic agents with dramatic antiretroviral activity and 

little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin. Proc. Natl. 

Acad. Sci. USA 85(14), 5230–4. 

Vandenbogaerde, A.L., Kamuhabwa, A., Delaey, E., Himpens, B.E., Merlevede, W.J. and de Witte, P.A. 

(1998) Photocytotoxic effect of pseudohypericin versus hypericin. J Photochem. Photobiol. B. 45(2–3), 

87–94. 

Juniperus virginiana L. (Juniperus (red cedar)) 


(Conifereae) 

Location: North America, Europe, North Africa, and North Asia. It is known as the American 

Juniper of Bermuda and also as “Pencil Cedar”. 


Stem: 1.5m high, erect trunk, spreading branches covered with a shreddy bark. 

Leaves: straight and rigid, awl-shaped, 0.8–1.5cm long, with sharp, prickly points. 

Flowers: in short cones.


Figure 3.14 Juniperus virginiana. 

In bloom: April–May. 

Tradition: It is used in the preparation of insecticides, in making liniments and other medicinal 

preparations and perfumed soaps. The leaves have diuretic properties. 

Parts used: ripe, carefully dried fruits, leaves. 

Active ingredients: Podophyllotoxin. 



● 

● 

Podophyllotoxin, the active principle of Juniperus virginiana is a tumor inhibitor 

(Kupchan et al., 1965). However, in mice the use of cedar shavings as bedding 

increased significantly the incidence of spontaneous tumors of the liver and mammary 

gland, and also reduced the average time at which tumors appeared (Sabine, 

1975). 

Both antitumor-promoting and antitumor activities have been attributed to the 

crude extract from the leaves of Juniperus chinensis (Ali et al., 1996).

References 


Ali, A.M., Mackeen, M.M., Intan-Safinar, I., Hamid, M., Lajis, N.H., el-Sharkawy, S.H. and Murakoshi, 

M. (1996) Antitumour-promoting and antitumour activities of the crude extract from the leaves of 

Juniperus chinensis. J. Ethnopharmacol. 53(3), 165–9. 

Kupchan, S.M., Hemingway, J.C. and Knox, J.R. (1965) Tumor inhibitors. VII. Podophyllotoxin, the 

active principle of Juniperus virginiana. J. Pharm. Sci. 54(4), 659–60. 

Sabine, J.R. (1975) Exposure to an environment containing the aromatic red cedar, Juniperus virginiana: 

procarcinogenic, enzyme-inducing and insecticidal effects. Toxicology 5(2), 221–35. 

Mallotus philippinensis (Mallotus (Kamala)) 


(Euphorbiaceae) 

Location: India, Malay Archipelago, Orissa, Bengal, Bombay, Southern Arabia, China, Australia. 

Appearance 

Stem: 7–10m high, 1–1.5cm in diameter. 

Leaves: alternate, articulate petioles 1–2in long, ovate with two obscure glands at base. 

Flowers: dioecious, covered with ferrugineous tomentosum. 

In bloom: November–January. 

Tradition: The root of the tree is used in dyeing and for cutaneous eruptions. It was used by the 

Arabs internally for leprosy and in solution to remove freckles and pustules. 

Part used: pericarps. 


● 

● 

Maytansinoid tumor inhibitors: rottlerin, mallotojaponin, phloroglucinol derivatives: 

mallotolerin, mallotochromanol, mallotophenone, mallotochromene. 

ent-kaurane and rosane diterpenoids. 


● 

● 

CaM kinase III inhibitor. Cytotoxic (glioblastomas-human, mice). 

Skin tumor (mice), human larynx (HEp-2) and lung (PC-13) carcinoma cells as well as 

mouse B16 melanoma, leukemia P388, and L5178Y cells. 



● 

Mallotus phillippinensis: pericarps contain rottlerin, a 5,7-dihydroxy-2,2-dimethyl-6- 

(2,4,6-trihydroxy-3-methyl-5-acetylbenzyl)-8-cinnamoyl-1,2-hromene which has 

been shown to be an effective CaM kinase III inhibitor. Rottlerin decreased growth 

and induced cytotoxicity in rat (C6) and two human gliomas (T98G and U138MG) 

at concentrations that inhibited the activity of CaM kinase III in vitro and in vivo 

(Parmer et al., 1997). Far less demonstrable effects were observed on other


● 

● 

● 

Ca 2 /CaM-sensitive kinases. Incubation of glial cells with rottlerin produced a 

block at the G1-S interface and the appearance of a population of cells with a complement 

of DNA. In addition, rottlerin induced changes in cellular morphology such 

as cell shrinkage, accumulation of cytoplasmic vacuoles, and packaging of cellular 

components within membranes. 

The pericarps of Mallotus japonicus (Euphorbiaceae) contain mallotojaponin, which 

inhibited the action of tumor promoter in vitro and in vivo (Satomi et al., 1994); it 

inhibited tumor promoter-enhanced phospholipid metabolism in cultured cells, and 

also suppressed the promoting effect of 12-O-tetradecanoylphorbol-13-acetate on 

skin tumor formation in mice initiated with 7,12-dimethylbenz-[a]anthracene 

(Satomi et al., 1994). 

In addition, pericarps contain a variety of phloroglucinol derivatives which were 

proved to be significantly cytotoxic in culture against human larynx (HEp-2) and 

lung (PC-13) carcinoma cells as well as mouse B16 melanoma, leukemia P-388, the 

KB system and L5178Y cells. These phloroglucinol derivatives are: mallotolerin 

(3-(3-methyl-2-hydroxybut-3-enyl)-5-(3-acetyl-2,4-dihydroxy-5-methyl- 

6-methoxybenxyl)-phlorbutyrophenone), mallotochromanol (8-acetyl-5,7-dihydroxy-6-(3-acetyl-2,4-dihydroxy-5-methyl-6-methoxybenxyl) 

2,2-dimethyl-3- 

hydroxychroman), allotophenone (5-methylene-bis-2, 6-dihydroxy-3-methyl-4- 

methoxyacetophenone), mallotochromene (8-acetyl-5, 7-dihydroxy-6-(3-acetyl-2,4- 

dihydroxy-5-methyl-6-methoxybenzyl)2,2-dimethylchromene), 

3-(3,3-dimethylallyl)-5-(3-acetyl-2,4-dihydroxy-5-methyl-6-methoxybenzyl)- 

phloracetophenone, and 2,6-dihydroxy-3-methyl-4-methoxyacetophenone 

(Arisawa et al., 1990). 

Mallotus anomalus Meer et Chun contains ent-kaurane and rosane diterpenoids 

(Xu, 1991). 

References 

Arisawa, M., Fujita, A., Morita, N. and Koshimura, S. (1990) Cytotoxic and antitumor constituents in 

pericarps of Mallotus japonicus. Planta Med. 56(4), 377–9. 

Arisawa, M., Fujita, A., Saga, M., Hayashi, T., Morita, N., Kawano, N. and Koshimura, S. (1986) Studies 

on cytotoxic constituents in pericarps of Mallotus japonicus, Part II. J. Nat. Prod. 49(2), 298–302. 

Arisawa, M., Fujita, A., Suzuki, R., Hayashi, T., Morita, N., Kawano, N. and Koshimura, S. (1985) Studies 

on cytotoxic constituents in pericarps of Mallotus japonicus, Part I. J. Nat. Prod. 48(3), 455–9. 

Mi, J.F., Xu, R.S., Yang, Y.P. and Yang, P.M. (1993) Studies on circular dichroism of diterpenoids from 

Mallotus anomalus and sesquiterpenoidtussilagone YaoXueXueBao 28(2), 105–9. 

Parmer, T.G., Ward, M.D. and Hait, W.N. (1997) Effects of rottlerin, an inhibitor of calmodulindependent 

protein kinase III, on cellular proliferation, viability, and cell cycle distribution in malignant 

glioma cells. Cell Growth Differ. 8(3), 327–34. 

Satomi, Y., Arisawa, M., Nishino, H., Iwashima, A. (1994) Antitumor-promoting activity of mallotojaponin, 

a major constituent of pericarps of Mallotus japonicus. Oncology, 51(3), 215–9. 

Xu, R.S., Tang, Z.J., Feng, S.C., Yang, Y.P., Lin, W.H., Zhong, Q.X. and Zhong, Y. (1991) 

Studies on bioactive components from Chinese medicinal plants. Mem. Inst. Oswaldo Cruz 86(Suppl 2), 

55–9.


Maytenus boaria (Maytenus) (Celastraceae) 

Location: Mountains of South America. 

Appearance 

Stem: 34m. 

Leaves: alternate, simple, narrow, elliptic to lanceolate, tiny teeth, pointed tip. 

Active ingredients: Maytenin 

Ansa macrolide (maytansine). 

Documented target cancers: basic cellular carcinoma, Kaposi’s sarcomatosis, leukemia. 

Cytotoxic 



● 

● 

● 

Maytenin demonstrates a low irritant action and late antineoplastic properties (Melo 

et al., 1974). 

Some more species of the same genus appear to have a cytotoxic effect against cancer 

tumors such as: Maytenus guangsiensis Cheng et Sha (anti-leukemic) (Qian et al., 

1979), Maytenus ovatus (anti-leukemic) (maytansine) (Kupchan et al., 1972), Maytenus 

senegalensis (Tin-Wa et al., 1971). 

Maytenus wallichiana Raju et Babu and Maytenus emarginata Ding Hou (lymphocytic 

leukemia). 

Biotechnology 

● Plant tissue cultures of Maytenus wallichiana Raju et Babu and Maytenus emarginata 

Ding Hou were initiated (Dymowski and Furmanowa, 1989) Growth conditions of 

the callus and the optimum medium composition have been established. Increments 

of callus wet mass and dynamics of callus growth were determined. Morphological 

and microscopic observations were also performed. The most efficient growth of the 

callus, resulting in increments of its wet mass up to 6460%, was obtained on the 

modified Murashige and Skoog medium. Extracts of the callus were found to be 

inactive against microorganisms, but proved cytotoxic for lymphocytic leukemia. 

References 

Dymowski, W. and Furmanowa, M. (1989) The search for cytostatic substances in the tissues of plants of 

the genus Maytenus molina in vitro culture. I. Callas culture and biological studies of its extracts. Acta 

Pol. Pharm. 46(1), 81–9. 

Dymowski, W. and Furmanowa, M. (1990) Investigating cytostatic substances in tissue of plants Maytenus 

Molina in in-vitro cultures. II. chromatographic test of extracts from callus of Maytenus wallichiana R. et 

B. Acta Pol. Pharm. 47(5–6), 51–4. 

Dymowski, W. and Furmanowa, M. (1992) Searching for cytostatic substances in plant tissue of Maytenus 

molina by in vitro culture. III. Release of substances from active biological fractions from the callus 

extract of Maytenus wallichiana R. and B. Acta Pol. Pharm. 49(1–2), 29–33. 

Kuo, Y.H., Chen, C.H., Kuo, L.M., King, M.L., Wu, T.S., Haruna, M. and Lee, K.H. (1990) Antitumor 

agents, 112. Emarginatine B, a novel potent cytotoxic sesquiterpene pyridine alkaloid from Maytenus 

emarginata. J. Nat. Prod. 53(2), 422–8.


Kuo, Y.H., King, M.L., Chen, C.F., Chen, H.Y., Chen, C.H., Chen, K. and Lee, K.H. (1994) Two new 

macrolide sesquiterpene pyridine alkaloids from Maytenus emarginata: emarginatine G and the cytotoxic 

emarginatine F. J. Nat. Prod. 57(2), 263–9. 

Kupchan, S.M., Komoda, Y., Court, W.A., Thomas, G.J., Smith, R.M., Karim, A., Gilmore, C.J., 

Haltiwanger, R.C. and Bryan, R.F. (1972) Maytansine, a novel anti-leukemic ansa macrolide from 

Maytenus ovatus. J. Am. Chem. Soc. 94(4), 1354–6. 

Melo, A.M., Jardim, M.L., De Santana, C.F., Lacet, Y., Lobo Filho, J., De Lima and Ivan Leoncio, O.G. 

(1974) First observations on the topical use of Primin, Plumbagin and Maytenin in patients with skin 

cancer. Rev. Inst. Antibiot. (Recife) 14(1–2), 9–16. 

Pandey, R.C. (1998) Prospecting for potentially new pharmaceuticals from natural sources. Med. Res. Rev. 

18(5), 333–46. Review. 

Qian, X., Gai, C. and Yao, S. (1979) Studies on the anti-leukemic principle of Maytenus guangsiensis. Cheng 

et Sha. Yao Hsueh Hsueh Pao. 14(3), 182. 

Sneden, A.T. and Beemsterboer, G.L. (1980) Normaytansine, a new anti-leukemic ansa macrolide from 

Maytenus buchananii. J. Nat. Prod. 43(5), 637–40. 

Tin-Wa, M., Farnsworth, N.R., Fong, H.H., Blomster, R.N., Trojanek, J., Abraham, D.J., Persinos, G.J. 

and Dokosi, O.B. (1971) Biological and phytochemical evaluation of plants. IX. Antitumor activity of 

Maytenus senegalensis (Celastraceae) and a preliminary phytochemical investigation. Lloydia, 34(1), 79–87. 

Melia azedarach (Melia) (Meliaceae) 

Cytotoxic 

Location: Northern India, China, the Himalayas. 


Stem: 10–17m high, reddish brown bark. 

Leaves: bipinnate, 1–2in long. The individual leaflets, each about 2cm long, are pointed at the 

tips and have toothed edges. 

Flowers: large branches of lilac, fragrant, star shaped flowers, that arch or droop in 8cm panicles. 

In bloom: spring – early summer. 

Parts used: the bark of the root and trunk, seed. 

Figure 3.15 Melia azedarach.



● Limonoids: toosendanal, 28-deacetyl sendanin,12-O-methylvolkensin, meliatoxin B1, trichillin H, 

and toosendanin, 12-deacetyltrichilin I 1-acetyltrichilin H, 3-deacetyltrichilin H, 1-acetyl-3- 

deacetyltrichilin H, 1-acetyl-2-deacetyltrichilin H, meliatoxin B1, trichilin H, trichilin D and 

1,12-diacetyltrichilin B. 

● Meliavolkinin, melianin C, 3-diacetylvilasinin and melianin B. 


● KB cells (meliatoxin B1 and toosendanin). 

● P388 cells (limonoids of Melia azedarach) (Itokawa et al., 1995). 

● Human prostate (PC-3) and pancreatic (PACA-2) cell lines (3, 23,24-diketomelianin B). 



● 

● 

● 

● 

The root bark of Melia azedarach, contains the trichilin-type limonoids 12-deacetyltrichilin 

I 1-acetyltrichilin H, 3-deacetyltrichilin H, 1-acetyl-3-deacetyltrichilin H, 

1-acetyl-2-deacetyltrichilin H, meliatoxin B1, trichilin H, trichilin D and 1,12- 

diacetyltrichilin B (Takeya et al., 1996). 

The limonoid compound (28-deacetyl sendanin) isolated from the fruit of Melia toosendan 

SIEB. et ZUCC. was evaluated on anticancer activity. It has been proved that 28- 

deacetyl sendanin has more sensitive and selective inhibitory effects on in vitro growth 

of human cancer cell lines in comparison with adriamycin (Tada et al., 1999). 

The fruits of Melia toosendan Sieb. et Zucc. contain the limonoids toosendanal, 12-Omethylvolkensin, 

meliatoxin B1, trichillin H, toosendanin and 28-deacetyl sendanin 

(Tada et al., 1999). 

The root bark of Melia volkensii contains meliavolkinin, melianin C, 1,3-diacetylvilasinin 

and melianin B, which all showed marginal cytotoxicities against certain human tumor 

cell lines (Rogers et al., 1998). Jones oxidation of melianin B4 gave 3, 23,24-diketomelianin 

B, which showed selective cytotoxicities for the human prostate (PC-3) and 

pancreatic (PACA-2) cell lines with potencies comparable to those of adriamycin. 

References 

Itokawa, H., Qiao, Z.S., Hirobe, C. and Takeya, K. (1995) Cytotoxic limonoids and tetranortriterpenoids 

from Melia azedarach. Chem Pharm. Bull. (Tokyo) 43(7), 1171–5. 

Rogers, L.L., Zeng, L., Kozlowski, J.F., Shimada, H., Alali, F.Q., Johnson, H.A. and McLaughlin, J.L. 

(1998) New bioactive triterpenoids from Melia volkensii. J. Nat. Prod. 61(1), 64–70. 

Tada, K., Takido, M. and Kitanaka, S. (1999) Limonoids from fruit of Melia toosendan and their cytotoxic 

activity. Phytochemistry 51(6), 787–91. 

Takeya, K., Quio, Z.S., Hirobe, C. and Itokawa, H. (1996) Cytotoxic trichilin-type limonoids from Melia 

azedarach. Bioorg. Med. Chem. 4(8), 1355–9.


Mormodica charantia (Mormodica (Bitter melon)) 

(Cucurbitaceae) 

Location: East India. 


Stem: thin, crawly. 

Leaves: dark, green, and deeply lobed. 

Flowers: dioecious, yellow. 

Anti-leukemic 

Part used: the fruit deprived of the seeds. 

Active ingredients: Protein (molecular weight of 11,000 Da). 

Documented target cancers: The fruit and seeds of the bitter melon (Momordica charantia) have 

been reported to have anti-leukemic and antiviral activities: 

● 

● 

● 

Antitumor (mice), 

Antiviral–anti-leukemic (human, selective), 

Immunostimulating (mice). 



● 

This anti-leukemic and antiviral action was associated with an activation of murine 

lymphocytes. This activity is associated with a single protein component with an apparent 

molecular weight of 11,000Da. The factor is not sensitive to boiling or to pretreatments 

with trypsin, ribonuclease (RNAse), or deoxyribonuclease (DNAse) (Cunnick 

et al., 1990). As determined by radioactive precursor uptake studies, the purified factor 

preferentially inhibits RNA synthesis in intact tissue culture cells. Some inhibition of 

protein synthesis and DNA synthesis also occurs. The factor is preferentially cytostatic 

Figure 3.16 Mormodica.


● 

for IM9 human leukemic lymphocytes when compared to normal human peripheral 

blood lymphocytes. In addition, it preferentially inhibits the soluble guanylate cyclase 

from leukemic lymphocytes. This inhibition correlates with its preferential cytotoxic 

effects for these same cells, since cyclic GMP is thought to be involved in lymphocytic 

cell proliferation and leukemogenesis and, in general, the nucleotide is elevated in 

leukemic versus normal lymphocytes and changes have been reported to occur during 

remission and relapse of this disease (Takemoto et al., 1980, 1982). 

At least part of the anti-leukemic activity of the bitter melon extract is due to the 

activation of NK cells in the host organism (mouse), that is, in vivo enhancement of 

immune functions may contribute to the antitumor effects of the bitter melon extract. 

In humans, the extract has both cytostatic and cytotoxic activities and can kill 

leukemic lymphocytes in a dose-dependent manner while not affecting the viability of 

normal human lymphocyte cells at these same doses (Takemoto et al., 1982). These 

activities are not due to the presence of the lectins from bitter melon seeds, as these 

purified proteins had no activity against human lymphocytic cells (Jilka et al., 1983). 

References 

Cunnick, J.E., Sakamoto, K., Chapes, S.K., Fortner, G.W. and Takemoto, D.J. (1990) Induction of tumor 

cytotoxic immune cells using a protein from the bitter melon (Momordica aharantia). Cell Immunol. 126 

(2), 278–89. 

Jilka, C., Strifler, B., Fortner, G.W., Hays, E.F. and Takemoto, D.J. (1983) In vivo antitumor activity of the 

bitter melon (Momordica charantia). Cancer Res. 43(11), 5151–5. 

Lin, J.Y., Hou, M.J. and Chen, Y.C. (1978) Isolation of toxic and non-toxic lectins from the bitter pear 

melon Momordica charantia Linn. Toxiconomis 16(6), 653–60. 

Takemoto, D.J., Dunford, C. and McMurray, M.M. (1982) The cytotoxic and cytostatic effects of the bitter 

melon (Momordica charantia) on human lymphocytes. Toxiconomy 20(3), 593–9. 

Takemoto, D.J., Dunford, C., Vaughn, D., Kramer, K.J., Smith, A. and Powell, R.G. (1982) Guanylate 

cyclase activity in human leukemic and normal lymphocytes. Enzyme inhibition and cytotoxicity of 

plant extracts. Enzyme 27(3), 179–88. 

Takemoto, D.J., Jilka, C. and Kresie, R. (1982) Purification and characterization of a cytostatic factor from 

the bitter melon Momordica charantia. Prep. Biochem. 12(4), 355–75. 

Takemoto, D.J., Kresie, R. and Vaughn, D. (1980) Partial purification and characterization of a guanylate 

cyclase inhibitor with cytotoxic properties from the bitter melon (Momordica charantia). Biochem. Biophys. 

Res. Commun. 14 94(1), 332–9. 

Nigella sativa L. (Nigella (Fennel flower)) (Ranunculaceae) 

Location: Asia. 


Stem: stiff, erect, branching. 

Leaves: bears deeply cut greyish-green. 

Flowers: greyish blue. 

In bloom: early summer. 

Cytotoxic 

Tradition: In India, the seeds are believed to increase the secretion of milk and are considered as 

stimulant, diaphoretic. They also use it in tonics. Romans used it in cooking (Roman 

Coriander). The French used it as a substitute for pepper.


Figure 3.17 Nigella. 

Parts used: seed, herb. 

Active ingredients: thymoquinone and dithymoquinone, fatty acids. 

Documented target cancers: multi-drug resistant (MDR) human tumor cell lines, Ehrlich ascites 

carcinoma (EAC), Dalton’s lymphonia ascites (DLA) and Sarcoma-180 (S-180) cells. Skin cancer 

(mice). 



● 

Nigella sativa: Seeds contain thymoquinone (TQ) and dithymoquinone (DIM), which 

were cytotoxic in vitro against MDR human tumor cell lines (IC50’s 78–393M). 

Both the parental cell lines and their corresponding MDR variants, over 10-fold more 

resistant to the standard antineoplastic agents doxorubicin (DOX) and etoposide 

(ETP), as compared to their respective parental controls, were equally sensitive to TQ 

and DIM. The inclusion of the competitive MDR modulator quinine in the assay 

reversed MDR Dx-5 cell resistance to DOX and ETP by 6- to 16-fold, but had no 

effect on the cytotoxicity of TQ or DIM. Quinine also increased MDR Dx-5 cell accumulation 

of the P-glycoprotein substrate 3H-taxol in a dose-dependent manner. 

However, neither TQ nor DIM significantly altered cellular accumulation of 3Htaxol. 

The inclusion of 0.5% v/v of the radical scavenger DMSO in the assay reduced 

the cytotoxicity of DOX by as much as 39%, but did not affect that of TQ or DIM. 

These studies suggest that TQ and DIM, which are cytotoxic for several types of 

human tumor cells, may not be MDR substrates, and that radical generation may not 

be critical to their cytotoxic activity (Salomi et al., 1992).


● 

● 

Nigella sativa seeds also contain certain fatty acids which are cytotoxic in vitro against 

Ehrlich ascites carcinoma (EAC), Dalton’s lymphonia ascites (DLA) and Sarcoma-180 

(S-180) cells. In vitro cytotoxic studies showed 50% cytotoxicity to Ehrlich ascites 

carcinoma, Dalton’s lymphoma ascites and Sarcoma-180 cells at a concentration of 

1.5g, 3g and 1.5g respectively with little activity against lymphocytes. The 

cell growth of KB cells in culture was inhibited by the active principle while K-562 

cells resumed near control values on day 2 and day 3. Tritiated thymidine incorporation 

studies indicated the possible action of an active principle at DNA level. In vivo 

EAC tumor development was completely inhibited by the active principle at the dose 

of 2mg per day10 for each mouse (Salomi et al., 1992). 

Topical application of Nigella sativa inhibited two-stage initiation/promotion 

[dimethylbenz[a]anthracene (DMBA)/croton oil] skin carcinogenesis in mice. A dose 

of 100mgkg 1 body wt of these extracts delayed the onset of papilloma formation 

and reduced the mean number of papillomas per mouse, respectively. The possibility 

that these extracts could inhibit the action of 20-methylcholanthrene (MCA)- 

induced soft tissue sarcomas was evaluated by studying the effect of these extracts on 

MCA-induced soft tissue sarcomas in albino mice. Intraperitoneal administration of 

Nigella sativa (100mgkg 1/ body wt) and oral administration of Crocus sativus 

(100 mgkg 1 body wt) 30 days after subcutaneous administration of MCA (745 

nmol2 days) restricted tumor incidence to 33.3% and 10%, respectively, 

compared with 100% in MCA-treated controls (Salomi et al., 1991). 

References 

Salomi, N.J., Nair, S.C., Jayawardhanan, K.K., Varghese, C.D. and Panikkar, K.R. (1992) Antitumour 

principles from Nigella sativa seeds. Cancer Lett. 63(1), 41–6. 

Salomi, M.J., Nair, S.C. and Panikkar, K.R. (1991) Inhibitory effects of Nigella sativa and saffron (Crocus 

sativus) on chemical carcinogenesis in mice. Nutr. Cancer 16(1), 67–72. 

Worthen, D.R., Ghosheh, O.A. and Crooks, P.A. (1998) The in vitro anti-tumor activity of some crude and 

purified components of blackseed, Nigella sativa L. Anticancer Res. 18(3A), 1527–32. 

Origanum vulgare, O. majorana 

Anticancer 

(Oregano (marjoram)) (Lamiaceae) 

Location: Mediterranean region of Europe and Asia. 


Stem: bushy, semi-woody sub-shrub with upright or spreading stems and branches. 

Leaves: aromatic, oval-shaped, about 4cm long and usually pubescent. 

Flowers: throughout the summer oregano bears tiny (0.3cm long) purple tube-shaped flowers 

that peek out of whorls of purplish-green leafy bracts about an inch long. 


Tradition: It was used from very early years for its medicinal properties, as a remedy for narcotic 

poisons, convulsions and dropsy. The whole plant has a strong fragrant, balsamic odor and an 

aromatic taste.


Figure 3.18 Origanum majorana. 

Parts used: herb, oil, leaves. 

Active ingredients: flavonoids, galangin and quercetin, water-alcoholic extracts and of isolated compounds 

(arbutin, methylarbutin and their aglycons – hydroquinone and hydroquinone monomethyl ether). 

Antitumor-promoting activity or in vitro cytotoxic effects towards different tumor cell lines 

were attributed also to Origanum majorana extracts or their constituents. When studying cytotoxic 

activity of O. majorana water-alcoholic extracts and of isolated compounds (arbutin, methylarbutin 

and their aglycons – hydroquinone and hydroquinone monomethyl ether) towards cultured rat 

hepatoma cells (HTC line), a high dose-dependent HTC cytotoxicity of hydroquinone. 

Indicative dosage and application: At 300M hydroquinone caused 40% cellular mortality after 

24h of incubation. 


● 

● 

● 

Antitumor-promoting activity or in vitro cytotoxic effects towards different tumor cell lines 

(rat hepatoma cells (HTC line)) 

Immunostimulant 

Antimutagenic. 



● Some studies have shown that oregano extracts or herbal mixtures with Origanum spp. 

possess in vitro antiviral activity or have immunostimulating effects both in vitro and 

in vivo. However, little knowledge has been attained so far on mechanisms of


● 

immunomodulating activity or underlying active compounds. It has been shown that 

ethanol extracts of Origanum vulgare inhibited intracellular propagation of ECHO 9 

Hill virus and also showed interferon inducing activity in vitro. Flavonoid luteoline, a 

constituent of Origani herba, has been considered as responsible for the induction of 

an interferon-like substance. A mixture of herbal preparation containing rosemary, 

sage, thyme and oregano (Origanum vulgare) showed radical scavenging activity and 

inhibition of the human immunodeficiency virus (HIV) infection at very low concentrations. 

It was suggested that the main active compounds of herbal preparations 

were carnosol, carnosic acid, carvacrol and thymol. Significant inhibitory effects of 

Origanum vulgare extracts against HIV-1 induced cytopathogenicity in MT-4 cells 

were also observed by Yamasaki et al. (1998). According to Krukowski and co-workers, 

an increase in immunoglobulin (IgG) levels was observed in reared calves, fed with a 

conventional concentrate supplemented by a mineral–herbal mixture containing 

Origanum majorana. 

A strong and dose-dependent capacity of inactivating dietary mutagen Trp-P-1 in the 

Salmonella typhimurium TA 98 assay was observed in Origanum vulgare water extracts, 

that exhibited significant antimutagenic effects in vitro (Ueda et al., 1991). Origanum 

majorana aqueous extracts were also able to suppress the mutagenicity of liver-specific 

carcinogen Trp-P-2 (Natake et al., 1989). When studying the mechanism of suppressing 

the mutagenicity of Trp-P-2 in Origanum vulgare, it was found that two 

flavonoids, galangin and quercetin acted as Trp-P-2 specific desmutagens, which 

neutralized this mutagen during or before mutating the bacteria (Salmonella 

typhimurium TA 98) (Kanazawa et al., 1995). The amounts of galangin and quercetin 

required for 50% inhibition (IC 50 ) against 20ng of Trp-P-2 were 0.12g and 0.81g, 

respectively. It was also found that quercetin acted as a mutagen at high concentrations 

(10 g per plate), but was a desmutagen when applied at low (0.110 g per 

plate) concentrations. Milic and Milic (1998) have found that isolated phenolic compounds 

from different spice plants, including Origanum vulgare, strongly inhibited 

pyrazine cation free radical formation in the Maillard reaction and the formation of 

mutagenic and carcinogenic amino-imidazoazarene in creatinine containing model 

systems. 


● 

In a literature survey, referring to the anticancer activity of Origanum genus, different 

approaches, testing systems and cell lines have been used by different authors when 

assessing the carcinogenic potential of plants or their isolated compounds. However, 

there are no available data on practical/clinical use of oregano in cancer prevention. 

In 1966, an international project was performed with the aim of screening the native 

plants of former Yugoslavia for their potential agricultural use in the USA and 

Yugoslavia. In the frame of this project 1,466 samples of 754 plant species were analyzed 

for chemical and antitumor activity. According to the results of the Cancer 

Chemotherapy National Service Center Screening Laboratories (Washington, DC) 

a high carvacrol (60–85%) containing Origanum heracleoticum (O. vulgare spp. hirtum 

(Link) Ietswaart) was reported to show high antitumor activity. Zheng (1991) has 

found that essential oil of Origanum vulgare fed to mice, induced the activity of


● 

glutathione S-transferase (GST) in various tissues. The GST enzyme system is 

involved in detoxification of chemical carcinogens and plays an important role in prevention 

of carcinogenesis, which would explain the anticancer potential of O. vulgare 

essential oil. This oil exhibited high levels of cytotoxicity (at dilutions of up to 

1:10,000) against four permanent eukaryotic cell lines including two derived from 

human cancers (epidermoid larynx carcinoma: Hep-2 and epitheloid cervix carcinoma: 

HeLa). Other studies, that refer to in vitro cytotoxic and/or anti-proliferative 

effects of Origanum vulgare extracts or isolated compounds (carvacrol, thymol) include 

those of Bocharova and He, who observed moderate suppressing activities of O. vulgare 

extracts (CE 50 220mgml 1 ) on human ovarian carcinoma cells (CaOv), or of 

isolated carvacrol and thymol (IC 50 120moll 1 ) on Murine B 16(F10) melanoma 

cells – a tumor cell line with high metastatic potential. 

Antitumor-promoting activity or in vitro cytotoxic effects towards different tumor 

cell lines were attributed also to Origanum majorana extracts or their constituents. 

When studying the cytotoxic activity of O. majorana water-alcoholic extracts and of 

isolated compounds (arbutin, methylarbutin and their aglycons – hydroquinone and 

hydroquinone monomethyl ether) towards cultured rat hepatoma cells (HTC line), a high 

dose-dependent HTC cytotoxicity of hydroquinone was observed, whilst arbutin was 

not active (Assaf et al., 1987). At 300M hydroquinone caused 40% cellular mortality 

after 24h of incubation, but no cells remained viable after 72h. It has been established 

that this well-known antiseptic of the urinary tract was a more potent 

cytotoxic compound towards rat hepatoma cells than many classic antitumor agents 

like azauridin or colchicin, but less than valtrate, a monoterpenic ester of Valeriana spp. 

References 

Adam, K., Sivropoulou, A., Kokkini, S., Lanaras, T. and Arsenakis, M. (1998) Antifungal activities of 

Origanum vulgare subsp. hirtum, Mentha spicata, Lavandula angustifolia, and Salvia fruticosa essential oils 

against human pathogenic fungi. J. Agri. Food Chem. 46(5), 1739–45. 

Aruoma, O.I., Spencer, J.P.E., Rossi, R., Aeschbach, R., Khan, A., Mahmood, N., Munoz, A., Murcia, A., 

Butler, J. and Halliwell, B. (1996) An evaluation of the antioxidant and antiviral action of extracts of 

rosemary and provencal herbs. Food Chem. Toxicol. 34(5), 449–56. 

Assaf, M.H., Ali, A.A., Makboul, M.A., Beck, J.P. and Anton, R. (1987) Preliminary study of phenolic 

glycosides from Origanum majorana, quantitative estimation of arbutin, cytotoxic activity of hydroquinone. 

Planta Med. 53(4), 343–5. 

Bocharova, O.A., Karpova, R.V., Kasatkina, N.N., Polunina, L.G., Komarova, T. S. and Lygenkova, M.A. 

(1999) The antiproliferative activity for tumor cells is important to compose the phytomixture for 

prophylactic oncology. Farmacevtski Vestnik 50, 378–379. 

Kanazawa, K., Kawasaki, H., Samejima, K., Ashida, H. and Danno, G. (1995) Specific desmutagens 

(antimutagens) in Oregano against dietary carcinogen, Trp-P-2, are galangin and quercetin. J. Agri. Food 

Chem. 43(2), 404–9. 

Mayer, E., Sadar, V. and Spanring, J. (1971) New crops screening of native plants of Yugoslavia of potential 

use in the agricultures of the USA and SFRJ. University of Ljubljana, Biotechical Faculty, Final 

Technical Report. Printed by Partizanska knjiga Ljubljana, 210 pp. 

Milic, B.L. and Milic, N.B. (1998) Protective effects of spice plants on mutagenesis. Phytotherapy Res. 

12(Suppl. 1), S3–6.


Sivropoulou, A., Papanikolaou, E., Nikolaou, C., Kokkini, S., Lanaras, T. and Arsenakis, M. (1996) 

Antimicrobial and cytotoxic activities of Origanum essential oils. J. Agri. Food Chem. 44(5), 1202–5. 

Skwarek, T., Tynecka, Z., Glowniak, K. and Lutostanska, E. (1994) Plant inducers of interferons. Herba 

Polonica 40(1–2), 42–9. 

Ueda, S., Kuwabara, Y., Hirai, N., Sasaki, H. and Sugahara, T. (1991) Antimutagenic capacities of different 

kinds of vegetables and mushrooms. J. Jap. Soc. Food Sci. Technol. 38(6), 507–14. 

Krukowski, H., Nowakowicz-Debek, B., Saba, L. and Stenzel, R. (1998) Effect of mineral–herbal mixtures 

on IgG blood serum level in growing calves. Roczniki Naukowe Zootechniki 25(4), 97–103. 

Yamasaki, K., Nakano, M., Kawahata, T., Mori, H., Otake, T., Ueba, N., Oishi, I., Inami, R., Yamane, M., 

Nakamura, M., Murata, H. and Nakanishi, T. (1998) Anti-HIV-1 activity of herbs in Labiatae. Biol. 

Pharm. Bull. 21(8), 829–33. 

Natake, M., Kanazawa, K., Mizuno, M., Ueno, N., Kobayashi, T., Danno, G. and Minamoto, S. (1989) 

Herb-water extracts markedly suppress the mutagenicity of Trp-P-2. Agri. Biol. Chem. 53(5), 1423–5. 

Zheng, S., Wang, X., Gao, L., Shen, X. and Liu, Z. (1997) Studies on the flavonoid compounds of 

Origanum vulgare L. Indian J. Chem. 36, 104–106. 

Paeonia officinalis L. (Paeonia (Paeony)) 


(Ranunculaceae) 

Location: Only grows wild on an island called the Steep Holmes, in the Severn, Great Britain. 


Stem: green (red when quite young), about 1m high. 

Root: composed of several roundish, thick knobs of tubers, which hang below each other’s, 

connected by strings. 

Leaves: composed of several unequal lobes, which are cut into many segments. 

Flowers: deep purple, fragrant. 

In bloom: late spring. 

Figure 3.19 Paeonia officinalis.


Tradition: The genus is supposed to have been named after the physician Paeos, who cured gods 

of wounds received during the Trojan War with the aid of this plant. In ancient times it was 

connected with many superstitions. It was used as antispasmodic and tonic. 

Part used: root. 

Active ingredients: LHRH antagonist and a weak anti-estrogen on the uterine DNA synthesis 

in immature rats. 

Documented target cancers: Intestinal metaplasia, atypical hyperplasia of the gastric mucosa 

(Paeonia lactiflora), uterine myomas (Paeonia lactiflora, Paeonia suffruticosa). 



● 

● 

● 

Shi-Quan-Da-Bu-Tang (Ten Significant Tonic Decoction), or SQT ( Juzentaihoto, 

TJ-48) was formulated by Taiping Hui-Min Ju (Public Welfare Pharmacy Bureau) in 

Chinese Song Dynasty in AD 1200. It is prepared by extracting a mixture of ten medical 

herbs (Rehmannia glutinosa, Paeonia lactiflora, Liqusticum wallichii, Angelica sinesis, 

Glycyrrhiza uralensis, Poria cocos, Atractylodes macrocephala, Panax ginseng. Astragalus 

membranaceus and Cinnamomum cassia) that tone the blood and vital energy, and 

strengthen health and immunity. This potent and popular prescription has traditionally 

been used against anemia, anorexia, extreme exhaustion, fatigue, kidney and spleen 

insufficiency and general weakness, particularly after illness (Zee-Cheng, 1992). 

Paeonia alba is one of the herbal constituents of Xiao Wei Yan Powder (some of the 

other constituents are Smilax glabrae, Hedyotis diffusae, Taraxacum mongolicum, 

Caesalpinia sappan, Cyperus rotundus, Bletilla striata and Glycyrrhiza uralensis). This 

preparation has been used for the treatment of intestinal metaplasia and 

atypical hyperplasia of the gastric mucosa of chronic gastritis, administrated orally at 

5–7gd. 1 After 2–4 months of administration, the total remission rate exceeded 

90%. It was 91.3% and that of the AH was 92.16%, while in control group, they 

were 21.3% and 14.46% respectively. The animal experiments revealed no toxic 

effect, so safety guarantee was provided for its clinical application (Liu et al., 1992). 

The root of Paeonia lactiflora Pall. and the root bark of Paeonia suffruticosa Andr. 

(Paeoniaceae) are components of Kuei-chih-fu-ling-wan (Keishi-bukuryo-gan), a 

traditional Chinese herbal remedy which contains three components: the bark of 

Cinnamomum cassia Bl. (Lauraceae), seeds of Prunus persica Batsch. or P. persiba 

Batsch.var.davidiana Maxim. (Rosaceae) and carpophores of Poria cocos Wolf. 

(Polyporaceae). This prescription has been frequently used in the treatment of gynecological 

disorders such as hypermenorrhea, dysmenorrhea and sterility. After treatment 

with the preparation, clinical symptoms of hypermenorrhea and dysmenorrhea 

were improved in more than 90% of the cases with shrinking of uterine myomas in 

roughly 60% of the cases (Sakamoto et al., 1992).

References 


Aburada, M., Takeda, S., Ito, E., Nakamura, M. and Hosoya, E. (1983) Protective effects of juzentaihoto, 

dried decoctum of 10 Chinese herbs mixture, upon the adverse effects of mitomycin C in mice. 

J. Pharmacobiodyn. 6(12), 1000–4. 

Liu, X.R., Han, W.Q. and Sun, D.R. (1992) Treatment of intestinal metaplasia and atypical hyperplasia of 

gastric mucosa with xiao wei yan powder. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 12(10), 580, 602–3. 

Sakamoto, S., Yoshino, H., Shirahata, Y., Shimodairo, K. and Okamoto, R. (1992) Pharmacotherapeutic 

effects of kuei-chih-fu-ling-wan (keishi-bukuryo-gan) on human uterine myomas. Am. J. Chin. Med. 

20(3–4), 313–17. 




Panax quinquefolium (Linn.) (Ginseng) (Araliaceae) 


Location: Of Manchuria, China and other parts of eastern Asia origin. It is easy to find it in most 

of the forests of the countries of Southeast Asia but also in the United States and Canada. It is 

also cultivated. 


Stem: simple, erect about 30.5cm high. 

Root: it is 10–25cm long and 1–2cm diameter. 

Leaves: each divided into five finely toothed leaflets. 

Flowers: single terminal umbel, with a few small, yellowish flowers. 

Figure 3.20 Ginseng/Panax.


Tradition: The root has been used for centuries in traditional Chinese medicine. It is believed 

that it makes those who use it stronger and younger. 

Part used: Roots (Ginseng radix). 

Active ingredients: Ginsenosides (saponins), ginsan (acidic polysaccharide), panaxytriol and panaxydol 

(polyacetylenic alcohols). 

Particular value: It is used particularly for dyspepsia, vomiting and nervous disorders. 


● 

● 

● 

Ginsenosides appear to have antitumor promoting activity and antimetastatic action in 

several cancers such as ovarian cancer, breast cancer, stomach cancer and melanoma. 

Ginsan has antineoplastic activity. It has been proved that it induces Th1 cell and 

macrophage cytokines (Kim et al., 1998). 

Antineoplastic activity, cancer chemoprevention, effects on cytochemical components of 

SGC-823 gastriccarcinoma (in cell culture), Ehrlich ascites tumor cells (mouse), inhibition 

of autochthonous tumor, effects on adenocarcinoma of the human ovary, stomach cancer, 

melanoma cells (Xiaoguang et al., 1998). 



● 

Panaxytriol (possible action) is cytotoxic. It is responsible for inhibition of 

mitochondrial respiration. Panaxydol has antiproliferative activity and has affinity for 

target cell membrane. 


● 

● 

Red ginseng is a traditional Chinese medicine. Its extracts A and B are the active components 

of Panax ginseng. As it is considered as a tonic many studies have been carried 

out on ginseng and the immune function of the human body. Some studies refer to the 

effects of red ginseng extracts on transplantable tumors and proliferation of lymphocyte. 

It has been proved that in a two-stage model, red ginseng extracts had a significant 

cancer chemoprevention (Xiaoguang et al., 1998). At the dose of 50–400mgkg 1 , 

the extracts could inhibit DMBA/Croton oil-induced skin papilloma in mice and 

decrease the incidence of papilloma. The red ginseng extract B seems to have a 

stronger antioxidative effect than that of extract A. Those doses (50 approximately 

400mgkg 1 ) could significantly inhibit the growth of transplantable mouse sarcoma 

S-180 and melanoma B16. In lower doses (extract A 0.5mgml 1 and B 0.1 and 

0.25 mgml 1 ) might effectively promote the transformation of T lymphocyte. 

Another study took place in Korea with Korean red ginseng, evaluating the effects of 

ginseng in inhibition or prevention of carcinogenesis. It was administered orally to 

ICR new born mice (Yun et al., 1983). Tumors were induced by various chemical carcinogens 

within 24h after birth. The newborn mices were injected in the ubscapular


region by 9, 10-dimethyl-1, 2-benzanthracene (DMBA), urethane, and aflatoxin B1. 

Autopsy was done on the mices immediately following sacrifice and an examination 

of all their organs was conducted (histopathological examinations, weight, etc.). The 

decrease in the average diameter and in the weight of lung adenomas was over 23%, 

while the incidence of diffuse pulmonary infiltration was 63%. The results of the 

study indicate that Korean red ginseng extract inhibited the incidence and also the 

proliferation of tumors induced by DMBA, urethane and aflatoxin B1. 


● 

● 

● 

● 

Panax ginseng: most of the compounds come from the methanolic extract of the root. 

Only the roots are used in medicine. It contains ginsenosides, ginsan, panaxytriol and 

panaxydol. A new chloride is also produced that is cytotoxic. It is used against various 

human cancers such stomach, breast, ovary, lung, leukemia, hepatoma, adenocarcinomas. 

Administration is either oral or by injection (shenmai injection). 

Panax vietnamensis: The root contains the ginsenosides: majonoside R2, ginsenoside 

R2, and ginsenoside –Rg1. It is used for its inhibitory effects on tumor growth 

(human ovarian cancer cells) and for its antitumor promoting activity. Ginsenoside 

Rg1 seems to downregulate glycocorticoid receptors and displays synergistic 

effects with CAMP (Lee et al., 1997). 

Panax quinquefolius L.: It is the American version of the ginseng. The extract of the 

root was used in studies and the administration was done orally. Ginsenosides were 

contained, also, and the effects showed a decrease of serum gamma globulin and IgG1 

isotype (in mice) and ps2 expression in MCF-7 breast cancer cells (Kim et al., 1997). 

Panax ginseng (red): It is the Korean Panax ginseng. The extract of the root is used in 

medicine: A and B which contain ginsenoside Rg3, Rb2, Rh2, Rh4, 20(R), 

20(S). Inhibits the tumor metastasis, tumor angiogenesis and improves the cell 

immune system. In studies related to stomach cancer the shenmai injection is used 

which is produced from red ginseng extract. 

References 

Bernart, M.W., Cardellina, II J.H. Balaschak, M.S., Alexander, M.R., Shoemaker, R.H. and Boyd, M.R. 

(1996) Cytotoxic falcarinol oxylipins from Dendropanax arboreus. J. Nat. Prod. 59(8), 748–53. 

Kim, K.H., Lee, Y.S., Jung, I.S., Park, S.Y., Chung, H.Y., Lee, I.R. and Yun, Y.S. (1998) Acidic polysaccharide 

from Panax ginseng, ginsan, induces Th1 cell and macrophage cytokines and generates LAK 

cells in synergy with rIL-2. Planta Med. 64(2), 110–15. 

Kim, Y.W., Song, D.K., Kim, W.H., Lee, K.M., Wie, M.B., Kim, Y.H., Kee, S.H. and Cho, M.K. (1997) 

Long-term oral administration of ginseng extract decreases serum gamma-globulin and IgG1 isotype in 

mice. J. Ethnopharmacol. 58(1), 55–8. 

Lee, Y.J., Chung, E., Lee, K.Y., Lee, Y.H., Huh, B. and Lee, S.K. (1997) Ginsenoside-Rg1, one of the major 

active molecules from Panax ginseng, is a functional ligand of glucocorticoid receptor. Mol. Cell 

Endocrinol. 133(2), 135–40. 

Li, C.P. (1975) A new medical trend in China. Am. J. Chin. Med. 3(3), 213–21. 

Lin, S.Y., Liu, L.M. and Wu, L.C. (1995) Effects of Shenmai injection on immune function in stomach 

cancer patients after chemotherapy Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 15(8), 451–3.


Yamamoto, M., Kumagai, A. and Yamamura, Y. (1983) Plasma lipid-lowering and lipogenesis-stimulating 

actions of ginseng saponins in tumor-bearing rats. Am. J. Chin. Med. 11(1–4), 88–95. 

Wakabayashi, C., Hasegawa, H., Murata, J. and Saiki, I. (1997) In vivo antimetastatic action of ginseng 

protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration. 

Oncol. Res. 9(8), 411–17. 

Wakabayashi, C., Murakami, K., Hasegawa, H., Murata, J. and Saiki, I. (1998) An intestinal bacterial 

metabolite of ginseng protopanaxadiol saponins has the ability to induce apoptosis in tumor cells. 

Biochem. Biophys. Res. Commun. 246(3), 725–30. 

Xiaoguang, C., Hongyan, L., Xiaohong, L., Zhaodi, F., Yan, L., Lihua, T. and Rui, H. (1998) Cancer 

chemopreventive and therapeutic activities of red ginseng. J Ethnopharmacol. 60(1), 71–8. 

Yun, T.K., Yun, Y.S. and Han, I.W. (1983) Anticarcinogenic effect of long-term oral administration of red 

ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detect. Prev. 6(6), 515–25. 

Salikhova, R.A., Umnova, N.V., Fomina, M.M. and Poroshenko, G.G. (1994) An antimutagenicity study 

of bioginseng. Izv Akad Nauk Ser Biol 1, 48–55. 

Phyllanthus niruri (Phyllanthus) (Euphorbiaceae) 

Location: Northern Asia. 

Appearance 

Stem: 0.5m high, erect, red. 

Leaves: small, green, oblonged and feathered. 

Flowers: greenish white. 

Antitumor 

Cytotoxic 

Parts used: root, fruit, leaf. 

Active ingredients: Glycosides: phyllanthoside, phyllanthostatin (Phyllanthus acuminatus). 

Particular value: It is used as antitumor, anti-leukemic (Phyllanthus acuminatus), antiviral, cytotoxic, 

chemopreventive. 

Indicative dosage and application: Against the growth of the murine P-388 lymphocytic 

leukemia cell line in a dose of 0.35gml 1 . 


● 

● 

● 

Treatment of acute and chronic hepatitis B and healthy carriers of HBV hepatocellular 

carcinoma (liver cancer) (Phyllanthus urinaria, Phyllanthus amarus) (Blumberg et al., 1989, 

1990). 

Dalton’s lymphoma ascites (DLA) tumor (mice) (Phyllanthus emblica) (Suresh and 

Vasudevan, 1994). 

Phyllanthostatin inhibits the growth of the murine P-388 lymphocytic leukemia cell line 

(Pettit et al., 1990). 



● 

The aqueous extract of Phyllanthus amarus contains some components that are able to 

inhibit in vitro HBsAg secretion on a dose-dependent manner. Various hepatoma cell


● 

lines, such as the Alexander cell line, human-derived cell line which has the property 

of secreting HBsAg in the supernatant (Jayaram and Thyagarajan, 1996). 

Extracts of Phyllanthus amarus have also been shown to inhibit the DNA polymerase 

of HBV and woodchuck hepatitis virus (WHV) in vitro (Blumberg et al., 1989). 


● 

● 

● 

Phyllanthus niruri L.: the MeOH extract of the dried leaf contains niruriside, a potent 

antiviral compound (Qian-Cutrone et al., 1996). 

The roots of Phyllanthus acuminatus contain the glycosides, phyllanthoside (a major 

antineoplastic constituent) and phyllanthostatin which inhibits (ED 50 0.35 

g ml 1 ) the growth of the murine P-388 lymphocytic leukemia cell line. This 

species contains also didesacetylphyllanthostatin and descinnamoylphyllanthocindiol 

(Pettit et al., 1990). 

Aqueous extracts of edible dried fruits of Phyllanthus emblica prevented the incidence 

of carcinogenesis in mice treated with nickel chloride. Ascorbic acid, a major constituent 

of the fruit, fed for seven consecutive days in equivalent concentration as that 

present in the fruit, however, could only alleviate the cytotoxic effects induced by low 

doses of nickel; at the higher doses it was ineffective. The greater efficacy of the fruit 

extract could be due to the interaction of its various natural components rather than 

to any single constituent (Dhir et al., 1991). 


● 

Phyllanthus emblica is an excellent source of vitamin C (ascorbate) and, when administered 

orally, has been found to enhance natural killer (NK) cell activity and antibodydependent 

cellular cytotoxicity. Enhanced activity was highly significant on days 3, 5, 

7 and 9 after tumor inoculation with respect to the untreated tumor bearing control. 

The following have been documented: (a) an absolute requirement for a functional NK 

cell or K-cell population in order that P. emblica can exert its effect on tumor-bearing 

animals, and (b) the antitumor activity of P. emblica is mediated primarily through the 

ability of the drug to augment natural cell-mediated cytotoxicity (Suresh and 

Vasudevan, 1994). 

References 

Blumberg, B.S., Millman, I., Venkateswaran, P.S. and Thyagarajan, S.P. (1990) Hepatitis B virus and primary 

hepatocellular carcinoma: treatment of HBV carriers with Phyllanthus amarus. Vaccine 8(Suppl.S), 

86–92. 

Blumberg, B.S., Millman, I., Venkateswaran, P.S. and Thyagarajan, S.P. (1989) Hepatitis B virus and hepatocellular 

carcinoma – treatment of HBV carriers with Phyllanthus amarus. Cancer Detect Prev. 14(2), 

195–201. 

Dhir, H., Agarwal, K., Sharma, A. and Talukder, G. (1991) Modifying role of Phyllanthus emblica and ascorbic 

acid against nickel clastogenicity in mice. Cancer Lett. 59(1), 9–18. 

Jayaram, S. and Thyagarajan, S.P. (1996) Inhibition of HBsAg secretion from Alexander cell line by 

Phyllanthus amarus. Indian J. Pathol. Microbiol. 39(3), 211–15.


Ji, X.H., Qin, Y.Z., Wang, W.Y., Zhu, J.Y. and Liu, X.T. (1993) Effects of extracts from Phyllanthus 

urinaria L. on HBsAg production in PLC/PRF/5 cell line. Chung Kuo Chung Yao Tsa Chih. 18(8), 

496–8, 511. 

Pettit, G.R., Schaufelberger, D.E., Nieman, R.A., Dufresne, C. and Saenz-Renauld, J.A. (1990) 

Antineoplastic agents, 177. Isolation and structure of phyllanthostatin 6. J. Nat. Prod. 53(6), 1406–13. 

Qian-Cutrone, J., Huang, S., Trimble, J., Li, H., Lin, P.F., Alam, M., Klohr, S.E. and Kadow, K.F. (1996) 

Niruriside, a new HIV REV/RRE binding inhibitor from Phyllanthus niruri. J. Nat. Prod. 59(2), 196–9. 

Suresh, K. and Vasudevan, D.M. (1994) Augmentation of murine natural killer cell and antibody dependent 

cellular cytotoxicity activities by Phyllanthus emblica, a new immunomodulator. J. Ethnopharmacol. 

44(1), 55–60. 

Yeh, S.F., Hong, C.Y., Huang, Y.L., Liu, T.Y., Choo, K.B. and Chou, C.K. (1993) Effect of an extract from 

Phyllanthus amarus on hepatitis B surface antigen gene expression in human hepatoma cells. Antiviral 

Res. 20(3), 185–92. 

Plumeria sp. (Plumeria) 

Cytotoxic 

(Apocynaceae) 

Location: warm tropical areas of the Pacific Islands, Caribbean, South America and Mexico 

(Plumeria rubra: Indonesia, Thailand). 


Stem: 10–12m, widely spaced thick succulent branches. 

Leaves: round or pointed, long leather, fleshy leaves in clusters near the branch tips. 

Flowers: large, waxy, red, white, yellow, pink and multiple pastels, fragrant. 

In bloom: early summer through the early fall months. 

Tradition: Traditional medicinal plant of Thailand. 

Part used: bark. 

Figure 3.21 Plumeria.



● 

● 

Petroleum-ether- and CHCl3-soluble extracts: (1) iridoids: fulvoplumierin, allamcin and 

allamandin, (2) 2,5-dimethoxy-p-benzoquinone. 

H 2 O-soluble extract: (1) iridoids: plumericin, isoplumericin, (2) lignan: liriodendrin. 

Documented target cancers: murine lymphocytic leukemia (P-388) and a number of human 

cancer cell types (breast, colon, fibrosarcoma, lung, melanoma, KB). 



● 

The iridoids: plumericin, isoplumericin except their cytotoxic activity, they also have 

antibacterial activity 


● 

Five additional iridoids, 15-demethylplumieride, plumieride, alpha-allamcidin], 

beta-allamcidin, and 13-O-trans-p-coumaroylplumieride, were obtained as inactive 

constituents (Hamburger et al., 1991). Compound 15-demethylplumieride was 

found to be a novel natural product, and its structure was determined by spectroscopic 

methods and by conversion to plumieride (Kardono et al., 1990). 

References 

Borchert, R. and Rivera, G. (2001) Photoperiodic control of seasonal development and dormancy in tropical 

stem-succulent trees. Tree Physiol. 21(4), 213–21. 

Franca, O.O., Brown, R.T. and Santos, C.A. (2000) Uleine and demethoxyaspidospermine from the bark 

of Plumeria lancifolia. Fitoterapia 71(2), 208–10. 

Guevara, A.P., Amor, E. and Russell, G. (1996) Antimutagens from Plumeria acuminata Ait. Mutat. Res. 

12, 361, (2–3), 67–72. 

Hamburger, M.O., Cordell, G.A. and Ruangrungsi, N. (1991) Traditional medicinal plants of Thailand. 

XVII. Biologically active constituents of Plumeria rubra. J. Ethnopharmacol. 33(3), 289–92. 

Kardono, L.B., Tsauri, S., Padmawinata, K., Pezzuto, J.M. and Kinghorn, A.D. (1990) Cytotoxic constituents 

of the bark of Plumeria rubra collected in Indonesia. J. Nat. Prod. 53(6), 1447–55. 

Muir, C.K. and Hoe, K.F. (1982) Pharmacological action of leaves of Plumeria acuminata. Planta Med. 44(1), 

61–3. 

Tan, G.T., Pezzuto, J.M., Kinghorn, A.D. and Hughes, S.H. (1991) Evaluation of natural products as 

inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. J. Nat. Prod. 54(1), 

143–54. 

Radford, D.J., Gillies, A.D., Hinds, J.A. and Duffy, P. (1986) Naturally occurring cardiac glycosides. Med. 

J. Aust. 12, 144(10), 540–4.


Polanisia dodecandra L. (Polanisia) (Capparaceae) 

Cytotoxic 

Location: plants are found from Quebec and Maryland to southern Saskatchewan and Manitoba 

south to Arkansas and northern Mexico at elevations under 6,000 feet. 


Stem: 0.3–1m, simple, strong dark odor. 

Leaves: 5cm long and bear three leaflets about an inch long. 

Flowers: 20 flowers are clustered at the top of the plant. 1cm long, white with purple basis. 

In bloom: May–October. 

Active ingredients: Flavonols: 5,3-dihydroxy-3,6,7,8,4-pentamethoxyflavone [1], 5,4-dihydroxy-3,6,7,8,3-pentamethoxyflavone 

[2]. 

Documented target cancers: It is used in: cancer of the central nervous system (SF-268, SF-539, 

SNB-75, U-251), non-small cell lung cancer (HOP-62, NCI-H266, NCI-H460, NCI-H522), 

small-cell lung cancer (DMS-114), ovarian cancer (OVCAR-3, SK-OV-3), colon cancer (HCT- 

116), renal cancer (UO-31), melanoma cell line (SK-MEL-5), leukemia cell lines (HL-60 [TB], 

SR), medulloblastoma (TE-671) tumor cells. 



● 

5,3-dihydroxy-3,6,7,8,4-pentamethoxyflavone inhibited tubulin polymerization 

(IC 50 0.830.2M) and the binding of radiolabeled colchicine to tubulin with 

59% inhibition when present in equimolar concentrations with colchicine. It is the 

first example of a flavonol that exhibits potent inhibition of tubulin polymerization 

and, therefore, warrants further investigation as an antimitotic agent (Shi et al., 1995). 

Figure 3.22 Polanisia dodecandra.

References 


Shi, Q., Chen, K., Li, L., Chang, J.J., Autry, C., Kozuka, M., Konoshima, T., Estes, J.R., Lin, C.M. and 

Hamel, E. (1995) Antitumor agents, 154. Cytotoxic and antimitotic flavonols from Polanisia dodecandra. 

J. Nat. Prod. 58(4), 475–82. 

Wang, H.K., Xia, Y., Yang, Z.Y., Natschke, S.L. and Lee, K.H. (1998) Recent advances in the discovery 

and development of flavonoids and their analogues as antitumor and anti-HIV agents. Adv. Exp. Med. 

Biol. 439, 191–225. 

Shi, Q., Chen, K., Fujioka, T., Kashiwada, Y., Chang, J.J., Kozuka, M., Estes, J.R., McPhail, A.T., 

McPhail, D.R. and Lee, K.H. (1992) Antitumor agents, 135. Structure and stereochemistry of polacandrin, 

a new cytotoxic triterpene from Polanisia dodecandra. J. Nat. Prod. 55(10), 1488–97. 

Rabdosia rubescens (Rabdosia) (Lamiaceae) 

Location: West China. 

Tradition: It is a traditional medicinal herb of China. 


Cytotoxic 

● 

● 

● 

● 

Unsaturated lactone: 10-epi-olguine (Rabdosia ternifolia (D. Don) Hara) 

Oridonin (Rabdosia rubescens) (cytotoxic cisplatin, inducing DNA damage) 

Diterpenoids: enmein-, oridonin- and trichorabdal-type (Rabdosia trichocarpa) 

Antitumor constituent: rabdophyllin G (Rabdosia macrophylla). 

Particular value: Important use in medicine for fighting cancer. 

Precautions: Careful use because of its toxicity. 

Documented target cancers: Human cancer cell lines, Ehrlich ascites carcinoma (mice), antileukemic. 



● 

● 

Trichorabdal-type diterpenoids showed the highest antitumor activity against 

Ehrlich ascites carcinoma in mice. In vitro activity against HeLa cells and in vivo activity 

against P-388 lymphocytic leukemia were also determined, but no synergistic 

increase in activity due to plural active sites was observed in those cases (Fuji et al., 

1989). 

From August 1974 to January 1987, 650 cases of moderate and advanced esophageal 

carcinoma were treated with a combination of chemotherapy and Rabdosia rubescens 

and/or traditional Chinese medicinal prescription. After treatment, 40 patients survived 

for over 5 years (5-year survival rate 6.15%): 32 for over 6 years, 23 for more 

than 10 years, 5 for more than 15 years and 20 died of tumors (16 cases) or other diseases 

(4 cases). There were 20 patients who lived or more than 18 years (Wang, 

1993). Analyzing the data, it is believed that the age, the state of activity, the length


● 

of illness, the effectiveness of primary treatment, the multi-course extensive therapy, 

long-term maintenance treatment, etc. are all important factors affecting the results 

of drug treatment. 

One hundred and fifteen patients with inoperable esophageal carcinoma were treated 

by either chemotherapy alone or chemotherapy plus Rabdosia rubescens. In group A, 

out of 31 patients treated with pingyangmycin (P) and nitrocaphane (N), 10 (32.3%) 

responded to the treatment. Among them, 2 showed partial response (greater than 

50% tumor regression) and 8 minimal response (greater than 50% tumor regression). 

In group B, out of 84 patients treated with PN plus Rabdosia rubescens, 59 (70.2%) 

responded. Of them, 10 showed complete response (100% tumor regression), 16 partial 

response and 33 minimal response. The one-year survival rates of group A and B 

were 13.6% and 41.3%. Statistical significance was present in these two groups both 

in the response rate and one-year survival rate. As regards the drug toxicity, there was 

no significant difference between these two groups. Alopecia, anorexia, nausea and 

hyperpyrexia occurred in more than 30% of patients. Mild leukopenia and thrombocytopenia 

and interstitial pneumonia were noted in some patients, and two patients 

died of toxicity in the lungs (Wang, 1993; Wang et al., 1986). 

References 

Cheng, P.Y., Xu, M.J., Lin, Y.L. and Shi, J.C. (1982) The structure of rabdophyllin G, an antitumor constituent 

of Rabdosia macrophylla. Yao Hsueh Hsueh Pao. 17(12), 917–21. 

Fuji, K., Node, M., Sai, M., Fujita, E., Takeda, S. and Unemi, N. (1989) Terpenoids. LIII. Antitumor activity 

of trichorabdals and related compounds. Chem. Pharm. Bull. (Tokyo) 37(6), 1472–6. 

Gao, Z.G., Ye, Q.X. and Zhang, T.M. (1993) See RSynergistic effect of oridonin and cisplatin on cytotoxicity 

and DNA cross-link against mouse sarcoma S180 cells in culture. Chung Kuo Yao Li Hsueh Pao 

14(6), 561–4. 

Lu, G.H., Wang, F.P., Pezzuto, J.M., Tam, T.C., Williams, I.D. and Che, C.T. (1997) 10-Epi-olguine from 

Rabdosia ternifolia. J. Nat. Prod. 60(4), 425–7. 

Nagao, Y., Ito, N., Kohno, T., Kuroda, H. and Fujita, E. (1982) Antitumor activity of Rabdosia and 

Teucrium diterpenoids against P 388 lymphocytic leukemia in mice. Chem. Pharm. Bull. (Tokyo) 30(2), 

727–9. 

Wang, R.L. (1993) A report of 40 cases of esophageal carcinoma surviving for more than 5 years after treatment 

with drugs. Chung Hua Chung Liu Tsa Chih. 15(4), 300–2. 

Wang, R.L., Gao, B.L., Xiong, M.L., Mei, Q.D., Fan, K.S., Zuo, Z.K., Lang, T.L., Gao, G.Q., Ji, Z.C. and 

Wie, D.C. (1986) Potentiation by Rabdosia rubescens on chemotherapy of advanced esophageal carcinoma. 

Chung Hua Chung Liu Tsa Chih 8(4), 297–9. 

Rubia cordifolia L. (Rubia (Bengal madder)) (Rubiaceae) 

Antitumor 

Location: India 

Appearance 

Stem: 3m high, stalks are very weak that they often lie along the ground preventing the plant 

from rising. 

Root: main and side roots, the side roots run under the surface of the ground for some distance 

sending up shoots.


Leaves: have spines along the midrib on the underside. 

Flowers: the flower-shoots spring from the joints in pairs, the loose spikes of yellow 

In bloom: June. 



● 

● 

The root of R. cordifolia: naphthohydroquinones, naphthohydroquinone dimers, naphthohydroquinone, 

naphthoquinone, anthraquinones, naphthohydroquinone dimer, bicyclic 

hexapeptides: RA-XI, -XII, XIII, -XIV, -XV and -XVI (P388). 

Rubia akane, R. cordifolia: cyclic hexapeptide: RA-700. 

Indicative dosage and application: RA-700 was given from 0.2 to 1.4mgm 2 in single i.v. dose 

study, from 0.4 to 2.0mgm 2 in 5-day i.v. 

Documented target cancers: Various tumors in vivo and in vitro (such as: P388, L1210, L5178Y, 

B16 melanoma, Lewis lung carcinoma and sarcoma-180) (Brunet et al., 1997; Larana et al., 

1997; Sanz et al., 1998; Urbano-Ispizua et al., 1997, 1998). 



● 

RA-700 has been tested in a phase I clinical study conducted by the RA-700 clinical 

study group consisting of 6 institutions. A single dose administration and 5-day 

schedule administration were evaluated with 14 patients respectively. RA-700 was 

given from 0.2 to 1.4mgm 2 in single i.v. dose study, from 0.4 to 2.0mgm 2 in 

5-day i.v. schedule study. Nausea and vomiting, fever, stomachache, mild hypotension 

and slight abnormality of electric-cardiogram were observed as the toxicities. In 

a pharmacokinetic study, the elimination half-lives (t1/2) of RA-700 in plasma were 

55min, of alpha-phase and 3.9h of beta-phase by single dose study, and 23–25min 

of alpha-phase and 6–14h of beta-phase by a 5-day schedule study. Accumulation 

was not found by 5-day schedule administration, and metabolite were not observed 

in plasma and urine. It seems that RA-700 is metabolized by the liver and excreted 

in the feces (Yoshida et al., 1994). In conclusion, the maximum tolerated dose was 

1.4mgm 2 for 5-day schedule administration. 


● 

Further studies have shown that: (1) changes in cardiac function were noted in both 

groups, (2) changes in blood pressure, sigma QRS, ejection fraction, and fractional 

shortening of the second group tended to be more extreme than those of the first 

group. Care for continuity is a concern with long-term and high doses of RA-700,


(3) because of the small sample, we could find no relationship between the changes 

in cardiac function and the injection doses of RA-700, (4) therefore, the cardiac 

function must be checked by giving anti-neoplastic drugs to neoplastic patients. 


● 

The antitumor activity of RA-700 was evaluated in comparison with deoxy-bouvardin 

and vincristine (VCR). As regards the proliferation of L1210 cultured cells, the cytotoxicity 

of RA-700 was similar to that of VCR but superior to that of deoxybouvardin 

(Yoshida et al., 1994). The IC50 value of RA-700 was 0.05mcgml 1 

under our experimental conditions. RA-700 inhibited the incorporation of 14 C- 

leucine at a concentration at which no effects were observed on the incorporation of 

3H-thymidine and 3H-uridine in L1210 culture cells in vitro. The antitumor activity 

of RA-700 was similar to that of deoxy-bouvardin and VCR against P388 

leukemia. Daily treatment with RA-700 at an optimal dose resulted in 118% ILS. 

As with deoxy-bouvardin and VCR, the therapeutic efficacy of RA-700 depends on 

the time schedule. RA-700 showed marginal activity against L1210 leukemia (50% 

ILS), similar to that of deoxy-bouvardin but inferior to that of VCR. RA-700 inhibited 

Lewis tumor growth in the early stage after tumor implantation, whereas deoxybouvardin 

and VCR did not. As regards toxicity, a slight reduction of peripheral 

WBC counts was observed with the drug, but no reduction of RBC and platelet 

counts. BUN, creatinine, GPT and GOT levels in plasma did not change with the 

administration of the drug. 


● 

Another anticancer principle isolated from Rubia cordifolia is RC-18, which has been 

used against a spectrum of experimental murine tumors, namely P388, L1210, 

L5178Y, B16 melanoma, Lewis lung carcinoma and sarcoma-180. RC-18 exhibited 

significant increase in the life span of ascites leukaemia P388, L1210, L5178Y and a 

solid tumor B16 melanoma. However, it failed to show any inhibitory effect on solid 

tumors, Lewis lung carcinoma and sarcoma-180. Promising results against a spectrum 

of experimental tumors suggest that RC-18 may lead to the development of a 

potential anti-cancer agent (Brunet et al., 1997; Larana et al., 1997; Sanz et al., 1998; 

Urbano-Ispizua et al., 1997, 1998). 


● 

Madder root, Rubia tinctorum L., is a traditional herbal medicine used against kidney 

stones. This species contains lucidin, a hydroxyanthraquinone derivative present in 

this plant and is mutagenic in bacteria and mammalian cells. In these respect, the use 

of madder root for medicinal purposes is associated with a carcinogenic risk 

(Westendorf et al., 1998).

References 


Alegre, A., Diaz-Mediavilla, J., San-Miguel, J., Martinez, R., Garcia Larana, J., Sureda, A., Lahuerta, J.J., 

Morales, D., Blade, J., Caballero, D., De la Rubia, J., Escudero, A., Diez-Martin, J.L., Hernandez- 

Navarro, F., Rifon, J., Odriozola, J., Brunet, S., De la Serna, J., Besalduch, J., Vidal, M.J., Solano, C., 

Leon, A., Sanchez, JJ., Martinez-Chamorro, C. and Fernandez-Ranada, J.M. (1998) Autologous peripheral 

blood stem cell transplantation for multiple myeloma: a report of 259 cases from the Spanish 

Registry. Spanish Registry for Transplant in MM (Grupo Espanol de Trasplante Hematopoyetico- 

GETH) and PETHEMA. Bone Marrow Transplant. 21(2), 133–40. 

Brunet, S., Urbano-Ispizua, A., Solano, C., Ojeda, E., Caballero, D., Torrabadella, M., de la Rubia, J., 

Perez-Oteiza, J., Moraleda, J., Espigado, I., de la Serna, J., Petit, J., Bargay, J., Mataix, R., Vivancos, P., 

Figuera, A., Sierra, J., Domingo-Albos, A., Hernandez, F., Garcia Conde, J. and Rozman, C. (1997) 

Allogenic transplant of non-manipulated hematopoietic progenitor peripheral blood cells. Spanish experience 

of 79 cases. Allo-Peripheral Blood Transplantation Group. Sangre (Barc) 42(Suppl. 1), 42–3. 

Garcia Larana, J., Diaz Mediavilla, J., Martinez, R., Lahuerta, J.J., Alegre, A., Odriozola, J., Sureda, A., 

San Miguel, J., De la Rubia, J., Escudero, A., Conde, E., Blade, J., Cabrera, R., Gastearena, J., 

Besalduch, J., Vidal, M.J., Hernandez, F., Rifon, J., Leon, A., Mataix, R., Parody, R., Moraleda, J.M., 

Solano, C., de Pablos, J.M. and Sanchez, J.J. (1997) Maintenance treatment with interferon-alfa in multiple 

myeloma after autotransplantation of peripheral blood progenitor cells. Spanish Register of 

Transplantation in Myeloma. Sangre (Barc) 42(Suppl. 1), 38–41. 

Lopez, F., Jarque, I., Martin, G., Sanz, G.F., Palau, J., Martinez, J., de la Rubia, J., Larrea, L., Arnao, M., 

Solves, P., Cervera, J., Martinez, M.L., Peman, J., Gobernado, M. and Sanz, M.A. (1998) Invasive fungal 

infections in patients with blood disorders. Med. Clin. (Barc) 110(11), 401–5. 

Lopez, A., de la Rubia, J., Arriaga, F., Jimenez, C., Sanz, G.F., Carpio, N. and Marty, M.L. (1998) Severe 

hemolytic anemia due to multiple red cell alloantibodies after an ABO-incompatible allogeneic bone 

marrow transplant. Transfusion 38(3), 247–51. 

Sanz, M.A., de la Rubia, J., Bonanad, S., Barragan, E., Sempere, A., Martin, G., Martinez, J.A., Jimenez, C., 

Cervera, J., Bolufer, P. and Sanz, G.F. (1998) Prolonged molecular remission after PML/RAR alpha-positive 

autologous peripheral blood stem cell transplantation in acute promyelocytic leukemia: is relevant 

pretransplant minimal residual disease in the graft Leukemia 12(6), 992–5. 

Urbano-Ispizua, A., Solano, C., Brunet, S., de la Rubia, J., Odriozola, J., Zuazu, J., Figuera, A., Caballero, D., 

Martinez, C., Garcia, J., Sanz, G., Torrabadella, M., Alegre, A., Perez-Oteiza, J., Jurado, M., Oyonarte, 

S., Sierra, J., Garcia-Conde, J. and Rozman, C. (1998) Allogeneic transplantation of selected CD34 

cells from peripheral blood: experience of 62 cases using immunoadsorption or immunomagnetic technique. 

Spanish Group of Allo-PBT. Bone Marrow Transplant. 22(6), 519–25. 

Urbano-Ispizua, A., Solano, C., Brunet, S., de la Rubia, J., Odriozola, J., Zuazu, J., Figuera, A., Caballero, D., 

Martinez, C., Garcia, J., Sanz, G., Torrabadella, M., Alegre, A., Perez-Oteyza, J., Sierra, J., Garcia- 

Conde, J. and Rozman, C. (1997) Allogeneic transplant of CD34 peripheral blood cells from HLAidentical 

donors: Spanish experience of 40 cases. Allo-Peripheral Blood Transplantation Group. Sangre 

(Barc) 42(Suppl. 1), 44–5. 

Westendorf, J., Pfau, W. and Schulte, A. (1998) Carcinogenicity and DNA adduct formation observed in 

ACI rats after long-term treatment with madder root, Rubia tinctorum L. Carcinogenesis 19(12), 2163–8. 

Salvia sclarea (Salvia (Clarry)) (Lamiaceae) 

Location: Middle Europe. 

Anti-leukemic 


Stem: It is a biennial plant with square brownish stems 0.5–1m high, hairy, with few new branches.


Figure 3.23 Salvia sclarea. 

Leaves: are arranged in pairs, almost stalkless, almost as large as the hand, heart-shaped and 

covered with velvety hairs. 

Flowers: are interspersed with large colored, membraneous bracts, longer than the spiny calyx. 

Blue or white. 


Tradition: This herb was first brought into use by the wine merchants of Germany and later 

was employed as a substitute for sophisticating beer, communicating considerable bitterness 

and intoxicating property. In ancient times and in the middle ages it was used for its curative 

properties. 

Part used: seeds. 

Active ingredients: A specific lectin from the seeds of Salvia sclarea. 

Documented target cancers: Inhibitory activity against human erythroleukemic cell line K562, 

T leukemia cells Jurkat. 



● 

From the seeds of Salvia sclarea (SSA) was isolated a lectin specific for Ga1Nac- 

Ser/Thr studied in human erythroleukemic cell line K562. Another study proved 

that glycoproteins from the human T leukemia cells Jurkat were found to bind to the 

Ga1Nac-Ser/Thr specific lectin from SSA. Studies show that this specific lectin has 

an inhibitory activity against the human erythroleukemic cell line K562 and T 

leukemia cells.



● 

Some strong natural antioxidants like carnosol were proved to exhibit anti-inflammatory 

and inhibitory effects with regard to tumor-initiation activities in mice test 

systems. Also some sage compounds (ursolic and/or oleanolic acid) that show no 

antioxidant may turn promising in future research of inflammation and of cancer prevention. 

A squalene derived triterpenoid ursolic acid and its isomer oleanolic acid 

(up to 4% in sage leaves, dry weight basis) act anti-inflammatory and inhibit 

tumorigenesis in mouse skin. Recent data on the anti-inflammatory activity of sage 

(S. officinalis L.) extracts when applied topically (ID 50 2040gcm 2 ) and 

evaluated as edema inhibition after Croton oil-induced dermatitis in mouse ear, 

confirm/suggest ursolic acid to be the main active ingredient, responsible for sage 

anti-inflammatory effect. The data on the pharmacological effects of these 

metabolites promise new therapeutic possibilities of sage extracts. 


● Ursolic acid showed significant cytotoxicity in lymphatic leukemia cells P-388 (ED 50 

3.15gml 1 ) and L-1210 (ED 50 4.00gml 1 ) as well as human lung carcinoma 

cell A-549 (ED 50 4.00gml 1 ) (Lee et al., 1987; Fang and McLaughlin, 

1989). Both carnosol and ursolic acid are referred to as being strong inhibitors of 12- 

O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase activity 

and of TPA-induced tumor promotion in mouse skin. The tumorigenesis-prevention 

potential of ursolic acid was comparable to that of retinoic acid (RA) – a known 

inhibitor of tumor promotion. Both ursolic acid- and oleanolic acid- treatment 

(41 nmol of each), when applied continuously before each TPA-treatment (4.1nmol), 

delayed the formation of papillomas in mouse skin, significantly reduced the rate of 

papilloma-bearing mice and reduced the number of papillomas per mouse, when 

compared with the control group (only TPA treatment). Ursolic acid acted more 

effectively in a single application before initial TPA-treatment when compared to the 

effect of RA and/or oleanolic acid. So, the mechanism of the inhibitory action of ursolic 

acid (inhibition of the first critical cellular event in tumor promotion step caused 

by TPA) may differ slightly from those of RA and/or oleanolic acid, which block a 

critical second stage process in tumor promotion by TPA (induction of ornithine 

decarboxylase and polyamine levels). 


● 

● 

A possible tumorigenesis preventing effect can be predicted for abietane diterpene 

galdosol, isolated from S. canariensis L., which showed significant cytostatic activity 

(ID 50 0.50gml 1 ) when inhibition of development of single-layer culture of 

HeLA 229 cells was measured in in vitro experiment. 

One of the most dangerous environmental sources of cytogenetic damage is ionizing 

radiation, which acts either directly or by secondary reactions and induces ionization 

in tissues. Interaction of ionizing radiation with water and other protoplasmatic constituents 

in oxidative metabolism causes formation of harmful oxygen radicals. DNA 

lesions, caused by reactive oxygen species in mammalian cells are the initial event


● 

which may lead to possible mutagenesis and/or carcinogenesis and form the basis of 

spontaneous cancer incidence. Free radicals play an important role in preventing 

deleterious alterations in cellular DNA and genotoxic effects caused by ionizing radiation 

in mammalian tissues. Many drugs and chemicals (for example sulfhydryl compounds) 

are known to increase the survival rate in animals. Based on animal models 

studies, S. miltiorrhiza and its extracts were shown to have a potential to prevent 

X-radiation-induced pulmonary injuries and high dosage gamma-irradiationinduced 

platelet aggregation lesions. 

The antiproliferative activity of tanshinones against five human tumor cells, that is, 

A-549 (lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF-498 (central nerve 

system) and HCT-15 (colon), was evaluated by sulfrhodamine-B method. Eighteen 

isolated tanshinones exhibited significant but presumably nonspecific cytotoxicity 

against all tested tumor cells, which might be attributed to common naphtoquinone 

skeleton rather than to substituents attached to it. Methylenetanshiquinone and tanshindiol 

C exhibited most powerful cytotoxic effects against tested tumor cells, with 

IC 50 ranging from 0.4gml 1 in A-549 cells to 2.2gml 1 in SK-MEL-2 cells and 

IC 50 from 0.3gml 1 in SK-MEL-2 cells to 0.9gml 1 in SK-OV-3 cancer cell 

lines respectively. 


● 

From S. przewalskii Maxim. var. mandarinorum Stib., a strong bacteriostatic compound, 

przewaquinone A was isolated (Yang et al., 1981, 1984). Przewaquinone A 

was reported to possess potential for inhibiting Lewis lung carcinoma and melanoma 

B-16. 

References 

Darias, V., Bravo, L., Rabanal, R., Snchez-Mateo, C.C. and Martn-Herrera, D.A. (1990) Cytostatic and 

antibacterial activity of some compounds isolated from several lamiaceae species from the Canary 

Islands. Planta Med. 56, 70–2. 

Du, H., Quian, Z. and Wang, Z. (1990) Prevention of radiation injury of the lungs by Salvia miltiorrhiza 

in mice. Chinese J. Mod. Develop. Trad. Med. 10(4), 230–1. 

Fang, X.P. and McLaughlin, J.L. (1989) Ursolic acid, a cytotoxic component of the berries of Ilex verticillata. 

Fitoterapia 61(1), 176–7. 

Hanawalt, P.C. (1998) Genomic instability: environmental invasion and the enemies within. Mutation Res. 

400(1–2), 117–25. 

Huang, M.T., Ho, C.T., Wang, Z.X., Ferraro, T., Lou, Y.R., Stauber, K., Ma, W., Georgiadis, C., Laskin, 

J.D. and Conney, A.H. (1994) Inhibition of skin tumorigenesis by Rosemary and its constituents 

carnosol and ursolic acid. Cancer Res. 54, 701–8. 

Lee, A.R., Chang, W.L., Lin, H.C. and King, M.L. (1987) Isolation and bioactivity of new tanshinones. 

J. Nat. Prod., 50, 157–61. 

Lutz, W.K. (1998) Dose–response relationships in chemical carcinogenesis: superposition of different 

mechanisms of action, resulting in linear–nonlinear curves, practical treshholds, J-shapes. Mutation Res. 

405(2), 117–24.


Ryu, S.Y., Lee, C.O. and Choi, S.U. (1997) In Vitro cytotoxicity of tanshinones from Salvia Miltiorrhiza. 

Planta Med. 63, 339–42. 

Tokuda, H., Onigashi, H. and Koshimizu, K. (1986) Inhibitory effects of ursolic and oleanolic acid on skin 

tumor promotion by 12-o-tetradecanoilphorbol-13-acetate. Cancer Lett. 33, 279–85. 

Wang, H.F., Li, X.D., Chen, Y.M., Yuan, L.B. and Foye, W.O. (1991) Radiation-protective and platelet 

aggregation inhibitory effects of five traditional Chinese drugs and acetylsalicylic acid following highdose-gamma-irradiation. 

J. Ethnopharmacol. 34(2–3), 215–19. 

Xiao, P.G. (1989) Excerpts of the Chinese pharmacopoeia. In Herbs, Spices and Medicinal Plants. (Eds. L.E. 

Craker and J.E. Simon), Recent advances in Botany, Horticulture and Pharmacology, vol. 4, Oryx Press, 

Arizona, pp. 42–114. 

Sargassum bacciferum (Sargassum) (Fucaceae) 

Antimetastatic 

Location in: North Atlantic Ocean. 


Thallus: coarse, light yellow or brownish-green, erect, 0.5–1m in height. Attaches itself to the 

rocks by branched, rootlike, woody extremities, developed from the base of the stalk. The front 

is almost fan shaped, narrow and trap shaped at the base, the rest is flat and leaf-like in form, 

wavy, many times divided into two, with erect divisions having a very strong, broad, compressed 

midrib running to the apex. 

Parts used: dried mass of root, stem and leaves. 


● 

● 

Aqueous extract: Fucoidan polysaccharides. 

Methanolic extract: dihydroxysargaquinone. 

Documented target cancers: Antimetastatic (lung cancer, Ehrlich carcinoma) (mice); Antileukemic 

(dihydroxysargaquinone); Immunostimulatory; Cytotoxic (dihydroxysargaquinone). 

Figure 3.24 Sargassum.




● 

● 

● 

● 

Sargassum thunbergii, the brown seaweed umitoranoo contains neutral and acidic polysaccharides. 

Antitumor activity has been attributed to two fractions, GIV-A ([] 25 D 

127 and mol. wt., 19,000) and GIV-B ([] 25 D 110 and mol. wt., 13,500) (Itoh 

et al., 1993). These compounds were found to be a fucoidan or L-fucan containing 

approx. 30% sulfate ester groups per fucose residue, about 10% uronic acid, and less 

than 2% protein. 

Sargassum fulvellum contains a polysaccharide fraction (either a sulphated peptidoglycuronoglycan 

or a sulphated glycuronoglycan) with remarkable tumor-inhibiting 

effect against sarcoma-180 implanted subcutaneously in mice. 

Sargassum tortile: The CCl4 partition fractions from methanolic extracts of this species 

contain dihydroxysargaquinone, which is cytotoxic against cultured P-388 lymphocytic 

leukemia cells (Numata et al., 1991). 

Sargassum kjellmanianum is also effective in the in vivo growth inhibition of the 

implanted Sarcoma-180 cells (Yamamoto et al., 1981). 


● 

GIV-A markedly inhibited the growth of Ehrlich ascites carcinoma at the dose of 

20 mgkg 1 X10 with no sign of toxicity in mice. It is acting as a so-called activator 

of the reticuloendothelial system. Fucoidan enhanced the phagocytosis and chemiluminescence 

of macrophages. By the immunofluorescent method, binding of the third 

component of complement (C3) cleavage product to macrophages and the proportion 

of C3 positive cells were increased. These results suggest that the antitumor activity 

of fucoidan is related to the enhancement of immune responses (Itoh et al., 1995). 

The present results indicate that fucoidan may open new perspectives in cancer 

chemotherapy. 

References 

Amagata, T., Minoura, K. and Numata, A. (1998) Cytotoxic metabolites produced by a fungal strain from 

a Sargassum alga. J. Antibiot. (Tokyo) 51(4), 432–4. 

Iizima-Mizui, N., Fujihara, M., Himeno, J., Komiyama, K., Umezawa, I. and Nagumo, T. (1985) 

Antitumor activity of polysaccharide fractions from the brown seaweed Sargassum kjellmanianum. Kitasato 

Arch. Exp. Med. 58(3), 59–71. 

Itoh, H., Noda, H., Amano, H. and Ito, H. (1995) Immunological analysis of inhibition of lung metastases 

by fucoidan (GIV-A) prepared from brown seaweed Sargassum thunbergii. Anticancer Res. 15(5B), 1937–47. 

Itoh, H., Noda, H., Amano, H., Zhuaug, C., Mizuno, T. and Ito, H. (1993) Antitumor activity and 

immunological properties of marine algal polysaccharides, especially fucoidan, prepared from Sargassum 

thunbergii of Phaeophyceae. Anticancer Res. 13(6A), 2045–52. 

Numata, A., Kanbara, S., Takahashi, C., Fujiki, R., Yoneda, M., Fujita, E. and Nabeshima, Y. (1991) 

Cytotoxic activity of marine algae and a cytotoxic principle of the brown alga Sargassum tortile. Chem. 

Pharm. Bull. (Tokyo) 39(8), 2129–31.


Yamamoto, I., Takahashi, M., Suzuki, T., Seino, H. and Mori, H. (1984) Antitumor effect of seaweeds. IV. 

Enhancement of antitumor activity by sulfation of a crude fucoidan fraction from Sargassum kjellmanianum. 

Jpn. J Exp. Med. 54(4), 143–51. 

Yamamoto, I., Nagumo, T., Takahashi, M., Fujihara, M., Suzuki, Y., Iizima, N. (1981) Antitumor effect 

of seaweeds. III. Antitumor effect of an extract from Sargassum kjellmanianum. Jpn. J. Exp. Med. 51(3), 

187–9. 

Zhuang, C., Itoh, H., Mizuno, T. and Ito, H. (1995) Antitumor active fucoidan from the brown seaweed, 

umitoranoo (Sargassum thunbergii). Biosci. Biotechnol. Biochem. 59(4), 563–7. 

Scutellaria baicalensis Georgii (Scutellaria (Scullcap)) 

Antitumor 

(Labiatae) 

Location: USA, Great Britain. 

Appearance 

Stem: square, 15–45cm high, somewhat slender, either paniculately branched or in small 

specimens. 

Root: perennial and creeping root-stock. 

Leaves: opposite downy leaves, oblong and tapering, heart-shaped at the base, 1–5cm long, 

notched and short petioles. 

Flowers: in pairs, each growing from the axils of the upper, leaf-like bracts, bright blue with 

white inside. 

In bloom: July–September. 

Part used: The whole herb. 


● 

● 

Flavonoids: baicalin, baicalein and wogonin. 

Flavones: 5,7,2-trihydroxy- and 5,7,2,3-tetrahydroxyflavone. 

Documented target cancers: Hepatoma cell lines, Pliss’ lymphosarcoma, Epstein–Barr virus, 

skin cancer (mice). 



● 

● 

Scutellaria baicalensis Georgi (methanol extract) contains the flavonoids baicalin, 

baicalein and wogonin which induce the quinone reductase in the Hepa 1c1c7 murine 

hepatoma cell line (Park et al., 1998). Baicalin may be the major active principle of 

QR induction mediated by scutellaria radix extract. In addition, the flavones 5,7,2trihydroxy- 

and 5,7,2,3-tetrahydroxyflavone exhibit remarkable inhibitory effects on 

mouse skin tumor promotion in an in vivo two-stage carcinogenesis test and on the 

Epstein–Barr virus early antigen activation. 

Isolation of E-1-(4-Hydroxyphenyl)-but-1-en-3-one from Scutellaria barbata (Ducki 

et al., 1996).


● 

Ten known glycosidic compounds, betulalbuside A (1), 8-hydroxylinaloyl,3-O-beta-Dglucopyranoside 

(2) (monoterpen glycosides), ipolamide (3) (iridoid glycoside), acteoside (verbascoside) 

(4), leucosceptoside A (5), martynoside (6), forsythoside B (7), phlinoside B (8), 

phlinoside C (9), and teuerioside (10) (phenylpropanoid glycosides) were isolated from 

methanolic extracts of Phlomis armeniaca and Scutellaria salviifolia (Labiatae) 

(Yamashiki et al., 1997). Structure elucidations were carried out using 1H-, 13C- 

NMR and FAB-MS spectra, as well as chemical evidence. The cytotoxic and 

cytostatic activities of isolated compounds were investigated by the 3-[4,5- 

dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method. Among the 

glycosides obtained here, caffeic acid-containing phenylpropanoid (or phenethyl 

alcohol, or phenylethanoid) glycosides were found to show activity against several 

kinds of cancer cells. However, they didn’t affect the growth and viability of primarycultured 

rat hepatocytes. Study of the structure–activity relationship indicated that 

ortho-dihydroxy aromatic systems of phenylpropanoid glycosides are necessary for 

their cytotoxic and cytostatic activities. 


● 

● 

● 

The advancement of Pliss’ lymphosarcoma in rats was shown to be associated with 

disorders of platelet-mediated hemostasis presenting with either lowered or increased 

aggregation activity of platelets. In the latter case, a direct correlation was observed 

between functional activity of thrombocytes, on the one hand, and degree of tumor 

advancement and its metastatic activity, on the other. The extract of Scutellaria 

baicalensis Georgi was shown to produce a normalizing effect on platelet-mediated 

hemostasis whatever the pattern of alteration that points to the adaptogenic activity 

of the drug (Gol’dberg et al., 1997). This activity is thought to be responsible for the 

drug’s antitumor and, particularly, metastasis-preventing effect. 

In experiments with murine and rat transplantable tumors, Scutellaria baicalensis 

Georgii extract treatment was shown to ameliorate cyclophosphamide and 5-fluorouracil-induced 

myelotoxicity and to decrease tumor cell viability. This was partly 

attributed to a pronounced antistressor action of the extract and its normalizing effect 

on some homeostatic parameters. 

As a supplement to conventional chemotherapy: cytostatic therapy of patients with 

lung cancer is attended with decrease in the relative number of T-lymphocytes and 

their theophylline-resistant population. Patients who were given Scutellaria barbata 

(SB) showed a tendency towards increase of these parameters during antitumor 

chemotherapy. The immunoregulation index (IRI) in this case was approximately 

twice the background values during the whole period of investigation. The inclusion 

of SB in the therapeutic complex promotes increase in the number of immunoglobulins 

A at a stable level of immunoglobulin G (Smol’ianinov et al., 1997). 


● 

Glial cells have a role in maintaining the function of neural cells. A study was 

undertaken to clarify the effects of baicalin and baicalein, flavonoids isolated from an


● 

important medicinal plant Scutellariae Radix (the root of Scutellaria baicalensis Georgi), 

on glial cell function using C6 rat glioma cells (Kyo et al., 1998). Baicalin and 

baicalein caused concentration-dependent inhibition of a histamine-induced increase 

in intracellular Ca 2 concentrations ([Ca 2 ] i ). The potency of baicalein was significantly 

greater than that of baicalin. The noradrenaline- and carbachol-induced 

increase in [Ca 2 ] i was also inhibited by baicalein and both drugs inhibited histamine-induced 

accumulation of total [3H]inositol phosphates, consistent with their 

inhibition of the increase in [Ca 2 ] i . These results suggest that baicalin and baicalein 

inhibit [Ca 2 ] i elevation by reducing phospholipase C activity. The inhibitory effects 

of baicalin and baicalein on [Ca 2 ] i elevation might be important in the interpretation 

of their pharmacological action on glial cells, such as inhibition of Ca 2 -required 

enzyme phospholipase A2. 

Hemopoiesis was studied in 88 patients with lung cancer during antitumor 

chemotherapy and its combination with a dry SB extract. Administration of the plant 

preparation was accompanied with hemopoiesis stimulation, intensification of bonemarrow 

erythro- and granulocytopoiesis and increase in the content of circulating 

precursors of the type of erythroid and granulomonocytic colony-forming units. 


● 

Oldenlandia diffusa (OD) and Scutellaria barbata (SB) have been used in traditional 

Chinese medicine for treating liver, lung and rectal tumors while Astragalus 

membranaceus (AM) and Ligustrum lucidum (LL) are often used as adjuncts in cancer therapy. 

The effects of aqueous extracts of these four herbs on aflatoxin B1 (AFB1)-induced 

mutagenesis were investigated using Salmonella typhimurium TA100 as the bacterial 

tester strain and rat liver 9000 xg supernatant as the activation system. The effects of 

these herbs on [3H]AFB1 binding to calf-thymus DNA were assessed. Organosoluble 

and water-soluble metabolites of AFB1 were extracted and analyzed by high-performance 

liquid chromatography (HPLC). Mutagenesis assays revealed that all of these 

herbs produced a concentration-dependent inhibition of histidine-independent revertant 

(His) colonies induced by AFB1. At a concentration of 1.5mgper plate, SB and 

OD in combination exhibited an additive effect. The trend of inhibition of these four 

herbs on AFB1-induced mutagenesis was: SB greater than LL greater than AM. LL, 

OD and SB significantly inhibited AFB1 binding to DNA, reduced AFB1–DNA 

adduct formation, and also significantly decreased the formation of organosoluble 

metabolites of AFB1. This data suggest that these Chinese medicinal herbs possess 

cancer chemopreventive properties (Yamashiki et al., 1997). 

References 

Ducki, S., Hadfield, J.A., Lawrence, N.J., Liu, C.Y., McGown, A.T. and Zhang, X. (1996) Isolation of 

E-1-(4-Hydroxyphenyl)-but-1-en-3-one from Scutellaria barbata. Planta Med. 62(2), 185–6. 

Gol’dberg, V.E., Ryzhakov, V.M., Matiash, M.G., Stepovaia, E.A., Boldyshev, D.A., Litvinenko, V.I. and 

Dygai, A.M. (1997) Dry extract of Scutellaria baicalensis as a hemostimulant in antineoplastic chemotherapy 

in patents with lung cancer. Eksp. Klin. Farmakol. 60(6), 28–30.


Kyo, R., Nakahata, N., Sakakibara, I., Kubo, M. and Ohizumi. Y. (1998) Effects of Sho-saiko-to, San’oshashin-to 

and Scutellariae Radix on intracellular Ca2 mobilization in C6 rat glioma cells. Biol. 

Pharm. Bull. 21(10), 1067–71. 

Kyo, R., Nakahata, N., Sakakibara, I., Kubo, M. and Ohizumi, Y. (1998) Baicalin and baicalein, constituents 

of an important medicinal plant, inhibit intracellular Ca2 elevation by reducing phospholipase 

C activity in C6 rat glioma cells. J. Pharm. Pharmacol. 50(10), 1179–82. 

Park, H.J., Lee, Y.W., Park, H.H., Lee, Y.S., Kwon, I.B. and Yu, J.H. (1998) Induction of quinone reductase 

by a methanol extract of Scutellaria baicalensis and its flavonoids in murine Hepa 1c1c7 cells. Eur. J. 

Cancer Prev. 7(6), 465–71. 

Razina, T.G., Zueva, E.P., Litvinenko, V.I. and Kovalev, I.P. (1998) A semisynthetic flavonoid from the 

Baikal skullcap (Scutellaria baicalensis) as an agent to enhance the efficacy of chemotherapy in experimental 

tumors. Eksp. Klin. Farmakol. 61(2), 54–6. 

Saracoglu, I., Inoue, M., Calis, I. and Ogihara, Y. (1995) Studies on constituents with cytotoxic and cytostatic 

activity of two Turkish medicinal plants Phlomis armeniaca and Scutellaria salviifolia. Biol. Pharm. 

Bull. 18(10), 1396–400. 

Smol’ianinov, E.S., Gol’dberg, V.E., Matiash, M.G., Ryzhakov, V.M., Boldyshev, D.A., Litvinenko, V.I. and 

Dygai, A.M. (1997) Effect of Scutellaria baicalensis extract on the immunologic status of patients with 

lung cancer receiving antineoplastic chemotherapy. Eksp. Klin. Farmakol. 60(6), 49–51. 

Yamashiki, M., Nishimura, A., Suzuki, H., Sakaguchi, S. and Kosaka, Y. (1997) Effects of the Japanese 

herbal medicine “Sho-saiko-to” (TJ-9) on in vitro interleukin-10 production by peripheral blood 

mononuclear cells of patients with chronic hepatitis C. Hepatology 25(6), 1390–7. 

Stellera chamaejasme (Stellera) (Thymelaceae) 

Cytotoxic 

Location: China. 

Active ingredients: Diterpene: gnidimacrin. 

Indicative dosage and application: Gnidimacrin has been used at the dosages of 0.02–0.03mgkg 1 . 

intraperitoneally against mouse leukemia P-388 and L-1210 in vivo and showed significant antitumor 

activities. 

Documented target cancers: Human leukemias, stomach cancers and non-small cell lung cancers 

in vitro. 



● 

Stellera chamaejasme L.: The root (methanolic extract) contains the daphnanetype 

diterpene gnidimacrin. Gnidimacrin acts as a protein kinase C activator for 

tumor cells. 


● 

Gnidimacrin was found to strongly inhibit cell growth of human leukemias, stomach 

cancers and non-small-cell lung cancers in vitro at concentrations of 10 9 to 10 10 M 

(Feng et al., 1995). On the other hand, even at 10 6 to 10 5 M, the small-cell lung


cancer cell line H69 and the hepatoma cell line HLE were refractory to gnidimacrin. 

The agent showed significant antitumor activity against murine leukemias and solid 

tumors in an in vivo system. In K562, a sensitive human leukemia cell line, gnidimacrin 

induced blebbing of the cell surface, which was completely inhibited by staurosporine 

at concentrations above 10 8 M, and arrested the cell cycle transiently to 

G2 and finally the G1 phase at growth-inhibitory concentrations. It inhibited phorbol-12,13-dibutyrate(PDBu) 

binding to K562 cells and directly stimulated protein 

kinase C (PKC) activity in the cells in a dose-dependent manner (3–100nM). 

Although activation of PKC isolated from refractory H69 cells was observed only 

with 100nM gnidimacrin, the degree of activation was lower than that produced by 

3nM in K562 cells. 

● Gnidimacrin showed significant antitumor activities against mouse leukemia P-388 

and L-1210 in vivo (Yoshida et al., 1996). At the dosages of 0.02–0.03mgkg 1 i.p., 

the increase in life span (ILS) was 70% and 80%, respectively. Gnidimacrin was also 

active against murine solid tumors in vivo, such as Lewis lung carcinoma, B-16 

melanoma and colon cancer 26. It showed ILSs of 40%, 49% and 41% at the dosages 

of 0.01–0.02mgkg 1 i.p., respectively. Gnidimacrin strongly inhibited cell proliferation 

of human cancer cell lines such as leukemia K562, stomach cancers Kato-III, 

MKN-28, MKN-45, and mouse L-1210 by the MTT assay and colony forming assay 

in vitro. The IC50 of gnidimacrin was 0.007–0.00012gml 1 . 

● Inhibitory effects of Stellera chamaejasme on the growth of a transplantable tumor in 

mice (Yang, 1986). 

References 

Feng, W., Tetsuro, I. and Mitsuzi, Y. (1995) The antitumor activities of gnidimacrin isolated from Stellera 

chamaejasme L. Chung Hua Chung Liu Tsa Chih 17(1), 24–6. 

Yang, B.Y. (1986) Inhibitory effects of Stellera chamaejasme on the growth of a transplantable tumor in 

mice. Chung Yao Tung Pao. 11(1), 58–9. 

Yoshida, M., Feng, W., Saijo, N. and Ikekawa, T. (1996) Antitumor activity of daphnane-type diterpene 

gnidimacrin isolated from Stellera chamaejasme L. Int. J. Cancer 66(2), 268–73. 

Trifolium pratense L. (Clover, Red) (Leguminosae) 

Chemopreventive 

Synonyms: Trefoil, purple clover. 

Location: It can be found throughout Europe, central and northern Asia from the Mediterranean 

to the Arctic Circle and high up in the mountains. 

Appearance 

Stem: several stems 0.3–0.6m high. 

Root: one root, slightly hairy. 

Leaves: ternate, leaflets ovate, nearly smooth. 

Tradition: Fomentations and poultices of the herb have been used as local treatment. 

Parts used: leaves, flowers.


Active ingredients: isoflavone biochanin A. 

Particular value: The fluid extract is used as an alterative and antispasmodic. 

Documented target cancers: The ability of the isoflavone biochanin A to inhibit carcinogen 

activation in cells in culture suggests that in vivo studies of this compound as a potential 

chemopreventive agent are warranted (Cassady et al., 1988). 


Chemopreventive activity 

● 

Based on the epidemiological evidence for a relationship between consumption of 

certain foods and decreased cancer incidence in humans, an assay was developed to 

screen and fractionate plant extracts for chemopreventive potential. This assay 

measures effects on the metabolism of [3H]benzo(a)pyrene [B(a)P] in hamster 

embryo cell cultures. Screening of several plant extracts has generated a number of 

activity leads. The 95% ethyl alcohol extract of one of these actives, Trifolium pratense L. 

Leguminosae, red clover, significantly inhibited the metabolism of B(a)P and 

decreased the level of binding of B(a)P to DNA by 30–40%. Using activity-directed 

fractionation by solvent partitioning and then silica gel chromatography, a major 

active compound was isolated and identified as the isoflavone, biochanin A. The pure 

compound decreased the metabolism of B(a)P by 54% in comparison to control 

cultures and decreased B(a)P-DNA binding by 37–50% at a dose of 25gml 1 . 

These studies demonstrate that the hydrocarbon metabolism assay can detect and 

guide the fractionation of potential anticarcinogens from plants (Cassady et al., 

1988). 


● 

The tannins, delphinidin and procyanidin were isolated from flowers of white clover 

(Trifolium repens) and the leaves of Arnot Bristly Locust (Robina fertilis) respectively, 

and tested for mutagenic properties in a range of systems. There was no evidence for 

either compound causing significant levels of frameshift or base-pair mutagenesis in 

bacterial mutagenicity assays, although both were weakly positive in a bacterial 

DNA-repair test. Both compounds very slightly increased the frequency of petite 

mutagenesis in Saccharomyces cerevisiae strain D5. In V79 Chinese hamster cells, 

both were efficient inducers of micronuclei. In each of these test systems, increasing 

the potential of the compound for metabolic activation by addition of “S9” mix had 

little effect on toxicity or mutagenicity of either tannin. It would seem that potential 

chromosome-breaking activity of condensed tannins could represent a carcinogenic 

hazard for animals grazing on pastures of white clover in flower. It may also 

have wider implications for human carcinogenesis by some, if not all, condensed 

tannins (Ferguson et al., 1985).

References 


Cassady, J.M., Zennie, T.M., Chae, Y.H., Ferin, M.A., Portuondo, N.E. and Baird, W.M. (1988) Use of a 

mammalian cell culture benzo(a)pyrene metabolism assay for the detection of potential anticarcinogens 

from natural products: inhibition of metabolism by biochanin A, an isoflavone from Trifolium pratense L. 

Cancer Res. 48(22), 6257–61. 

Ferguson, L.R., van Zijl, P., Holloway, W.D. and Jones, W.T. (1985) Condensed tannins induce micronuclei 

in cultured V79 Chinese hamster cells. Mutat. Res. 158(1–2), 89–95. 

Liu, J., Burdette, J.E., Xy, H., Gu, C.,Van Breemen, R.B., Bhat, K.P., Booth, N., Constantinou, A.I., 

Pezzuto, J.M., Fong, H.H., Farnsworth, N.R. and Bolton, J.L. (2001) Evaluation of estrogenic activity 

of plant extracts for the potential treatment of menopausal symptoms. J. Agric. Food Chem. 49(5), 

2472–9. 

Moyad, M.A. (2002) Complementary/alternative therapies for reducing hot flashes in prostate cancer 

patients: reevaluating the existing indirect data from studies of breast cancer and postmenopausal 

women. Urology 59(4 Suppl. 1), 20–33. Review. 

Viola odorata (Violet sweet) (Violaceae) 

Cytotoxic 

Other names: Sweet-scented violet. 

Location: It is found in tropical and temperate regions of the world, in deciduous woods and 

hedges. 

Appearance 

Stem: slightly hairy, up to 10cm high. 

Root: stolon, up to 20cm long. 

Leaves: Rounded, sagittate to heart-shaped, slightly hairy, alternate, up to 6cm long. The two 

halves of the young leaves are rolled in two coils. 

Flowers: Deep purple (occasionally white or pink), fragrant, with yellow stamens, 0.5–1.5cm. 

Fruit: 3-valved capsule. 

In bloom: February–April. Flowers produced in autumn are very small, with no apparent flowerlike 

structure and not fragrant (cleistogamous) but are highly seed-setting. 

Biology: A perennial plant, violet is propagated either by seed or cuttings (scions). The flowers 

are great attractors of bees and other insects, due to their high honey content. It is recommended 

to avoid cultivation near air-polluted areas, because the hairy parts can become accumulating 

points for smog. 

Tradition: The species is supposed to have derived its name from Viola, the Latin form of the 

Greek name Ione or Io, who was turned into a plant by her beloved Jupiter, the flowers emerging 

right above the earth so that she could use them as food. Another Greek myth claims that 

the violet emerged on the spot where a resting Orpheus laid his lyre. Homer and Virgil have 

mentioned the calming and sedative properties of the plant. It was exactly the same properties 

that made the species be associated with death, as referred to by Shakespeare in Hamlet. 

Parts used: whole plant fresh, flowers and leaves dried, rhizomes. 

Active ingredients: Cyclopentenyl cytosine. 

Particular value: Violet flowers possess slightly laxative properties, well known in the form of 

syrup. It is also used in ague, epilepsy inflammatation of the eyes, sleeplessness. 

Precautions: rhizomes are strongly emetic and purgative.


Indicative dosage and application: It has not yet been standardized as a dose, for example on 

human glioblastoma cells the levels of the drug range from 0.01 to 1M. 

Documented target cancers: Cyclopentenyl cytosine (CPEC) exerts an antiproliferative effect against 

a wide variety of human and murine tumor lines. 



● 

CPEC inhibits the proliferation of tumor cell lines, including a panel of human 

gliosarcoma and astrocytoma lines (Agdaria et al., 1997). This effect is produced primarily 

by the 5-triphosphate metabolite CPEC-TP, an inhibitor of cytidine-5triphosphate 

(CTP) synthase (EC 6.3.4.2). This has been demonstrated, for example, 

on human glioblastoma cells obtained at surgery and exposed to the drug at levels 

ranging from 0.01to 1M for 24h. Dose-dependent accumulation of CPEC-TP was 

accompanied by a concomitant decrease in CTP pools, with 50% depletion of the latter 

being achieved at a CPEC level of c.0.1M. Human glioma cell proliferation was 

inhibited 50% by 24-h exposure to 0.07M CPEC. Post-exposure decay of CPEC- 

TP was slow, with a half time of 30h. DNA cytometry showed a dose-dependent shift 

in cell cycle distribution, with an accumulation of cells in S-phase (Agdaria et al., 

1997). The pharmacological effects of CPEC on freshly excised glioblastoma cells are 

quantitatively similar to those seen in a range of established tissue culture lines, 

including human glioma, colon carcinoma, and MOLT-4 lymphoblasts, supporting 

the recommendation that the drug may be advantageous for the treatment of human 

glioblastoma. 

References 

Agbaria, R., Kelley, J.A., Jackman, J., Viola, J.J., Ram, Z. and Oldfield, E.J. (1997) Antiproliferative 

effects of cyclopentenyl cytosine (NSC 75575) in human glioblastoma cells. DG Oncoles 9(3), 111–8. 

Crucitti, F., Doglietto, G., Frontera, D., Viola, G. and Buononato, M. (1995) Carcinoma of the pancreatic 

head area. Therapy: resectability and surgical management of resectable tumors. Rays 20(3), 304–15. 

Review. 

De Berardis, B., Torresini, G., Viola, V., Imondi, G., Marinelli, S. and Di Pietrantonio, F. (2000) Recurrent 

giant retroperitoneal leiomyosarcoma. Report of a clinical case. G. Chir. 21(5), 239–41. 

Fazio, V., Messina, V., Marino, A., Di Trapani, F. and Viola, V. (2002) Treatment with self-expanding 

metallic enteral stents in occlusion caused by neoplastic stenosis of the sigmoid and rectum. Chir Ital. 

54(2), 233–9. 

Ferrara, F., Annunziata, M., Schiavone, E.M., Copia, C., De Simone, M., Pollio, F., Palmieri, S., Viola, A., 

Russo, C. and Mele, G. (2001) High-dose idarubicin and busulphan as conditioning for autologous stem 

cell transplantation in acute myeloid leukemia: a feasibility study. Hematol. J. 2(4), 214–9. 

Ferrara, F., Palmieri, S., Pocali, B., Pollio, F., Viola, A., Annunziata, S., Sebastio, L., Schiavone, E.M., Mele, 

G., Gianfaldoni, G. and Leoni, F. (2002) De novo acute myeloid leukemia with multilineage dysplasia: 

treatment results and prognostic evaluation from a series of 44 patients treated with fludarabine, cytarabine 

and G-CSF (FLAG). Eur. J. Haematol. 68(4), 203–9.


Frontera, D., Doglietto, G., Viola, G. and Crucitti, F. (1995) Carcinoma of the pancreatic head area. 

Epidemiology, natural history and clinical findings. Rays 20(3), 226–36. Review. 

Krygier, G., Lombardo, K., Vargas, C., Alvez, I., Costa, R., Ros, M., Echenique, M., Navarro, V., Delgado, L., 

Viola, A. and Muse, A. (2001) Familial uveal melanoma: report on three sibling cases. Br. J. Ophthalmol. 

85(8), 1007–8. 

Morini, A., Manera, V., Boninsegna, C., Viola, L. and Orrico, D. (2000) Mandibular drop resulting from 

bilateral metastatic trigeminal neuropathy as the presenting symptom of lung cancer. J. Neurol. 247(8), 

647–9. 

Longo, V.D., Viola, K.L., Klein, W.L. and Finch, C.E. (2000) Reversible inactivation of superoxidesensitive 

aconitase in Abeta1–42-treated neuronal cell lines. J. Neurochem. 75(5), 1977–85. 

Madajewicz, S., Hentschel, P., Burns, P., Caruso, R., Fiore, J., Fried, M., Malhotra, H., Ostrow, S., 

Sugarman, S. and Viola, M. (2000) Phase I chemotherapy study of biochemical modulation of folinic 

acid and fluorouracil by gemcitabine in patients with solid tumor malignancies. J. Clin. Oncol. 18(20), 

3553–7. 

Morini, A., Manera, V., Boninsegna, C., Viola, L. and Orrico, D. (2000) Mandibular drop resulting from 

bilateral metastatic trigeminal neuropathy as the presenting symptom of lung cancer. J. Neurol. 247(8), 

647–9. 

Palmieri, S., Sebastio, L., Mele, G., Annunziata, M., Annunziata, S., Copia, C., Viola, A., De Simone, M., 

Pocali, B., Schiavone, E.M. and Ferrara, F. (2002) High-dose cytarabine as consolidation treatment for 

patients with acute myeloid leukemia with t(8;21). Leuk. Res. 26(6), 539–43. 

Villani, F., Viola, G., Vismara, C., Laffranchi, A., Di Russo, A., Viviani, S. and Bonfante, V. (2002) Lung 

function and serum concentrations of different cytokines in patients submitted to radiotherapy and 

intermediate/high dose chemotherapy for Hodgkin’s disease. Anticancer Res. 22(4), 2403–8. 

Wikstroemia indica (Wikstroemia) (Thymelaeaceae) 

Location: Guam and Micronesia. 


Stem: shrub with smooth, reddish bark. 

Leaves: opposite, light green that is rounded at both ends. 

Flowers: small, yellowish green, grow in racemes from the leaf axils. 

Anti-leukemic 

Figure 3.25 Wikstroemia indica.


Active ingredients: Daphnoretin, tricin, kaempferol-3-O--D-glucopyranoside, and ()-nortrachelogenin, 

wikstroelides. 

Documented target cancers: It is used against Ehrlich ascites carcinoma (mice) (daphnoretin), as 

anti-leukemic (tricin, kaempferol-3-O--D-glucopyranoside, and nortrachelogenin), and against 

P-388 lymphocytic leukemia. 



● 

● 

Wikstroemia indica (Thymelaeaceae): The bark contains kaempferol-3-O--Dglucopyranoside, 

huratoxin, pimelea factor P2, wikstroelides A-G, daphnane-type 

diterpenoids (wikstroelides H-O), tricin, kaempferol-3-O--D-glucopyranoside, ()- 

nortrachelogenin, daphnoretin, tricin, kaempferol-3-O--D-glucopyranoside, and 

()-nortrachelogenin (Wang et al., 1998). 

The ethanol extracts of Wikstroemia foetida var. oahuensis and Wikstroemia uvaursi 

showed antitumor activity against the P-388 lymphocytic leukemia (3PS) test 

system. One PS-active constituent of both plants was the lignan wikstromol 

(Torrance, 1979). 

References 

Abe, F., Iwase, Y., Yamauchi, T., Kinjo, K., Yaga, S., Ishii, M. and Iwahana, M. (1998) Minor daphnane-type 

diterpenoids from Wikstroemia retusa. Phytochemistry 47(5), 833–7. 

Torrance, S.J., Hoffmann, J.J. and Cole, J.R. (1979) Wikstromol, antitumor lignan from Wikstroemia 

foetida var. oahuensis Gray and Wikstroemia uvaursi Gray Thymelaeaceae. J. Pharm. Sci. 68(5), 664–5. 



Biol. 439, 191–225. 

3.2.3. The fable: where tradition fails to meet reality 

Aconitum napellus L. (Aconite) 

Poisonous 

(Ranunculaceae) 

Location: It is found in lower mountain slopes of north portion of Eastern Hemisphere, from 

Himalayas through Europe to Great Britain. 


Stem: 3 ft. high. 

Root: fleshy, spindle-shaped, pale-colored when young, dark brown skin when mature. 

Leaves: dark, green glossy, deeply divided in palmate manner. 

Flowers: in erect clusters of a dark blue or white color. 

In bloom: late spring–early summer.


Figure 3.26 Aconitumfischeri. 

Tradition: One of the most useful drugs. It was used for many years as an anodyne, diuretic and 

diaphoretic. It was used, also, for poisoning the arrows. It is mentioned by Dioscorides that 

arrows tipped with the juice would kill wolves. 

Parts used: The whole plant, but especially the root (Aconiti tuber). 

Active ingredients: alkaloids: aconitine, aconine, benzaconine (picraconitine). 

Particular value: It produces highly toxic alkaloids, so all procedures must be done carefully. 

Precautions: Keep away from children, even in gardens. In the dose of 3–6mg it can cause death. 

Documented target cancers: It is tested as a possible anticancer drug. The results of the tests 

have not been announced yet. 



● 

The whole plant contains diterpene alkaloids (N-deethylaconotine) (Aconitum napellus 

and Aconitum napellus ssp. neomontanum) (Grieve, 1994).


References 

Ameri, A. and Simmet, T. (1999) Interaction of the structurally related aconitum alkaloids, aconitine and 

6-benzyolheteratisine, in the rat hippocampus. Eur. J. Pharmacol. 386(2–3), 187–94. 

Been, A. (1992) Aconitum: genus of powerful and sensational plants. Pharm. Hist. 34(1), 35–7. 

Cole, C.T. and Kuchenreuther, M.A. (2001) Molecular markers reveal little genetic differentiation among 

Aconitum noveboracense and A. columbianum (Ranunculaceae) populations. Am. J. Bot. 88(2), 337–47. 

Colombo, M.L, Bravin, M. and Tome, F. (1988) A study of the diterpene alkaloids of Aconitum napellus ssp. 

neomontanum during its onthogenetic cycle. Pharmacol. Res. Commun l5(Supp.), 123–8. 

Fico, G., Braca, A., De Tommasi, N., Tome, F. and Morelli, I. (2001) Flavonoids from Aconitum napellus 

subsp. neomontanum. Phytochemistry 57(4), 543–6. 

Grieve, M. (1994) A Modern Herbal. Edited and introduced by Mrs C.F. Leyel Tiger books international, 

London. 

Imazio, M., Belli, R., Pomari, F., Cecchi., E., Chinaglia, A., Gaschino, G., Ghisio, A., Trinchero, R. and 

Brusca, A. (2000) Malignant ventricular arrhythmias due to Aconitum napellus seeds. Circulation 102(23), 

2907–8. 

Kim, D.K., Kwon, H.Y., Lee, K.R., Rhee, D.K. and Zee, O.P. (1998) Isolation of a multidrug resistance 

inhibitor from Aconitum pseudo-laeve var. erectum. Arch Pharm Res. 21(3), 344–7. 

Li, Z.B. and Wang, F.P. (1998) Two new diterpenoid alkaloids, beiwusines A and B, from Aconitum kusnezoffii. 

J. Asian Nat. Prod. Res. 1(2), 87–92. 

Marchenko, M.M., Kopylchuk, H.P. and Hrygorieva, O.V. (2000) Activity of cytoplasmic proteinases from 

rat liver in Heren’s carcinoma during tumor growth and treatment with medicinal herbs. Ukr. Biokhim. 

Zh. 72(3), 91–4. 

Peng, C.S., Wang, F.P. and Jian, X.X. (2000) New norditerpenoid alkaloids from Aconitum hemsley anum 

var. pengzhouense. J. Asian Nat Prod Res. 2(4), 245–9. 

Ulubelen, A., Mericli, A.H., Mericli, F., Kilincer, N., Ferizli, A.G., Emekci, M. and Pelletier, S.W. (2001) 

Insect repellent activity of diterpenoid alkaloids. Phytother. Res. 15(2), 170–1. 

Wang, F.P., Peng, C.S., Jian, X.X. and Chen, D.L. (2001) Five new norditerpenoid alkaloids from Aconitum 

sinomontanum. J. Asian Nat. Prod. Res. 3(1), 15–22. 

Yamanaka, H., Doi, A., Ishibashi, H. and Akaike, N. (2002) Aconitine facilitates spontaneous transmitter 

release at rat ventromedial hypothalamic neurons. Br. J. Pharmacol. 135(3), 816–22. 

Strychnos Nux-vomica (Strychnos) 

(Loganiaceae) 

Location: India, in the Malay Archipelago. 

Appearance 

Stem: medium-sized tree with short, thick trunk. 

Root: very bitter. 

Leaves: opposite. 

Flowers: small, greeny-white. 

Cytotoxic 

Poisonous 

Tradition: The powdered seeds are employed in atonic dyspepsia. The tincture of Nux Vomica is 

often used in mixtures, for its stimulant action on the gastro-intestinal track. 

Parts used: seeds. 

Active ingredients: strychnopentamine (a dimeric indole alkaloid) from Strychnos usambarensis. 

Particular value: Strychnine is the chief alkaloid constituent of the seeds and acts as a bitter. It 

improves the pulse and raises blood pressure, acts as a tonic to the circulatory system in cardiac 

failure, but in small doses, because it can be poisonous.


Precautions: Application of the drug can cause partial haemolysis and liver damage. 


● 

● 

Four subcutaneous injections of 1.5mg strychnopentamine (one per day) induce a significant 

decrease of the number of Ehrlich ascites tumor cells. 

Strychnopentamine at a relatively low concentration (less than 1g) after 72h of treatment on 

B16 melanoma cells and on non-cancer human fibroblasts cultured in vitro. 


● 

● 

Against Ehrlich ascites tumor cells with a significant increase of the survival of the 

treated mice. 

Strychnopentamine applied on B16 melanoma cells and on non-cancer human fibroblasts 

cultured in vitro strongly inhibits cell proliferation and induces cell death. 



● 

● 

● 

Strychnopentamine (SP) is an alkaloid isolated from Strychnos usambarensis Gilg, is a 

potential anticancer agent, which strongly inhibits cell proliferation and induces cell 

death on B16 melanoma cells and on non-cancer human fibroblasts cultured in vitro 

and induce a significant decrease of the number of Ehrlich ascites tumor cells 

(Quetin-Leclercq et al., 1993). 

Strychnopentamine, in a low concentration (less than 1g) after 72h showed that 

incorporation of thymidine and leucine by B16 cells significantly decreases after only 

1 h of treatment. SP induces the formation of dense lamellar bodies and vacuolization 

in the cytoplasm intense blebbing at the cell surface and various cytological 

alterations leading to cell death (Quetin-Leclercq et al., 1991 and 1993). 

Three more alkaloids isolated from Strychnos usambarensis on cancer cells in culture 

(Bassleer et al., 1992). 

References 

Bassleer, R., Depauw-Gillet, M.C., Massart, B., Marnette, J.M., Wiliquet, P., Caprasse, M. and Angenot, L. 

(1982) Effects of three alkaloids isolated from Strychnos usambarensis on cancer cells in culture. Planta 

Med. 45(2), 123–6. 

Cai, B.C., Hattori, M. and Namba, T. (1990) Processing of nux vomica. II. Changes in alkaloid composition 

of the seeds of Strychnos nux-vomica on traditional drug-processing. Chem. Pharm. Bull. (Tokyo) 

38(5), 1295–8. 

Chin, V.T., Hue, P.G., Zwaving, J.H. and Hendriks, H. (1987) Some adaptations in the method of the 

“pharmacopoeia helvetica editio sixta” for the determination of total alkaloids in Strychnos seeds. Pharm. 

Weekbl. [Sci]. 9(6), 324–5. 

Gao, H., Sun, W. and Sha, Z. (1990) Quantitative determination of strychnine and brucine in semen 

Strychni and its preparations by gas chromatography. Chung Kuo Chung Yao Tsa Chih 15(11), 670–1, 703.


Gong, L.G. (1984) Studies on the processing method of Strychnos nux-vomica. Chung Yao Tung Pao 

9(2), 67–9. 

Jacob, M., Soediro-Soetarno, Puech, A., Casadebaig-Lafon, J., Duru, C. and Pellecuer, J. (1985) 

Comparative study of availability of various extracts of Strychnos Ligustrina B. L. Pharm. Acta Helv. 

60(1), 13–6. 

Melo, M.F., Santos, C.A., Chiappeta, A.A., de Mello, J.F. and Mukherjee, R. (1987) Chemistry and pharmacology 

of a tertiary alkaloid from Strychnos trinervis root bark. J. Ethnopharmacol. 19(3), 319–25. 

Nikoletti, M., Goulart, M.O., de Lima, R.A., Goulart, A.E., Delle Monache, F. and Marini Bettolo, G.B. 

(1984) Flavonoids and alkaloids from Strychnos pseudoquina. J. Nat. Prod. 47(6), 953–7. 

Ogeto, J.O., Juma, F.D. and Muriuki, G. (1984) Practical therapeutics: some investigations of the toxic 

effects of the alkaloids extracted from Strychnos henningsii (Gilg) “muteta.” East Afr. Med. J. 61(5), 427–32. 

Quetin-Leclercq, J., Angenot, L. and Bisset, N.G. (1990) South American Strychnos species. Ethnobotany 

(except curare) and alkaloid screening. J. Ethnopharmacol. 8(1), 1–52. Review. 

Quetin-Leclercq, J., Bouzahzah, B., Pons, A., Greimers, R., Angenot, L., Bassleer, R. and Barbason, H. 

(1993) Strychnopentamine, a potential anticancer agent. Planta Med. 59(1), 59–62. 

Quetin-Leclercq, J., De Pauw-Gillet, M.C., Angenot, L. and Bassleer, R. (1991) Effects of strychnopentamine 

on cells cultured in vitro. Chem. Biol. Interact. 80(2), 203–16. 

Tits, M., Damas, J., Quetin-Leclercq, J. and Angenot, L. (1991) From ethnobotanical uses of Strychnos 

henningsii to antiinflammatories, analgesics and antispasmodics. J. Ethnopharmacol. 34(2–3), 261–7. 

Verpoorte, R., Aadewiel, J., Strombom, J. and Baerheim Svendsen, A. (1984) Alkaloids from Strychnos 

chrysophylla. J. Ethnopharmacol. 10(2), 243–7. 

Weeratunga, G., Goonetileke, A., Rolfsen, W., Bohlin, L. and Sandberg, F. (1984) Alkaloids in Strychnos 

aculeata. Acta Pharm. Suec. 21(2), 135–40. 

Wright, C.W., Bray D.H., O’Neill, M.J., Warhust, D.C., Phillipson, J.D., Quetin-Leclercq, J. and 

Angenot, L. (1991) Antiamoebic and antiplasmodial activities of alkaloids isolated from Strychnos 

usambarensis. Planta Med. 57(4), 337–40. 

Yuno, K., Yamada, H., Oguri, K. and Yoshimura, H. (1990) Substrate specificity of guinea pig liver flavincontaining 

monooxygenase for morphine, tropane and strychnos alkaloids. Biochem Pharmacol. 15, 

40(10), 2380–2. 

Symphytum officinale L. (Comfrey) 

Antimitotic 

(Boraginaceae) 

Carcinogenic 

Probably nature’s most famous wound-healing species, comfrey has been often referred to as a 

cancer-fighting drug. Quite ironically, its use may actually increase the possibility of contracting 

the disease. 

Location: It is found in Europe and temperate Asia, usually in watery places. 

Appearance 

Stem: leafy, angular, covered with bristly hairs, 60–90cm high. 

Root: fibrous, fleshy, and spindle-shaped. 

Leaves: radical leaves are very large (they decrease in size), shape ovate, covered with rough hairs. 

Flowers: yellow or purple, growing on short stalks, scorpoid in form. 

In bloom: May–July. 

Tradition: A green vegetable (roots and leaves). Decoction used as herbal tea. 

Parts used: Leaves, root. 

Active ingredients: pyrrolizidine alkaloid-N-oxides: 7-acetyl intermedine, 7-acetyl lycopsamine, 

lycopsamine, intermedine, symphytine.


Documented carcinogenic properties 

● 

● 

● 

● 

Its crude watery extract and its protein fraction stimulate the in vivo proliferation of 

neoplastic cells and exert an antimitotic effect on human T lymphocytes (Olinescu et al., 

1993). 

When digested, it may cause hepatocellular adenomas (at least in rats!). 

Contains hepatotoxic pyrrolizidine alkaloids. 

Alkaloid fractions obtained from the roots demonstrate antimitotic and mutagenic 

activities against both animal and plant cells. 



● 

● 

The crude watery extract of Symphytum officinale and certain protein and carbohydrate 

components had remarkable effects on the respiratory burst of human PMN granulocytes 

stimulated via Fc receptors. 

Pyrrolizidine alkaloids have been linked to liver and lung cancers and a range of other 

deleterious effects. Some comfrey-containing products were found to contain measurable 

quantities of one or more of the hepatotoxic pyrrolizidine alkaloids, in ranges 

from 0.1 to 400.0ppm. Products containing comfrey leaf in combination with one or 

more other related compounds were found to contain the lowest alkaloid levels 

(Couet et al., 1996). Highest levels were found in bulk comfrey root, followed by 

bulk comfrey leaf. 

Carcinogenic activity 

● 

The carcinogenicity of Symphytum officinale L. was studied in inbred ACI rats. Three 

groups of 19–28 rats each were fed comfrey leaves for 480–600 days; four additional 

groups of 15–24 rats were fed comfrey roots for varying lengths of time. A control 

group was given a normal diet were induced in all experimental groups that received 

the diets containing comfrey roots and leaves (Hirono et al., 1978). 

Hemangioendothelial sarcoma of the liver was infrequently induced. 


● 

Mutagenic and antimitotic effects have been attributed to aqueous solutions of alkaloid 

fractions obtained from infusions of Symphytum officinale L. (Furmanowaa et al., 1983). 

References 

Aftab, K., Shaheen, F., Mohammad, F.V., Noorwala, M. and Ahmad, V.U. (1996) Phyto-pharmacology of 

saponins from Symphytum officinale L. Adv. Exp. Med. Biol. 404, 429–42. 

Ahmad, V.U., Noorwala, M., Mohammad, F.V. and Sener, B. (1993) A new triterpene glycoside from the 

roots of Symphytum officinale. J. Nat. Prod. 56(3), 329–34.


Ahmad, V.U., Noorwala, M., Mohammad, F.V., Sener, B., Gilani, A.H. and Aftab, K. (1993) Symphytoxide A, 

a triterpenoid saponin from the roots of Symphytum officinale. Phytochemistry 32(4), 1003–6. 

Barbakadze, V.V., Kemertelidze, E.P., Targamadze, I.L., Shashkov, A.S. and Usov, A.I. (2002) Novel biologically 

active polymer of 3-(3,4-dihydroxyphenyl)glyceric acid from two types of the comphrey 

Symphytum asperum and S. caucasicvum (Boraginoceae). Bioorg Khim. 28(4), 362–6. 

Barthomeuf, C.M., Debiton, E., Barbakadze, V.V. and Kemertelidze, E.P. (2001) Evaluation of the dietetic 

and therapeutic potential of a high molecular weight hydroxycinnamate-derived polymer from 

Symphytum asperum Lepech. Regarding its antioxidant, antilipoperoxidant, antiinflammatory, and cytotoxic 

properties. J. Agric. Food Chem. 49(8), 3942–6. 

Behninger, C., Abel, G., Roder, E., Neuberger, V. and Goggelmann, W. (1989) Studies on the effect of an 

alkaloid extract of Symphytum officinale on human lymphocyte cultures. Planta Med. 55(6), 518–22. 

Betz, J.M., Eppley, R.M., Taylor, W.C. and Andrzejewski, D. (1994) Determination of pyrrolizidine alkaloids 

in commercial comfrey products (Symphytum sp.). J. Pharm. Sci. 83(5), 649–53. 

Couet, C.E., Crews, C. and Hanley, A.B. (1996) Analysis, separation, and bioassay of pyrrolizidine alkaloids 

from comfrey (Symphytum officinale). Nat. Toxins 4(4), 163–7. 

Furmanowa, M., Guzewska, J. and Beldowska, B. (1983) Mutagenic effects of aqueous extracts of 

Symphytum officinale L. and of its alkaloidal fractions. J. Appl. Toxicol. 3(3), 127–30. 

Hirono, I., Mori, H. and Haga, M. (1978) Carcinogenic activity of Symphytum officinale. J. Natl. Cancer Inst. 

61(3), 865–9. 

Johnson, B.M., Bolton, J.L. and Van Breemen, R.B. (2001) Screening botanical extracts or quinoid 

metabolites. Chem. Res. Toxicol. 14(11), 1546–51. 

Kim, N.C., Oberlies, N.H., Brine, D.R., Handy, R.W., Wani, M.C. and Wall, M.E. (2001) Isolation of symlandine 

from the roots of common comfrey (Symphytum officinale) using countercurrent chromatography. 

J. Nat. Prod. 64(2), 251–3. 

Lenghel, V., Radu, D.L., Chirila, P. and Olinescu, A. (1995) The influence of some vegetable extracts on 

the in vitro adherence of mouse and human lymphocytes to nylon fibers. Roum Arch. Microbiol. 

Immunol. 54(1–2), 15–30. 

Mohammad, F.V., Noorwala, M., Ahmad, V.U. and Sener, B. (1995a) A bidesmosidic hederagenin hexasaccharide 

from the roots of Symphytum officinale. Phytochemistry 40(1), 213–8. 

Mohammad, F.V., Noorwala, M., Ahmad, V.U. and Sener, B. (1995b) Bidesmosidic triterpenoidal saponins 

from the roots of Symphytum officinale. Planta Med. 61(1), 94. 

Mroczek, T., Glowniak, K. and Wlaszczyk, A. (2002) Simultaneous determination of N-oxides and free 

bases of pyrrolizidine alkaloids by cation-exchange solid-phase extraction and ion-pair high-performance 

liquid chromatography. J. Chromatogr. A. 949(1–2), 249–62. 

Noorwala, M., Mohammad, F.V., Ahmad, V.U. and Sener, B. (1994) A bidesmosidic triterpene glycoside 

from the roots of Symphytum officinale. Phytochemistry 36(2), 439–43. 

Olinescu, A., Manda, G., Neagu, M., Hristescu, S. and Dasanu, C. (1993) Action of some proteic and carbohydrate 

components of Symphytum officinale upon normal and neoplastic cells. Roum Arch. Microbiol. 

Immunol. 52(2), 73–80. 

Stickel, F. and Seitz, H.K. (2000) The efficacy and safety of comfrey. Public Health Nutr. 3(4A), 501–8. 

Review. 

3.2.4. Other species with documented anticancer activity 

Acacia catechu (Willd.) (Catechu) (Leguminosae) 

Synonyms: Catechu nigrum (Leguminosae), catechu black, cutch. 

Location: It is found in Burma and India. 

Appearance 

Stem: handsome trees. 

Antitumor

Leaves: compoundly pinnate. 

Flowers: are arranged in rounded or elongated clusters. 


Tradition: Is sold under the name of Catechu. It occurs in commerce in black, shining pieces or 

cakes. 

Parts used: leaves, young shoots. 

Active ingredients: Proteins: Concanavalin A, abrin B chain and trypsin inhibitor (ACTI) (Acacia 

confusa). 

Particular value: It is used as an astringent to overcome relaxation of mucous membranes in general. 

An infusion can be employed to stop nose-bleeding, and is also employed as an injection for uterine 

hemorrhage leucorrhoea and gonorrhoea. Externally, it is applied in the form of powder, to boils, 

ulcers and cutaneous eruptions. 

Documented target cancers: sarcoma-180 cells and Hela cell culture (mice). 



● Synthetic chimeric protein (ANB-ACTI) of abrin B chain and trypsin inhibitor 

● Synthetic chimeric protein (Con A-ACTI) of Concanavalin A and trypsin inhibitor. 

Mode of action: Abrin B chain of chimeric protein may act as a vector to carry ACTI into 

the tumor cells. ACTI in the chimeric protein potentiates its antitumor activity as well as 

its resistance to tryptic digestion (Lin et al., 1989). 

References 

Agrawal, S. and Agarwal, S.S. (1990) Preliminary observations on leukaemia specific agglutinins from 

seeds. Indian J. Med. Res. 92, 38–42. 

Hanausek, M., Ganesh, P., Walaszek, Z., Arntzen, C.J., Slaga, T.J. and Gutterman, J.U. (2001) Avicins, a 

family of triterpenoid saponins from Acacia victoriae (Bentham), suppress H-ras mutations and 

aneuploidy in a murine skin carcinogenesis model. Proc. Natl. Acad. Sci. USA. 98(20), 11551–6. 

Kaur, K., Arora, S., Hawthorne, M.E., Kaur, S., Kumar, S. and Mentha, R.G. (2002) A correlativestudyon 

antimutagenic and chemopreventive activity of Acacia auriculiformis A. Cunn. and Acacia nilotica (L.) 

Willd. ExDel. Drug Chem. Toxicol. Feb., 25(1), 39–64. 

Lin, J.Y., Hsieh, Y.S. and Chu, S.C. (1989) Chimeric protein: abrin B chain-trypsin inhibitor conjugate as 

a new antitumor agent. Biochem. Int. 19(2), 313–23. 

Lin, J.Y. and Lin, L.L. (1985) Antitumor lectin-trypsin inhibitor conjugate. J. Natl. Cancer. Inst., 74(5), 

1031–6. 

Lo, Y.L., Hsu, C.Y. and Huang, J.D. (1998) Comparison of effects of surfactants with other MDR reversing 

agents on intracellular uptake of epirubicin in Caco-2 cell line. Anticancer Res. 18(4C), 3005–9. 

Pico, J.L., Choquet, C., Rosenfeld, C., Sharif, A. and Bourillon, R. (1976) Quantitative variations of three 

different lectin receptors as a function of establishment and metabolism of normal and leukaemic human 

cell lines. Differentiation 4, 5,(2–3), 115–7. 

Popoca, J., Aguilar, A., Alonso, D. and Villarreal, M.L. (1998) Cytotoxic activity of selected plants used as 

antitumorals in Mexican traditional medicine. J. Ethnopharmacol. 59(3), 173–7.


Aristolochia elegans (Aristolochia) (Aristolochiaceae) 

Location: South America, with Brazil being its home territory. 


Stem: slender woody stems twine gracefully in tight coils around fence wire and other supports 

to lift the vine to heights of 10 or 12 feet. 

Root: short horizontal rhizome with numerous long, slender roots below. 

Leaves: rich glossy green, about 3in long by 2in wide and grow closely, creating a dense mass of 

foliage. 

Flowers: light green and covered with purple brown spots on the flared lips of the blossom in a 

pattern reminiscent of calico fabric. 


Parts used: dried rhizome and roots. 

Active ingredients: sesquiterpene lactone versicolactone A. 

Indicative dosage and application: it is still under tests. 

Documented target cancers: mutagenic activity in the Ames test. 


Other species 

● Aristolochia versicolar: Roots contain the sesquiterpene lactone versicolactone A. 

● Aristolochia tagala, Aristolochia rigida. Two aristolochia acids and a flavonol glycoside 

have been isolated from A. rigida. Only Aristolochic acid IV has shown a weak direct 

mutagenic activity in the Ames test. 

Figure 3.27 Chamaecyparis.

References 


Konigsbauer, H. (1968) On the usability of Aristolochia tagala Cham. in dermatology. Z. Haut. 

Geschlechtskr. 43(4), 159–63. 

Pistelli, L., Nieri, E., Bilia, A.R., Marsili, A. and Scarpato, R. (1993) Chemical constituents of Aristolochia 

rigida and mutagenic activity of aristolochic acid IV. J. Nat. Prod. 56(9), 1605–8. 

Zhang, J., He, L.X., Xue, H.Z., Feng, R. and Pu, Q.L. (1991) The structure of versicolactone A from 

Aristolochia versicolar S.M. Hwang. Yao Hsueh Hsueh Pao 26(11), 846–51. 

Chamaecyparis lawsonianna (Cypress hinoki) 

Anti-leukemic 

(Cupressaceae) 

Location: Of southern Japan and the island of Taiwan origin, it is found in eastern Asia and 

North America. The typical form of the Hinoki false cypress is rarely cultivated, and most gardeners 

are more familiar with one or more of the many dwarf cultivars selected for size, form and 

foliage color. 


Stem: reddish evergreen conifer with attractive soft and stringy brown bark, cypress can grow 

over 3m tall with a trunk diameter of 12cm. 

Leaves: drooping flat frondlike branchlets bearing small scalelike leaves. Has two kinds of leaves: 

adult leaves are like closely adpressed overlapping scales; leaves on juvenile branchlets and 

young plants don’t overlap and are shaped more like tiny awls or broad needles. The scalelike 

leaves are borne in pairs of two unequal sizes and shapes. 

Tradition: is used as specimens and for hedging, screening and windbreaks. 

Active ingredients: Alkaloids; hinokitiol, tropolone. 

Documented target cancers: high potency in the P-388 leukemia assay. 



● 

Tropolone derivatives prepared from hinokitiol, which naturally occurs in the plants 

of Chamaecyparis species, show high potency in the P-388 leukemia assay. It preferentially 

inhibits the soluble guanylate cyclase from leukemic lymphocytes (Yamato et al., 

1986). This inhibition correlates with its preferential cytotoxic effects for these same 

cells, since cyclic GMP is thought to be involved in lymphocytic cell proliferation 

and leukemogenesis and, in general, the nucleotide is elevated in leukemic versus 

normal lymphocytes and changes have been reported to occur during remission and 

relapse of this disease. 

References 

Debiaggi, M., Pagani, L., Cereda, P.M., Landini, P. and Romero, E., (1988) Antiviral activity of 

Chamaecyparis lawsoniana extract: study with herpes simplex virus type 2. Microbiologica 11(1), 55–61. 

Hiroi, T., Miyazaki, Y., Kobayashi, Y., Imaoka, S. and Funae, Y. (1995) Induction of hepatic P450s in rat 

by essential wood and leaf oils. Xenobiotica 25(5), 457–67.


Ito, H., Nishimura, J., Suzuki, M., Mamiya, S., Sato, K., Takagi, I. and Baba, S. (1995) Specific IgE to 

Japanese cypress (Chamaecyparis obtusa) in patients with nasal allergy. Ann. Allergy Asthma Immunol. 

74(4), 299–303. 

Kingetsu, I., Ohno, N., Hayashi, N., Sakaguchi, M., Inouye, S. and Saito, S. (2000) Common antigenicity 

between Japanese cedar (Cryptomeria japonica) pollen and Japanese cypress (Chamaecyparis obtusa) pollen, I. 

H-2 complex affects cross responsiveness to Cry j 1 and Cha o 1 at the T- and B-cell level in mice. 

Immunology 99(4), 625–9. 

Koyama, S., Yamaguchi, Y., Tanaka, S. and Motoyoshiya, J. (1997) A new substance (Yoshixol) with an 

interesting antibiotic mechanism from wood oil of Japanese traditional tree (Kiso-Hinoki), 

Chamaecyparis obtusa. Gen. Pharmacol. 28(5), 797–804. 

Kuo, Y.H., Chen, C.H. and Huang, S.L. (1998) New diterpenes from the heartwood of Chamaecyparis obtusa 

var. formosana. J. Nat. Prod. 26, 61(6), 829–31. 

Miura, H. (1967) The isolation of isocryptomerin from the leaves of Chamaecyparis obtusa Endlicher. 

Yakugaku Zasshi 87(7), 871–4. 

Muto, N., Dota, A., Tanaka, T., Itoh, N., Okabe, M., Inada, A., Nakanishi, T. and Tanaka, K. (1995) 

Hinokitiol induces differentiation of teratocarcinoma F9 cells. Biol. Pharm. Bull. 18(11), 1576–9. 

Okano, M., Nishioka, K., Nagano, T., Ohta, N. and Masuda, Y. (1994) Clinical characterization of allergic 

patients sensitized to Chamaecyparis obtusa – using AlaSTAT system. Arerugi 43(9), 1179–84. 

Panella, N.A., Karchesy, J., Maupin, G.O., Malan, J.C. and Piesman, J. (1997) Susceptibility of immature 

Ixodes scapularis (Acari: Ixodidae) to plant-derived acaricides. J. Med. Entomol. 34(3), 340–5. 

Suzuki, M., Ito, M., Ito, H., Baba, S., Takagi, I., Yasueda, H. and Ohta, N. (1996) Antigenic analysis of 

Cryptomeria japonica and Chamaecyparis obtusa using anti-Cry j 1 monoclonal antibodies. Acta Otolaryngol. 

525(Suppl.), 85–9. 

Takemoto, D.J., Dunford, C., Vaughn, D., Kramer, K.J., Smith, A. and Powell, R.G. (1982) Guanylate 

cyclase activity in human leukemic and normal lymphocytes. Enzyme inhibition and cytotoxicity of 

plant extracts. Enzyme 27(3), 179–88. 

Toda, T., Chong, Y.S. and Nozoe, T. (1967) New constituents of Chamaecyparis formosensis Matsum. 

Chem. Pharm. Bull. (Tokyo) 15(6), 903–5. 

Yamato, M., Hashigaki, K., Kokubu, N., Tashiro, T. and Tsuruo, T. (1986) Synthesis and antitumor activity 

of tropolone derivatives. 3. J. Med. Chem. 29(7), 1202–5. 

Crinum asiaticum (Crinum) 

Inhibitor 

(var. toxicarium (Hubert)) (Liliaceae) 

Location: wild in low, humid spots in various parts of India and on the coast of Ceylon. It is 

cultivated in Indian gardens. 

Appearance 

Stem: large plant. 

Root: fibrous. 

Leaves: showy. 

Flowers: handsome, white. 

In bloom: April and May. 

Tradition: It was used in India for many years. 

Part used: bulbs, leaves. 

Active ingredients: alkaloid: lycorine. 

Particular value: the bulb was admitted to the Pharmacopoeia of India as a valuable emetic.



● 

● 

Lycorine inhibits not only induction of MM46 cell death by calprotectin but also inhibits the 

suppressive effect of calprotectin on target DNA synthesis at a half effective concentration of 

0.1–0.5gml 1 . 

Lycorine has been reported to posses inhibitory activity against protein translation. 



It has been demostrated that calprotectin, an abundant calcium-binding protein complex 

in polymorphonuclear leukocytes (PMNs), has the capacity to induce growth inhibition 

and apoptotic cell death against a variety of tumor cell lines and normal cells such as 

fibroblasts. Therefore, calprotectin which is released to extracellular spaces, might cause 

tissue destruction in severe inflammatory conditions. Using MM46 mouse mammary 

carcinoma cells as targets, hot water extracts of Crinum asiaticum (lycorine, is the active 

inhibitory molecule) showed strong inhibition of calprotectin-induced cytotoxicity in vitro. 

The dose–response relationship between the inhibitory effects of lycorine on calprotectin 

action and target protein synthesis shows that lycorine inhibition for calprotectin 

cytotoxicity is not solely due to its inhibitory effect on protein synthesis (Yui et al., 1998). 

References 

Elgorashi, E.E., Drewes, S.E. and van Staden, J. (2001) Alkaloids from Crinum moorei. Phytochemistry 56(6), 

637–40. 

Fennell, C.W. and van Staden, J. (2001) Crinum species in traditional and modern medicine. 

J. Ethnopharmacol. 78(1), 15–26. Review. 

Kapu, S.D., Ngwai, Y.B., Kayode, O., Akah, P.A., Wambebe, C. and Gamaniel, K. (2001) Antiinflammatory, 

analgesic and anti-lymphocytic activities of the aqueous extract of Crinum giganteum. 

J. Ethnopharmacol. 78(1), 7–13. 

Min, B.S., Gao, J.J., Nakamura, N., Kim, Y.H. and Hattori, M. (2001) Cytotoxic alkaloids and a flavan 

from the bulbs of Crinum asiaticum var. japonicum. Chem. Pharm. Bull. (Tokyo) 49(9), 1217–9. 

Min, B.S., Kim, Y.H., Tomiyama, M., Nakamura, N., Miyashiro, H., Otake, T. and Hattori, M. (2001) 

Inhibitory effects of Korean plants on HIV-1 activities. Phytother. Res. 15(6), 481–6. 

Okpo, S.O., Fatokun, F. and Adeyemi, O.O. (2001) Analgesic and anti-inflammatory activity of Crinum 

glaucum aqueous extract. J. Ethnopharmacol. 78(2–3), 207–11. 

Samud, A.M., Asmawi, M.Z., Sharma, J.N. and Yusof, A.P. (1999) Anti-inflammatory activity of Crinum 

asiaticum plant and its effect on bradykinin-induced contractions on isolated uterus. Immunopharmacology 

43(2–3), 311–6. 

Yui, S., Mikami, M., Kitahara, M. and Yamazaki, M. (1998) The inhibitory effect of lycorine on tumor cell 

apoptosis induced by polymorphonuclear leukocyte-derived calprotectin. Immunopharmacology 40(2), 

151–62. 

Zvetkova, E., Wirleitner, B., Tram, N.T., Schennach, H. and Fuchs, D. (2001) Aqueous extracts of Crinum 

latifolium (L.) and Camellia sinensis show immunomodulatory properties in human peripheral blood 

mononuclear cells. Int. Immunopharmacol. 1(12), 2143–50.


Casearia sylvestris Sw. (Casearia)(Flacourtiaceae) 

Parts used: leaves. 

Active ingredients: Clerodane diterpenes: casearins A-F. 

Antitumor 


The structures, of the Active ingredients mentioned before, have been completely elucidated 

by two dimensional nuclear magnetic resonance, circular dichroism spectroscopy, 

X-ray analysis, and chemical evidences (Itokawa et al., 1990). 

References 

De Carvalho, P.R., Furlan, M., Young, M.C., Kingston, D.G. and Bolzani, V.S. (1998) Acetylated 

DNA-damaging clerodane diterpenes from Casearia sylvestris. Phytochemistry 49(6), 1659–62. 

Itokawa, H., Totsuka, N., Morita, H., Takeya, K., Iitaka, Y. Schenkel, E.P. and Motidome (1990) New 

antitumor principles, casearins A-F, for Casearia sylvestris Sw. (Flacourtiaceae). Chem. Pharm. Bull. 

(Tokyo) 38(12), 3384–8. 

Oberlies, N.H., Burgess, J.P., Navarro, H.A., Pinos, R.E., Fairchild, C.R., Peterson R.W., Soejarto, D.D., 

Farnsworth, N.R., Kinghorn, A.D., Wani, M.C. and Wall, M.E. (2002) Novel bioactive clerodane 

diterpenoids from the leaves and twigs of Casearia sylvestris. J. Nat. Prod. 65(2), 95–9. 

Simonsen, H.T., Nordskjold, J.B., Smitt, U.W., Nyman, U., Palpu, P., Joshi, P. and Varughese, G. (2001) 

In vitro screening of Indian medicinal plants for antiplasmodial activity. J. Ethnopharmacol. 74(2), 

195–204. 

Eurycoma longifolia 

(Simaroubaceae) 

Location: Indonesia. 



Cytotoxic 

● 

● 

Four canthin-6-one alkaloids: 9-methoxycanthin-6-one, 9-methoxycanthin-6-one-N-oxide, 

9-hydroxycanthin-6-one, and 9-hydroxycanthin-6-one-N-oxide, and 

one quassinoid: eurycomanone. 


● 

● 

Canthin-6-ones 1–4 were found to be active with all cell lines tested: breast, colon, 

fibrosarcoma, lung, melanoma, KB and murine lymphocytic leukemia (P-388). 

Eurycomanone was significantly active against the human cell lines tested [breast, colon, 

fibrosarcoma, lung, melanoma, KB and KB-V1 (a multi-drug resistant cell line derived 

from KB)] but was inactive against murine lymphocytic leukemia (P-388).




● 

Two additional isolates from the roots of Eurycoma longifolia, the beta-carboline 

alkaloids beta-carboline-1-propionic acid and 7-methoxy-beta-carboline-1-propionic acid, 

were not significantly active with these cultured cells (Kardono et al., 1991). 

However, they were found to demonstrate significant antimalarial activity as judged 

by studies conducted with cultured Plasmodium falciparum strains. 

References 

Kanchanapoom, T., Kasai, R., Chumsri, P., Hiraga, Y. and Yamasah, K. (2001) Canthin-6-one and 

-carboline alkaloids from Eurycoma harmadiana. Phytochemistry 56(4), 383–6. 

Kardono, L.B., Angerhofer, C.K., Tsauri, S., Padmawinata, K., Pezzuto, J.M. and Kinghorn, A.D. (1991) 

Cytotoxic and antimalarial constituents of the roots of Eurycoma longifolia. J. Nat. Prod. 54(5), 1360–7. 

Glyptopetalum sclerocarpum (Celastraceae) 

Active ingredients: 22-hydroxytingenone. 

Cytotoxic 

Documented target cancers: Has been tested against P-388 lymphocytic leukemia, KB carcinoma 

of the nasopharynx, and a number of human cancer cell types, that is, HT-1080 fibrosarcoma, 

LU-1 lung cancer, COL-2 colon cancer, MEL-2 melanoma, and BC-1 breast cancer. 



● 

22-Hydroxytingenone was isolated from Glyptopetalum sclerocarpum M. Laws and its 

unambiguous 13 C-NMR assignments were accomplished through the use of APT, 

HETCOR, and selective INEPT spectroscopy. Intense, but nonspecific cytotoxic 

activity was observed when this substance was evaluated with a battery of cell lines 

comprised of the P-388 lymphocytic leukemia, KB carcinoma of the nasopharynx, 

and a number of human cancer cell types, that is, HT-1080 fibrosarcoma, LU-1 

lung cancer, COL-2 colon cancer, MEL-2 melanoma and BC-1 breast cancer 

(Bavovada et al., 1990). 

References 

Bavovada, R., Blasko, G., Shieh, H.L., Pezzuto, J.M. and Cordell, G.A. (1990) Spectral assignment and 

cytotoxicity of 22-hydroxytingenone from Glyptopetalum sclerocarpum. Planta Med. 56(4), 380–2. 

Sotanaphun, U., Suttisri, R., Lipipum, V. and Bavovada, R. (1998) Quinone-methide triterpenoids from 

Glyptopetalum sclerocarpum. Phytochemistry 49(6), 1749–55.


Kigelia pinnata (Kigelia) (Bigoniaceae) 


Parts used: stembark, fruits. 

Active ingredients: Lapachol. 

Documented target cancers: Effects against four melanoma cell lines and a renal cell carcinoma 

line (Caki-2). 


Inhibitory activity 

● 

Significant inhibitory activity was shown by the dichloromethane extract of the stembark 

and lapachol (continuous exposure). Moreover, activity was dose-dependent, the 

extract being less active after 1h exposure. Chemosensitivity of the melanoma cell 

lines to the stembark was greater than that seen for the renal adenocarcinoma line. In 

marked contrast, sensitivity to lapachol was similar amongst the five cell lines 

(Houghton et al., 1994). Lapachol was not detected in the stembark extract. 

References 

Houghton, P.J., Photiou, A., Uddin, S., Shah, P., Browning, M., Jackson, S.J. and Retsas, S. (1994) 

Activity of extracts of Kigelia pinnata against melanoma and renal carcinoma cell lines. 

Planta Med. 60(5), 430–3. 

Jackson, S.J., Houghton, P.J., Retsas, S. and Photiou, A. (2000) In vitro cytotoxicity of norviburtinal and 

isopinnatal from Kigelia pinnata against cancer cell lines. Planta Med. 66(8), 758–61. 

Weiss, C.R., Moideen, S.V., Croft, S.L. and Houghton, P.J. (2000) Activity of extracts and isolated 

naphthoquinones from Kigelia pinnata against Plasmodium falciparum. J. Nat. Prod. 63(9), 1306–9. 

Moideen, S.V., Houghton, P.J., Rock, P., Croft, S.L. and Aboagye-Nyame, F. (1999) Activity of extracts 

and naphthoquinones from Kigelia pinnata against Trypanosoma brucei brucei and Trypanosoma brucei 

rhodesiense. Planta Med. 65(6), 536–40. 

Binutu, O.A., Adesogan, K.E. and Okogun, J.I. (1996) Antibacterial and antifungal compounds from 

Kigelia pinnata. Planta Med. 62(4), 352–3. 

Akunyili, D.N., Houghton, P.J. and Raman, A. (1991) Antimicrobial activities of the stembark of Kigelia 

pinnata. J. Ethnopharmacol. 35(2), 173–7. 

Kela, S.L., Ogunsusi, R.A., Ogbogu, V.C. and Nwude, N. (1989) Screening of some Nigerian plants for 

molluscicidal activity. Rev. Elev. Med. Vet. Pays Trop. 42(2), 195–202. 

Prakash, A.O., Saxena, V., Shukla, S., Tewari, R.K., Mathur, S., Gupta, A., Sharma, S. and Mathur, R. 

(1985) Anti-implantation activity of some indigenous plants in rats. Acta Eur Fertil. 16(6), 441–8. 

Koelreuteria henryi (Sapindaceae) 


Synonyms: varnish tree. 

Location: Of China and Korea origin, it is found in eastern Asia. It can be cultivated 


Stem: fast-growing, deciduous tree reaching about 7.5m in height. At maturity, it has a rounded 

crown, with a spread equal to or greater than the height.


Figure 3.28 Koelreuteria. 

Leaves: compound leaves that give it an overall lacy appearance. The leaves turn yellow before 

falling. 

Flowers: large clusters of showy yellow flowers. 

Active ingredients: Protein-tyrosine kinase inhibitors: anthraquinone, stilbene and flavonoid. 

Particular value: In cooler zones, used as a free-standing tree where it can be seen in all its glory! 

It is also good as a small shade tree where space is limited. Golden rain tree should be used more 

often as a street and park tree. 

Documented target cancers: anthraquinone inhibitor, emodin, displayed highly selective 

activities against src-Her-2/neu and ras-oncogenes. 



● 

Protein kinases encoded or modulated by oncogenes were used to prescreen the 

potential antitumor activity of medicinal plants (Chang et al., 1996). Protein-tyrosine 

kinase-directed fractionation and separation of the crude extracts of Polygonum 

cuspidatum and Koelreuteria henryi have led to the isolation of three different classes 

of protein-tyrosine kinase inhibitors, anthraquinone, stilbene and flavonoid.


References 

Chang, C.J., Ashendel, C.L., Geahlen, R.L., McLaughlin, J.L. and Waters, D.J. (1996) Oncogene signal 

transduction inhibitors from medicinal plants. In Vivo 10(2), 185–90. 

Bonap, U.S. (1998) Checklist, Provided by TAMU-BWG, Texas A&M Bioinformatics Working Group, 

Based on, Biota of North America Program. 

Landsburgia quercifolia (Cystoseiraceae, Phaeophyta) 

Cytotoxic 

Synonyms: brown algae. 

Location: New Zealand. 

Active ingredients: Deoxylapachol, 1,4-Dimethoxy-2-(3-methyl-2-butenyl)-naphthalene,2-(3-methyl- 

2-butenyl)-2,3-epoxy-1,4-naphthalenedione 4,4-dimethoxy ketal. 


● Deoxylapachol active against P-388 leukemia cells (IC50 0.6gml 1 ). 



● 1,4-Dimethoxy-2-(3-methyl-2-butenyl)-naphthalene was the major low polarity component 

of extracts of this seaweed, which also contained 2,3-dihydro-2,2-bis(3-methyl-2-butenyl)- 

1,4-naphthalenedione and 2-(3-methyl-2-butenyl)-2,3-epoxy-1,4-naphthalenedione 4,4- 

dimethoxy ketal. Compound 2-(3-methyl-2-butenyl)-2,3-epoxy-1,4-naphthalenedione 

4,4-dimethoxy ketal was converted to the 2,3-epoxide of deoxylapachol, which had biological 

activities similar to those of deoxylapachol (Perry et al., 1991). 

References 

Nelson, W.A. (1999) Landsburgia ilicifolia (Cystoseiraceae, Phaeophyta), a new deep-water species endemic to 

the Three Kings Islands, New Zealand. New Zealand Journal of Botany, 37(1). 

Perry, N.B., Blunt, J.W. and Munro, M.H. (1991) A cytotoxic and antifungal 1,4-naphthoquinone and 

related compounds from a New Zealand brown algae, Landsburgia quercifolia. J. Nat. Prod. 54(4), 

978–85. 

Villouta, E., Chadderton, W.L., Pugsley, C.W., Hay, C.H. (2001) Effects of sea urchin (Evechinus chloroticus) 

grazing in Dusky Sound, Fiordland, New Zealand New Zealand J. Mar Freshwater Res. 35, M00006. 

Magnolia virginiana L. (Magnolia) (Magnoliaceae) 


Location: North America. 


Stem: 8 or more ft in height, 3–5ft diameter, smooth gray trunk. 

Leaves: simple, oval, 6in long by 3in wide, broad, silvery and slightly hairy underneath. 

Flowers: large, white. 

In bloom: Spring. 

Tradition: It is used in rheumatism and malaria and is contra-indicated in inflammatory symptoms.


Figure 3.29 Magnoliavirginiana. 

Parts used: bark of stem and root. 


Neolignans: magnolol, honokiol and monoterpenylmagnolol 

Parthenolide. 

Indicative dosage and application: Is still being tested. 

Documented target cancers: Epstein–Barr virus, skin tumor (mice). 



● 

Magnolia officinalis: The bark contains the neolignans magnolol, honokiol and 

monoterpenylmagnolol. The MeOH extract of this plant and magnolol exhibited remarkable 

inhibitory effects on mouse skin tumor promotion in an in vivo two stage 

carcinogenesis test (Konoshima et al., 1991). 


● 

Another tumor inhibitory agent, parthenolide, has been isolated from Magnolia 

grandiflora I.P (Wiedhopf et al., 1973).


References 

Celle, G., Savarino, V., Picciotto, A., Magnolia, M.R., Scalabrini, P. and Dodero, M. (1988) Is hepatic 

ultrasonography a valid alternative tool to liver biopsy Report on 507 cases studied with both 

techniques. Dig. Dis. Sci. 33(4), 467–71. 

Konoshima, T., Kozuka, M., Tokuda, H., Nishino, H., Iwashima, A., Haruna, M., Ito, K. and Tanabe, L 

M. (1991) Studies on inhibitors of skin tumor promotion, IX. Neolignans from Magnolia officinalis. 

J. Nat. Prod. 54(3), 816–22. 

Wiedhopf, R.M., Young, M., Bianchi, E. and Cole, J.R. (1973) Tumor inhibitory agent from Magnolia 

grandiflora (Magnoliaceae). I. Parthenolide. J. Pharm. Sci. 62(2), 345. 

Nauclea orientalis (Rubiaceae) 

Antiproliferative 

Part used: leaves. 

Active ingredients: Nine angustine-type alkaloids were isolated from ammoniacal extracts of 

Nauclea orientalis (10-hydroxyangustine, two diastereoisomeric 3,14-dihydroangustolines). 

Documented target cancers: The compounds have been found to exhibit in vitro anti-proliferative 

activity against the human bladder carcinoma T-24 cell line and against EGF (epidermal growth 

factor)-dependent mouse epidermal keratinocytes. 



● 

The structures of the isolates were determined with spectroscopic methods, mainly 

1D- and 2D-NMR spectroscopy. By using overpressure layer chromatography, it was 

shown that minor quantities of these alkaloids occur in dried Nauclea orientalis leaves. 

The use of ammonia in the extraction process results in a significant increase in 

the formation of angustine-type alkaloids from strictosamide-type precursors 

(Erdelmeier et al., 1992). 

References 

Erdelmeier, C.A., Regenass, U., Rali, T. and Sticher, O. (1992) Indole alkaloids with in vitro antiproliferative 

activity from the ammoniacal extract of Nauclea orientalis. Planta Med. 58(1), 43–8. 

Hotellier, F., Delaveau, P. and Pousset, J.L. (1979) Alkaloids and glyco-alkaloids from leaves of Nauclea 

latifolia SM. Planta Med. 35(3), 242–6. 

Fujita, E., Fujita, T. and Suzuki T. (1967) On the constituents of Nauclea orientalis L. I. Noreugenin and 

naucleoside, a new glycoside (Terpenoids V). Chem. Pharm. Bull. (Tokyo) 5(11), 1682–6. 

Neurolaena lobata (Neurolaena) (Asteraceae) 

Location: Guatemala. 

Active ingredients: sesquiterpene lactones: of the germacranolide and furanoheliangolide type. 

Cytotoxic



Antitumour activity 

● Aqueous and lipophilic extracts of Neurolaena lobata were tested against human 

carcinoma cell lines with cytotoxic effects (Francois et al., 1996). In addition to that, 

they were tested, also, against Plasmodium falciparum in vitro. Sesquiterpene lactones, 

isolated from N. lobata, were shown to be active against P. falciparum in vitro 

(antiplasmodial activity). 

References 

Francois, G., Passreiter, C.M., Woerdenbag, H.J. and Van Looveren, M. (1996) Antiplasmodial activities 

and cytotoxic effects of aqueous extracts and sesquiterpene lactones from Neurolaena lobata. Planta 

Med. 62(2), 126–9. 

Passreiter, M.C., Stoeber, B.S., Ortega, A., Maldonado, E. and Toscano, A.R. (1999) Gemacranolide type 

sesquiterpene lactones from Neurolaena macrocephala. Phytochemistry 50(7), 1153–7. 

Passiflora tetrandra (Passifloraceae) 

Cytotoxic 

Parts used: leaves. 

Active ingredients: 4-Hydroxy-2-cyclopentenone. 

Documented target cancers: 4-Hydroxy-2-cyclopentenone is cytotoxic to P-388 murine leukemia 

cells (IC50 of less than 1gml 1 ). 



● 4-Hydroxy-2-cyclopentenone is also responsible for the anti-bacterial activity of 

an extract of leaves from Passiflora tetrandra with minimum inhibitory doses (MID) 

of c.10g per disk against Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa 

(Perry et al., 1991). 

References 

Bergner, P. (1995) Passionflower Med. Herbalism 7(1–2). 

Blumenthal, M. (ed.) (1998) The Complete German Commission E Monographs: Therapeutic Guide to 

Herbal Medicines. Integrative Medicine Communications, Massachusetts. 

Bruneton, J. (1995) Pharmacognosy, Phytochemistry, Medicinal Plants., Hampshire, England, Intercept, Ltd. 

Crellin, J.K. and Philpott, J. (1990) Herbal Medicine Past and Present. Duke Uni. Press, North Carolina. 

Duke, J.A. (1985) CRC Handbook of Medicinal Herbs, Ed. CRC Press Boca Raton, FL. 

Duke, J. and Vasquez, R. (1994) Amazonian Ethnobotanical Dictionary, CRC Press Inc., Boca Raton, FL.


HerbClip (1996) Passion Flower. “An Herbalist’s View of Passion Flower.” American Botanical Council, 

Austin, TX. 

Lung, A. and Foster, S. (1996) Encyclopedia of Common Natural Ingredients, Wiley & Sons, New York, NY. 

Mowrey, Daniel. (1986) The Scientific Validation of Herbal Medicine, Keats Publishing, Inc. New Canaan, CT. 

Perry, N.B., Albertson, G.D., Blunt, J.W., Cole, A.L., Munro, M.H. and Walker, (1991) 

JR4-Hydroxy-2-cyclopentenone: an anti-Pseudomonas and cytotoxic component from Passiflora tetrandra. 

Planta Med. 57(2), 129–31. 

Polyalthia barnesii (Polyalthia) (Annonaceae) 

Part used: stem bark. 


Cytotoxic 

● 

● 

clerodane diterpenes (cytotoxic): 16 alpha-hydroxycleroda-3,13(14)Z-dien-15,16-olide. 

3 beta, 16 alpha-dihydroxycleroda-4(18),13(14)Z-dien-15,16-olide and 4 beta, 16 alphadihydroxyclerod-13(14)Z-en-15,16-olide. 

Documented target cancers: The above compounds are found to exhibit broad cytotoxicity 

against a panel of human cancer cell lines. 


● 

The (three) cytotoxic clerodane diterpenes were purified from an ethyl acetate-soluble 

extract of the stem bark of Polyalthia barnesii, namely, 16 alpha-hydroxycleroda- 

3,13(14)Z-dien-15,16-olide (Ma et al., 1994). 

References 

Ma, X., Lee, I.S., Chai, H.B., Zaw, K., Farnsworth, N.R., Soejarto, D.D., Cordell, G.A., Pezzuto, J.M. and 

Kinghorn, A.D. (1994) Cytotoxic clerodane diterpenes from Polyalthia barnesii. Phytochemistry 37(6), 

1659–62. 

Tuchinda, P., Pohmakotr, M., Reutrakul, V., Thanyachareon, W., Sophasan, S., Yoosook, C., Santisuk, T. 

and Pezzuto, J.M. (2001) 2-substituted furans from Polyalthia suberosa. Planta Med. 67(6), 572–5. 

Chen, C.Y., Chang, F.R., Shih, Y.C., Hsieh, T.J., Chia, Y.C., Tseng, H.Y., Chen, H.C., Chen, S.J., 

Hsu, M.C. and Wu, Y.C. (2000) Cytotoxic constituents of Polyalthia longifolia var. pendula. J. Nat. Prod. 

63(11), 1475–8. 

Li, H.Y., Sun, N.J., Kashiwada, Y., Sun, L., Snider, J.V., Cosentino, L.M. and Lee, K.H. Anti-AIDS agents, 

9. Suberosol, a new C31 lanostane-type triterpene and anti-HIV principle from Polyalthia suberosa. 

J. Nat. Prod. 56(7), 1130–3. 

Zhao, G.X., Jung, J.H., Smith, D.L., Wood, K.V. and McLaughlin, J.L. (1991) Cytotoxic clerodane 

diterpenes from Polyalthia longifolia. Planta Med. 57(4), 380–3. 

Wu, Y.C., Duh, C.Y., Wang, S.K., Chen, K.S. and Yang, T.H. (1990) Two new natural azafluorene 

alkaloids and a cytotoxic aporphine alkaloid from Polyalthia longifolia. J. Nat. Prod. 53(5), 1327–31. 

Quevauviller, A. and Hamonniere, M. (1977) Activity of the principal alkaloids of Polyalthia oliveri Engler 

(Annonaceae) on the central nervous system and the cardiovascular system. CR Acad. Sci. Hebd. Seances 

Acad. Sci. D. 284(1), 93–6.


Pseudolarix kaempferi (Pseudoradix) (Pinaceae) 

Part used: seeds. 


Cytotoxic 

● 

● 

triterpene lactones pseudolarolides A, B, C and D and; 

diterpene acids pseudolaric acid-A and -B. 

Documented target cancers: Against 

● 

● 

Human cancer cell lines: KB (nasopharyngeal), A-549 (lung), and HCT-8 (colon) 

( pseudolarolide B, pseudolaric acid-A and -B). 

Murine leukemia cell line (P-388) (pseudolarolide B, pseudolaric acid-A and -B). 


● 

The seeds contain the triterpene lactones pseudolarolides A, B, C and D and the 

diterpene acids pseudolaric acid-A and -B (Chen et al., 1993). 

References 

Chen, G.F., Li, Z.L., Pan, D.J., Tang, C.M., He, X., Xu, G.Y., Chen, K. and Lee, K.H. (1993) The isolation 

and structural elucidation of four novel triterpene lactones, pseudolarolides A, B, C, and D, from 

Pseudolarix kaempferi. J. Nat. Prod., 56(7), 1114–22. 

Chen, G.F., Li, Z.L., Pan, D.J., Jiang, S.H. and Zhu, D.Y. (2001) A novel eleven-membered-ring triterpene 

dilactone, pseudolarolide F and A related compound, pseudolarolide E, from Pseudolarix kaempferi. 

J. Asian Nat. Prod. Res. 3(4), 321–33. 

Chen, K., Shi, Q., Li, Z.L., Poon, C.D., Tang, R.J. and Lee K.H. (1999) Structures and stereochemistry of 

pseudolarolides K and L, novel triterpene dilactones from pseudolarix kaempferi. J. Asian Nat. Prod. 

Res. 1(3), 207–14. 

Chen, K., Zhang, Y.L., Li, Z.L., Shi, Q., Poon, C.D., Tang, R.J., McPhail, A.T. and Lee, K.H. (1996) 

Structure and stereochemistry of pseudolarolide J, a novel nortriterpene lactone from Pseudolarix 

kaempferi. J. Nat. Prod. 59(12), 1200–2. 

Pan, D.J., Li, Z.L., Hu, C.Q., Chen, K., Chang, J.J. and Lee, K.H. (1990) The cytotoxic principles of 

Pseudolarix kaempferi: pseudolaric acid-A and -B and related derivatives. Planta Med. 56(4), 383–5. 

Yang, S.P. and Yue, J.M. (2001) Two novel cytotoxic and antimicrobial triterpenoids from Pseudolarix 

kaempferi. Bioorg. Med. Chem. Lett. 11(24), 3119–22. 

Yang, S.P., Wu, Y. and Yue, J.M. (2002) Five new diterpenoids from Pseudolarix kaempferi. J. Nat. 

Prod. 65(7), 1041–4. 

Zhang, Y.L., Lu, R.Z. and Yan, A.L. (1990) Inhibition of ova fertilizability by pseudolaric acid B in 

hamster. Zhongguo Yao Li Xue Bao 11(1), 60–2. 

Psychotria sp. (Psychotria) (Psychotrieae) 

Location: Pacific Islands. 

Appearance 

Stem: slender, which grows partly underground. 

Cytotoxic


Root: fibrous rootlets. 

In bloom: January–February. 

Parts used: aerial parts and stem bark. 

Active ingredients: Alkaloids. 


● 

● 

All members of the series exhibited readily detected cytotoxic activity against proliferating 

and non-proliferating Vero (African green monkey kidney) cells in culture. 

hodgkinsine A exhibited substantial antiviral activity against a DNA virus, herpes simplex 

type 1, and an RNA virus, vesicular stomatitis virus. 



● 

Calycodendron milnei, a species endemic to the Vate Islands (New Hebrides) synthesize 

a series of Nb-methyltryptamine-derived alkaloids made by linking together 2 to 8 

pyrrolidinoindoline units. Nine alkaloids of this class have been isolated from the 

aerial parts and stem bark of Calycodendron milnei, and examined for potential application 

as anti-cancer and anti-infective agents (Saad et al., 1995). All members of the 

series showed readily detected anti-bacterial, anti-fungal, and anti-candidal activities 

using both tube dilution and disc diffusion assay methods. The most potent antimicrobial 

alkaloids were hodgkinsine A and quadrigemine C, which exhibited 

minimum inhibitory concentration (MIC) values as low as 5gml 1 . 

References 

Adjibade, Y., Kuballa, B., Cabalion, P., Jung, M.L., Beck, J.P. and Anton, R. (1989) Cytotoxicity on 

human leukemic and rat hepatoma cell lines of alkaloid extracts of Psychotria forsteriana. Planta 

Med. 55(6), 567–8. 

Hayashi, T., Smith, F.T. and Lee, K.H. (1987) Antitumor agents. 89. Psychorubrin, a new cytotoxic naphthoquinone 

from Psychotria rubra and its structure–activity relationships. J. Med. Chem. 30(11), 2005–8. 

Roth, A., Kuballa, B., Bounthanh, C., Cabalion, P., Sevenet, T., Beck, J.P. and Anton, R. (1986) Cytotoxic 

activity of polyindoline alkaloids of Psychotria forsteriana (Rubiaceae) (1). Planta Med. Dec (6), 450–3. 

Saad, H.E., El-Sharkawy, S.H. and Shier, W.T. (1995) Biological activities of pyrrolidinoindoline alkaloids 

from Calycodendron milnei. Planta Med. 61(4), 313–6. 

Rhus succedanea (Sumach) (Anacardiaceae) 

Location: Japan. 

Appearance 

Stem: 1.2m high. 

Leaves: pinnate. 

Tumor inhibitor cytotoxic


Tradition: As the bark is rich in tannin, it is used in candle-making, for adulterating white 

beeswax and in making pomades. Japan Wax is obtained in Japan by expression and heat, or by 

the action of solvents from the fruit of sumach. 

Parts used: bark, root, fruit. 


● Tyrosinase inhibitor : 2-hydroxy-4-methoxybenzaldehyde. 

● Hinokiflavone (cytotoxic). 

Particular value: The root-bark is astringent and diuretic. Used in diabetes. 



● The root of Rhus vulgaris contains 2-hydroxy-4-methoxybenzaldehyde, which is also found 

in two other East African medicinal plants the root of Mondia whitei (Hook) Skeels 

(Asclepiaceae), and the bark of Sclerocarya caffra Sond (Anacardiaceae) ( Kubo, 1999). 

● The fruit of Rhus succedanea consists almost entirely of palmitin and free palmitic acid, 

and is not a true wax. 

References 

Kubo, I. (1999) Kinst-Hori I 2-Hydroxy-4-methoxybenzaldehyde: a potent tyrosinase inhibitor from 

African medicinal plants. Planta Med. 65(1), 19–22. 



Biol. 439, 191–225. 

Seseli mairei (Apiaceae) (Figure 3.30) 

Antitumor 

Location: China. 

Tradition: leaves are used for making salads. 


Active ingredients: Cytotoxic polyacetylene: seselidiol. 

Documented target cancers: cytotoxicity against KB, P-388, and L-1210 tumor cells. 


● 

Seselidiol is a new polyacetylene, that has been isolated from the roots of Seseli mairei. 

On the basis of chemical and spectroscopic evidence, its structure has been established 

as heptadeca-1,8(Z)-diene-4,6-diyne-3,10-diol. Seselidiol and its acetate have 

been demonstrated to show moderate cytotoxicity against KB, P-388, and L-1210 

tumor cells (Hu et al., 1990).


Figure 3.30 Seseli. 

References 

Hu, C.Q., Chang, J.J. and Lee, K.H. (1990) Antitumor agents, 115. Seselidiol, a new cytotoxic 

polyacetylene from Seseli mairei. J. Nat. Prod., 53(4), 932–5. 

Nielsen, B.E., Larsen, P.K. and Lemmich, J. (1971) Constituents of umbelliferous plants. XVII. Coumarins 

from Seseli gummiferum Pall. The structure of two new coumarins. Acta Chem Scand. 25(2), 529–33. 

Nielsen, B.E., Larsen, P.K., Lemmich, J. Constituents of umbelliferous plants. 13. Coumarins from Seseli 

gummiferum Pall. The structure of three new coumarins. Acta Chem Scand. 24(8), 2863–7. 

Xiao, Y., Yang, L., Cui, S., Liu, X., Liu, D., Baba, K. and Taniguchi, M. (1995) Chemical components of 

Seseli yunnanense Franch. Zhongguo Zhong Yao Za Zhi 20(5), 294–5, 319. 

Tamarindus indica (Tamarinds) (Leguminosae) 

Synonyms: Implee. Tamarinus officinalis (Hook). 


Location: It is found in India and tropical Africa, it is cultivated in West Indies. 

Appearance 

Stem: large handsome tree with spreading branches and a thick straight trunk, 12m high. 

Leaves: alternate, abruptly pinnated. 

Flowers: fragrant, yellow-veined, red and purple filaments. 

Tradition: In Mauritious the Creoles mix salt with the pulp and use it as a liniment for rheumatism 

and make a decoction of the bark for asthma. The Bengalese employ tamarind pulp in 

dysentery, and in times of scarcity use it as food. The natives of India consider that it is unsafe 

to sleep under the tree owing to the acid they exhale during the moisture of the night.


Parts used: fruits freed from brittle outer part of pericarp. 

Active ingredients: polysaccharide. 

Particular value: It is used as a cathartic, astrigent, febrifuge, antiseptic, refrigerant. It is useful 

in correcting bilious disorders. A tamarind pulp is made which is considered a useful drink in 

febrile conditions and a good diet in convalescence to maintain a slightly laxative action of the 

bowels. The pulp is said to weaken the action of resinous cathartics, but is frequently prescribed 

with them as a vehicle for jalap (Grieve, 1994). 

Documented target cancers: Immunomodulatory activities such as phagocytic enhancement, 

leukocyte migration inhibition and inhibition of cell proliferation. 


● 

A polysaccharide isolated and purified from Tamarindus indica shows immunomodulatory 

activities such as phagocytic enhancement, leukocyte migration inhibition and 

inhibition of cell proliferation (Sreelekha et al., 1993). These properties suggest that 

this polysaccharide from T. indica may have some biological applications. 

References 

Coutino-Rodriguez, R., Hernandez-Cruz, P. and Giles-Rios, H. (2001) Lectins in fruits having gastrointestinal 

activity. Their participation in the hemagglutinating property of Escherichia coli 0157:H7. Arch. 

Med. Res. 32(4), 251–7. 

Morton, J. (1987) Tamarind. In: Fruits of warm climates (Ed. F. Julia) Morton, Miami, FL, pp. 115–21. 

Sreelekha, T.T., Vijayakumar, T., Ankanthil, R., Vijayan, K.K. and Nair, M.K. (1993) Immunomodulatory 

effects of a polysaccharide from Tamarindus indica. Anticancer Drugs 4(2), 209–12. 

Terminalia arjuna (Combretaceae) 

Anticancer 

Location: Mauritius medicinal plant. 

Parts used: bark, stem and leaves. 

Active ingredients: ellagitannin arjunin along with gallic acid, ethyl gallate, the flavone luteolin and 

tannins. 

Documented target cancers: Luteolin has a well established record of inhibiting various cancer 

cell lines. 


● 

Luteolin has a well-established record of inhibiting various cancer cell lines and may 

account for most of the rationale underlying the use of T. arjuna in traditional cancer 

treatments (Pettit et al., 1996). Luteolin was also found to exhibit specific activity 

against the pathogenic bacterium Neisseria gonorrhoeae.


References 

Kandil, F.E. and Nassar, M.I. (1998) A tannin anti-cancer promotor from Terminalia arjuna. Phytochemistry 47(8), 

1567–8. 

Pettit, G.R., Hoard, M.S., Doubek, D.L., Schmidt, J.M., Pettit, R.K., Tackett, L.P. and Chapuis, J. C. 

(1996) Antineoplastic agents 338. The cancer cell growth inhibitory. Constituents of Terminalia arjuna 

(Combretaceae). J. Ethnopharmacol. 53(2), 57–63. 

Tropaeolum majus (Nasturtium) (Tropaeolaceae) 

Antitumor 

Synonyms: garden nasturtium, Indian cress. 

Location:It is found in the South American Andes from Bolivia to Columbia. 


Leaves: rounded or kidney shaped, with wavy margins. Are pale green, about 0.5–1.25cm across, 

and are borne on long petioles like an umbrella. 

Flowers: bright and happy little flowers, they typically have five petals, although there are double 

and semi-double varieties. The flowers are about 0.25–0.5cm in diameter and come in a 

kaleidoscope of colors including russet, pink, yellow, orange, scarlet and crimson. 

Parts used: flowers, leaves and immature seed. 

Active ingredients: benzyl glucosinolate which, through enzymatic hydrolysis, results in the 

production of benzyl isothiocyanate (BITC). 

Particular value: The dwarf, bushy nasturtiums add rainbows of cheerful color in annual beds 

and borders. Used as trailing forms on low fences or trellises, on a gravelly or sandy slope, or in 

a hanging container. Many gardeners include nasturtiums in the salad garden. 


● 

● 

Appears promising cytotoxicity in the low Molar range (0.86–9.4M) 

Toxic effects at a dose of 200mgkg 1 (within 24h of drug administration) but no reduction 

in tumor mass. 

Figure 3.31 Tropaeolum.


Documented target cancers: BITC has shows in vitro anticancer properties against a variety of 

human and murine tumor cell lines: human ovarian carcinoma cell lines (SKOV-3, 41-M, CHl, 

CHlcisR), a human lung tumor (H-69), a murine leukemia (L-1210), and a murine 

plasmacytoma (PC6/sens). 



● 

Cultured cells of Tropaeolum majus produce significant amounts of benzyl glucosinolate. 

The in vitro anticancer properties of BITC against a variety of human and murine 

tumor cell lines have been studied by four independent methods; SRB, MTT, cell 

counting, and clonogenic assays. Regardless of the assay used, BITC showed promising 

cytotoxicity in the low Molar range (0.86–9.4M) against four human ovarian 

carcinoma cell lines (SKOV-3, 41-M, CHl, CHlcisR), a human lung tumor (H-69), 

a murine leukemia (L-1210), and a murine plasmacytoma (PC6/sens). The L-1210 

cells were most sensitive. BITC administered to mice bearing the ADJ/PC6 plasmacytoma 

subcutaneous tumor showed toxic effects at a dose of 200mgkg 1 (within 24 

h of drug administration) but no reduction in tumor mass (Pintao et al., 1995). 

However, the growth inhibitory properties of BITC against a range of tumor cell 

types warrant further in vivo antitumor evaluation as well as its biotechnological 

production. 

References 

Baran, R., Sulova, Z., Stratilova, E. and Farkas, V. (2000) Ping-pong character of nasturtium-seed xyloglucan 

endotransglycosylase (XET) reaction. Gen. Physiol. Biophys. 19(4), 427–40. 

Bettger, W.J., McCorquodale, M.L. and Blackadar, C.B. (2001) The effect of a Tropaeolum speciosum oil 

supplement on the nervonic acid content of sphingomyelin in rat tissues. J. Nutr. Biochem. 12(8), 

492–6. 

Crombie, H.J., Chengappa, S., Jarman, C., Sidebottom, C. and Reid, J.S. (2002) Molecular characterisation 

of a xyloglucan oligosaccharide-acting alpha-D- xylosidase from nasturtium (Tropaeolum majus L.) 

cotyledons that resembles plant “apoplastic” alpha-D-glucosidases. Planta 214(3), 406–13. 

De Medeiros, J.M., Macedo, M., Contancia, J.P., Nguyen, C., Cunningham, G. and Miles, D.H. (2000) 

Antithrombin activity of medicinal plants of the Azores. J. Ethnopharmacol. 72(1–2), 157–65. 

Faik, A., Desveaux, D. and MacLachlan, G. (2000) Sugar-nucleotide-binding and autoglycosylating 

polypeptide(s) from nasturtium fruit: biochemical capacities and potential functions. Biochem. J. 347 

(Pt 3), 857–64. 

Fanutti, C., Gidley, M.J. and Reid, J.S. (1996) Substrate subsite recognition of the xyloglucan 

endo-transglycosylase or xyloglucan-specific endo-(1–4)-beta-D-glucanase from the cotyledons of 

germinated nasturtium (Tropaeolum majus L.) seeds. Planta 200(2), 221–8. 

Ludwig-Muller, J. and Cohen, J.D. (2002) Identification and quantification of three active auxins in 

different tissues of Tropaeolum majus. Physiol. Plant 115(2), 320–9. 

Lykkesfeldt, J. and Moller, B.L. (1993) Synthesis of Benzylglucosinolate in Tropaeolum majus L. 

(Isothiocyanates as Potent Enzyme Inhibitors). Plant Physiol. 102(2), 609–13. 

Pintao, A.M., Pais, M.S., Coley, H., Kelland, L.R. and Judson, I.R. (1995) in vitro and in vivo antitumor 

activity of benzyl isothiocyanate: a natural product from Tropaeolum majus. Planta Med. 61(3), 233–6.


Rose, J.K., Brummell, D.A. and Bennett, A.B. (1996) Two divergent xyloglucan endotransglycosylases 

exhibit mutually exclusive patterns of expression in nasturtium. Plant Physiol. 110(2), 493–9. 

Valeriana officinalis (Valerian) (Valerianaceae) 

Cytotoxic 

Synonyms: Amantilla, Setwall, All-Heal. 

Location: Throughout, mainly in Europe and Northern Asia, in meadows, borders of rivers and 

open woods on moist soil. 


Stem: erect, up to 1.5–2m high. 

Root: conical root-stock or rhizome. 

Leaves: opposite, pinnate, up to 20cm long. 

Flowers: Pink and small, in umbel-like clusters, 5–6mm long, with a stinking odor (as the whole 

plant). 

Fruit: capsule. 

In bloom: May–September. 

Tradition: The term Phu, a synonym of the root of valerian indicates its stinking scent. The 

species has probably derived its name from Valerius, who first used it in medicine or the Latin 

word valere (“to be in health”). Valerian is referred to as a calminative in medical texts of the 

Middle Age. 

Biology: The rhizome develops underground for several years before a flowering stem emerges 

(only one shoot per root). The plant can be propagated either by runners or by seed. For cultivation, 

adequate fertilization is recommended. 


Active ingredients: valerianic acid, borneol, a-pirene, camphene, valtrate, choline, valerianates 

(valerianic acid combines with various bases), chatarine and valerianine (alkaloids from the root). 

Figure 3.32 Valeriana.


Particular value: Valerian is a powerful nervine, stimulant, carminative and antispasmodic. It 

allays pain and promotes sleep. Oil of valerian is used as a remedy for cholera (in a form of 

cholera drops). The juice of the fresh root (Energetene of valerian) has been recommended as a 

narcotic in insomnia and as anti-convulsant in epilepsy. 

Precautions: Toxic in high doses. It can cause central paralysis, giddiness, headache, agitation, 

decrease sensibility, motility and reflex excitability, nausea. 

Indicative dosage and application: Still testing. A proposal dose is 300 and 500mgkg 1 per day 

(in rats) but not yet confirmed. 

Documented target cancers: Still testing. 



● Reiterated administration of Valeriana officinalis to laboratory animals has been 

associated with toxic effects. Rats receiving 300 and 600mgkg 1 per day of the drug 

for 30 days. During the period of the treatment, the animals’ weight and blood pressure 

were measured. At the end of the treatment the animals were sacrificed. The 

principal organs were weighed and hematological and biochemical parameters were 

determined in blood samples collected. This work is concerned with pharmacological 

properties which are related to the two plants. The influence of the drugs on the 

behavior, the pain, the intestinal peristalsis and strychnine convulsions are reported 

(Febri et al., 1991). 


● 

● 

Colchicine-treated suspension cultures of Valeriana wallichii produce higher amounts 

of valepotriates than did the respective untreated cultures. The ability to produce 

valepotriates in the treated culture remains in the absence of colchicine even if the chromosome 

status returns to normal. When the colchicine treatment is repeated, a further 

increase in valepotriate production can be obtained. Besides the known valepotriates, a 

series of fourteen new compounds, hitherto not described for the parent plant, were 

isolated from the cell suspension culture. Eight of them are also found in plant parts 

in minor amounts, but six seem to be present only in tissue cultures of V. wallichii 

(Becker and Chavadej 1985). 

Different in vitro cultures of Valerianaceae were analyzed for valepotriate content 

[(iso)valtrate, acevaltrate, didrovaltrate] in a study on properties of production in vitro 

(plant species, growth conditions, differentiation level, valepotriate content of the 

medium after growth). The in vitro cultures were: callus cultures of Valeriana 

officinalis L., Valerianella locusta L. and Centranthus ruber L.DC.; a suspension culture 

of Valeriana officinalis L. and a root organ culture of Centranthus ruber L.DC. All of the 

cultures produced valepotriates in vitro in different amounts. None of the media that 

had served for growth contained any valepotriates. In order to characterize the in vitro 

growth more precisely different parameters (such as fresh and dry weight, lipid and


● 

nitrogen content and (iso)valtrate content) were analyzed at different time intervals 

during a growth period in one of the cultures (callus culture of Valeriana officinalis L.) 

(Becker et al., 1977). 

It is possible directly to separate and analyze, quantitatively and qualitatively, the 

valepotriates from Valeriana crude extracts or from commercial Valeriana preparations 

by high-performance liquid chromatography. The separations are achieved on 

4 or 8 mm I.D. columns packed with silica gel (particle size 10micron) with 

n-hexane-ethyl acetate mixtures as eluent. A refractive index detection system is necessary 

for determining all of the valepotriates. If the concentration differences 

between didrovaltratum and valtratum are very great, an ultraviolet (UV) detector 

must be used and the determination must be conducted in two steps. For valtratum 

drugs UV detection alone will suffice. As internal standards p-dimethylaminobenzaldehyde 

should be used for extracts and preparations from valtratum races, and benzaldehyde 

in the presence of didrovaltratum races. This determination is superior to 

the combined thin-layer chromatographic-hydroxamic acid method used hitherto 

with respect to time consumption, precision, and sensitivity (Tittel and Wagner, 

1978; Suomi et al., 2001). 

References 

Albrecht, M. and Berger, W. (1995) Psychopharmaceuticals and safety in traffic. Zeits Allegmeinmed, 71, 

1215–21. 

Becker, H. and Chavadej, S. (1985) Valepotriate production of normal and colchicine- treated cell suspension 

cultures of Valeriana wallichii. J. Nat. Prod. 48(1), 17–21. 

Becker, H., Schrall, R. and Hartmann, W. (1977) Callus cultures of a Valerian species. 1. Installation of a 

callus culture of Valeriana Wallichii DC and 1st analytical studies Arch Pharm (Weinheim) 310(6), 481–4. 

Brown, D.J. (1996) Herbal Prescriptions for Better Health. Prima Publishing, Rocklin, CA. pp. 173–8. 

Buckova, A., Grznar, K., Haladova, M. and Eisenreichova, E. (1977) Active substances in Valeriana 

officinalis L. Cesk Farm 26(7), 308–9. 

Cavadas, C., Araujo, I., Cotrim, M.D., Amaral, T., Cunha, A.P., Macedo, T. and Ribeiro, C.F. (1995) 

In vitro study on the interaction of Valeriana officinalis L. extracts and their amino acids on GABAA 

receptor in rat brain. Arzneimittelforschung 45(7), 753–5. 

Czabajska, W., Jaruzelski, M. and Ubysz, D. (1976) New methods in the cultivation of Valeriana officinalis. 

Planta Med. 30(1), 9–13. 

Della Loggia, R., Tubaro, A. and Redaelli, C. (1981) Evaluation of the activity on the mouse CNS of several 

plant extracts and a combination of them. Riv Neurol. 51(5), 297–310. Review. 

Dressing, H., Köhler, S. and Müller, W.E. (1996) Improvement of sleep quality with a high-dose 

valerian/lemon balm preparation: a placebo-controlled double-blind study. Psychopharmakotherapie 6, 32–40. 

Fehri, B., Aiache, J.M., Boukef, K., Memmi, A. and Hizaoui, B. (1991) Valeriana officinalis and Crataegus 

oxyacantha: toxicity from repeated administration and pharmacologic investigations. J. Pharm. Belg. 46(3), 

165–76. 

Fursa, M.S. (1980) Composition of the flavonoids of Valeriana officinalis from the Asiatic part of the USSR. 

Farm Zh. (3), 72–3. 

Hendriks, H., Bos, R., Allersma, D.P., Malingre, T.M. and Koster, A.S. (1981) Pharmacological screening 

of valerenal and some other components of essential oil of Valeriana officinalis. Planta Med. 42(1), 62–8. 

Hromadkova, Z., Ebringerova, A. and Valachovic, P. (2002) Ultrasound-assisted extraction of water-soluble 

polysaccharides from the roots of valerian (Valeriana officinalis. Ultrason Sonochem (1), 37–44.


Janot, M.M., Guilhem, J., Contz, O., Venera, G. and Cionga, E. (1979) Contribution to the study of valerian 

alcaloids (Valeriana officinalis, L.): actinidine and naphthyridylmethylketone, a new alkaloid. 

Ann. Pharm. Fr. 37(9–10), 413–20. 

Kohnen, R. and Oswald, W.D. (1988) The effects of valerian, propranolol and their combination on activation 

performance and mood of healthy volunteers under social stress conditions. Pharmacopsychiatry 21, 

447–8. 

Kornilievs’kyi, I., Fursa, M.S., Rybal’chenko, A.S. and Koreshchuk, Kie. (1979) Flavonoid makeup of 

Valeriana officinalis from the southern and central provinces of the Ukraine. Farm Zh. (4), 71–2. 

Leathwood, P.D., Chauffard, F., Heck, E. and Munoz-Box, R. (1982) Aqueous extract of valerian root 

(Valeriana officinalis L.) improves sleep quality in man. Pharmacol. Biochem. Behav. 17, 65–71. 

Leathwood, P.D. and Chauffard, F. (1982–83) Quantifying the effects of mild sedatives. J. Psychiatr. 

Res. 17(2), 115–22. Review. 

Leathwood, P.D. and Chauffard, F. (1985) Aqueous extract of valerian reduces latency to fall asleep in man. 

Planta Med. 51, 144–8. 

Mennini, T. and Bernasconi, P.(1993) In vitro study on the interaction of extracts and pure compounds from 

Valeriana officinalis roots with GABA, benzodiazepine and barbiturate receptors. Fitoterapia 64, 291–300. 

Nikul’shina, N.I., Talan, V.A., Bukharov, V.G. and Ivanova, V.M. (1969) Valeroside A – a glycoside from 

valerian (Valeriana officinalis L.). Farmatsiia 18(6), 44–7. 

Pank, F., Hannig, H.J., Hauschild, J. and Zygmunt, B. (1980) Chemical weed control in the cropping of 

medicinal plants. Part 1: Valerian (Valeriana officinalis L.). Pharmazie 35(2), 115–9. 

Paris, R., Besson, P. and Herisset, A. (1966) Tests of “industrial lyophilization” of medicinal plants. 3. Valeriana 

officinalis L. Influence of lyophilization on the quality of the drug. Ann. Pharm. Fr. 24(11), 669–74. 

Perebeinos, V.S. (1974) Permissible content of stalk residues in crude Valeriana officinalis. 

Farmatsiia 23(3), 72–6. 

Santos, M.S., Ferreira, F., Cunha, A.P., Carvalho, A.P., Ribeiro, C.F. and Macedo, T. (1994) Synaptosomal 

GABA release as influenced by valerian root extract – involvement of the GABA carrier. Arch. Int. 

Pharmacodyn Ther. 327(2), 220–31. 

Suomi, J., Wiedmer, S.K., Jussila, M. and Riekkola, M.L. (2001) Determination of iridoid glycosides by 

micellar electrokinetic capillary chromatography-mass spectrometry with use of the partial filling 

technique. Electrophoresis 22(12), 2580–7. 

Tamamura, K., Kakimoto, M., Kawaguchi, M. and Iwasaki, T. (1973) Pharmacological studies on the 

constituents of crude drugs and plants. 1. Pharmacological actions of Valeriana officinalis Linne. var. 

latifolia Miquel. Yakugaku Zasshi 93(5), 599–606. 

Tittel, G. and Wagner, H. (1978) High-performance liquid chromatographic separation and quantitative 

determination of valepotriates in valeriana drugs and preparations. J. Chromatogr. 1, 148(2), 459–68. 

Torssell, K. and Wahlberg, K. (1967) Isolation, structure and synthesis of alkaloids from Valeriana 

officinalis L. Acta Chem. Scand. 21(1), 53–62. 

Tucakov, J. (1965) Comparative ethnomedical study of Valeriana officinalis L. Glas Srp Akad Nauka [Med.] 

(18), 131–50. 

Tufik, S., Fujita, K., Seabra, Mde, L. and Lobo, L.L. (1994) Effects of a prolonged administration of 

valepotriates in rats on the mothers and their offspring. J. Ethnopharmacol. 41(1–2), 39–44. 

Verzarne Petri, G. (1974) Biosynthesis of alkaloids, valtrates and volatile oils in the roots of Valeriana 

officinalis L. from radioactive precursors. Acta Pharm. Hung. 0(0 Suppl. 1), 54–65. 

Violon, C., Van Cauwenbergh, N. and Vercruysse, A. (1983) Valepotriate content in different in vitro 

cultures of Valerianaceae and characterization of Valeriana officinalis L. callus during a growth period. 

Pharm. Weekbl. Sci. 5(5), 205–9. 

Wagner, H., Schaette, R., Horhammer, L. and Holzl, J. (1972) Dependence of the valepotriate and essential 

oil content in Valeriana officinalis L.s.l. on various exogenous and endogenous factors. 

Arzneimittelforschung 22(7), 1204–9. 

Yang, G.Y. and Wang, W. (1994) Clinical studies on the treatment of coronary heart disease with Valeriana 

officinalis var latifolia. Zhongguo Zhong Xi Yi Jie He Za Zhi 14(9), 540–2. 

Zhang, B.H., Meng, H.P., Wang, T., Dai, Y.C., Shen, J., Tao, C., Wen, S.R., Qi, Z., Ma, L. and Yuan, S.H. 

(1982) Effects of Valeriana officinalis L. extract on cardiovascular system. Yao Xue Xue Bao 17(5), 382–4.


Xanthium strumarium (Cocklebur) (Compositae) 

Cytotoxic 

Location: South Europe, in America near sea-coast, central Asia northwards to the Baltic. 

Appearance 

Stem: coarse, erect, annual, 0.3–0.6m high. 

Leaves: on long stalks, large broad, heart-shaped, coarsely toothed or angular in both sides. 

Flowers: heads, greenish yellow, terminal clusters on short racemes, upper ones male, lower 

female. 

Parts used: the whole plant. 

Active ingredients: xanthatin. 

Particular value: A valuable and sure specific in the treatment of hydrophobia. 

Precautions: Intoxication. 

Indicative dosage and application: under investigation. 

Documented target cancers: serofibrinous ascites, edema of the gallbladder wall, and lobular 

accentuation of the liver. 



● 

Cocklebur (Xanthium strumarium) fed to feeder pigs was associated with acute to 

subacute hepatotoxicosis. Cotyledonary seedings fed at 0.75–3% of body weight or 

ground bur fed at 20–30% of the ration caused acute depression, convulsions, and 

death (Stuart et al., 1981). Principle gross lesions were marked serofibrinous ascites, 

edema of the gallbladder wall, and lobular accentuation of the liver. Acute to 

subacute centrilobular hepatic necrosis was present microscopically. The previously 

reported toxic principle, hydroquinone, was not recovered from the plant or bur of 

X. strumarium. Authentic hydroquinone administered orally failed to produce lesions 

typical of cocklebur intoxication but did produce marked hyperglycemia. 

Carboxyatractyloside recovered from the aqueous extract of X. strumarium and 

authentic carboxyatractyloside, when fed to pigs, caused signs and lesions typical of 

cocklebur intoxication. Marked hypoglycemia and elevated serum glutamic 

oxaloacetic transaminase and serum isocitric dehydrogenase concentrations occurred 

in pigs with acute hepatic necrosis that had received either cocklebur seedlings, 

ground bur or carboxyatractyloside (Stuart et al., 1981). 

References 

Battle, R.W., Gaunt, J.K. and Laidman, D.L. (1976) The effect of photoperiod on endogenous 

gamma-tocopherol and plastochromanol in leaves of Xanthium strumarium L. (cocklebur). Biochem. Soc. 

Trans. 4(3), 484–6. 

Chu, T.R. and Wei, Y.C. (1965) Studies on the principal unsaturated fatty acids of the seed oil of Xanthium 

strumarium L. Yao Xue Xue Bao 12(11), 709–12.


Cole, R.J., Stuart, B.P., Lansden, J.A. and Cox, R.H. (1980) Isolation and redefinition of the toxic agent 

from cocklebur (Xanthium strumarium). J. Agric. Food Chem. 28(6), 1330–2. 

Hatch, R.C., Jain, A.V., Weiss, R. and Clark, J.D. (1982) Toxicologic study of carboxyatractyloside (active 

principle in cocklebur – Xanthium strumarium) in rats treated with enzyme inducers and inhibitors and 

glutathione precursor and depletor. Am. J. Vet. Res. 43(1), 111–6. 

Jain, S.R. (1968) Investigations on antileucodermic activity of Xanthium strumarium. Planta Med. 16(4), 

467–8. 

Kapoor, V.K., Chawla, A.S., Gupta, A.K. and Bedi, K.L. (1976) Studies on the oil of Xanthium strumarium. 

J. Am. Oil. Chem. Soc. 53(8). 

Khafagy, S.M., Sabry, N.N., Metwally, A.M. and el-Naggar, S.F. (1974) Phytochemical investigation of 

Xanthium strumarium. Planta Med. 26(1), 75–8. 

Kuo, Y.C., Sun, C.M., Tsai, W.J., Ou, J.C., Chen, W.P. and Lin, C.Y. (1998) Chinese herbs as modulators 

of human mesangial cell proliferation: preliminary studies. J. Lab. Clin. Med. 132(1), 76–85. 

Kupiecki, F.P., Ogzewalla, C.D. and Schell, F.M. (1974) Isolation and characterization of a hypoglycemic 

agent from Xanthium strumarium. J. Pharm. Sci. 63(7), 1166–7. 

McMillan, C. (1973) Partial fertility of artificial hybrids between Asiatic and American cockleburs 

(Xanthium strumarium L.). Nat. New Biol. 246(153), 151–3. 

Pashchenko, M.M. and Pivnenko, G.P. (1970) Polyphenol substances in Xanthium riparium and Xanthium 

strumarium. Farm Zh. 25(6), 41–3. 

Roussakis, C., Chinou, I., Vayas, C., Harvala, C. and Verbist, J.F. (1994) Cytotoxic activity of xanthatin 

and the crude extracts of Xanthium strumarium. Planta Med. 60(5), 473–4. 

Stuart, B.P., Cole, R.J. and Gosser, H.S. (1981) Cocklebur (Xanthium strumarium, L. var. strumarium) intoxication 

in swine: review and redefinition of the toxic principle. Vet. Pathol. 18(3), 368–83. 

Sila, V.I. and Lisenko, L.V. (1971) A pharmacological study of the sum of Xanthium strumarium alkaloids. 

Farm Zh. 26(2), 71–3. 

Xylopia aromatica (Annonaceae) 

Cytotoxic 

Part used: bark. 

Active ingredients: Annonaceous acetogenins: asimicin, venezenin, xylopien, xylomaterin, xylopianin, 

xylopiacin, xylomaticin, annomontacin, gigantetronenin, gigantetrocin A, and annonacin. 

Documented target cancers: acetogenins showed cytotoxicity, comparable or superior to 

adriamycin, against three human solid tumor cell lines. 


● 

Xylopia aromatica: the bark (EtOH extract) contains the acetogenins we have already 

mentioned. These acetogenins showed reduction of the 10-keto of 1 to the racemic 

OH-10 derivative enhanced the bioactivity, as did the conversion of 1 to 6 and 7. 

Venezenin like other Annonaceous acetogenins, showed inhibition of oxygen uptake 

by rat liver mitochondria and demonstrated that the THF ring may not be essential 

to this mode of action (Colman-Saizarbitoria et al., 1994). 

References 

Ahammadsahib, K.I., Hollingworth, R.M., McGovren, J.P., Hui, Y.H. and McLaughlin, J.L. (1993) Mode 

of action of bullatacin: a potent antitumor and par pesticidal annonaceous acetogenin. Life Sciences 53, 

1113–20.


Colman-Saizarbitoria, T., Zambrano, J., Ferrigni, N.R., Gu, Z.M., Ng, J.H., Smith, D.L. and McLaughlin, J.L. 

(1994) Bioactive annonaceous acetogenins from the bark of Xylopia aromatica. J. Nat. Prod. 57(4), 486–93. 

Moerman, D.E. (1986) Medicinal plants of native America. U. Mich. Mus. Anthop. Tech. Rept. No. 19. 

2 vols. Ann Arbor, Michigan. 

Zieridium pseudobtusifolium (Rutaceae) 

Tumor inhibitor cytotoxic 

Active ingredients: flavonols: 5,3-dihydroxy-3,6,7,8,4-pentamethoxyflavone, digicitrin, 

5-hydroxy-3,6,7,8,3,4-hexamethoxyflavone, 3-O-demethyldigicitrin, 3,5,3-trihydroxy-6,7,8,4tetramethoxyflavone, 

and 3,5-dihydroxy-6,7,8,3,4-pentamethoxyflavone. 


● 

● 

IC50 0.04gml 1 against (KB) human nasopharyngeal carcinoma cells 

IC50 12M inhibited tubulin. 


● 

● 

● 

cytotoxic activity against KB cells 

human nasopharyngeal carcinoma cells 

inhibits tubulin assembly into microtubules. 


● 

Bioassay-guided fractionation of the extracts of Zieridium pseudobtusifolium and 

Acronychia porteri led to the isolation of 5,3-dihydroxy-3,6,7,8,4-pentamethoxyflavone 

which showed activity against (KB) human nasopharyngeal carcinoma cells (IC50 

0.04gml 1 ) and inhibited tubulin assembly into microtubules (IC50 12M). Of 

all these mentioned (in the Active ingredients) flavonols showed cytotoxic activity 

against KB cells (Lichius et al., 1994). 

References 

Jaffré, T., Reeves, R., Becquer, Th. (eds), 1997. Ecologie des milieux sur roches ultramafiques et sur sols 

métallifères. Actes de la deuxième Conférence Internationale sur les Milieux Serpentiniques. Nouméa, 

ORSTOM, (Documents scientifiques et techniques, III : 2), 306 p. 

Jaffré, T., Morat, Ph., Veillon, J.M., Rigault, F., Dagostini, G., 2001. Composition et caractéristiques de 

la flore de la Nouvelle-Calédonie/Composition and Characteristics of the native flora of New Caledonia. 

Nouméa, IRD (Documents scientifiques et techniques, II :4), 121 p 16 planches photos. 

Le Pierres, D., 1999. Les apports des recherches en génétique sur l’avenir de la culture du café en Nouvelle- 

Calédonie. La Calédonie Agricole, 76, 34–37; 77, 36–8. 

Lichius, J.J., Thoison, O., Montagnac, A., Pais, M., Gueritte-Voegelein, F., Sevenet, T., Cosson, J.P., 

Hadi, A.H. (1994) Antimitotic and cytotoxic flavonols from Zieridium pseudobtusifolium and Acronychia 

porteri. J. Nat. Prod. 57(7), 1012–6. 

Verotta, L., Dell’Agli, M., Giolito, A., Guerrini, M., Cabalion, P., Bosisio, E. 200. In vitro antiplasmodial 

activity of extracts of Tristaniopsis species and identification of the active constituents : Ellagic acid and 

3,4,5-trimethoxyphenyl-(6-O-galloyl)-O--D-glucopyranoside. Journal of Natural Products 64(5), 

603–7.

Chapter 4 

Cytotoxic metabolites from 

marine algae 

Vassilios Roussis, Costas Vagias and 

Leto A. Tziveleka 

4.1 Cytotoxic metabolites from marine algae 

The pharmacological importance of hundreds of plants has been known since ancient times and 

there are documents on their properties dating as early as 2000 BC. The vast majority of bioactive 

metabolites though has only been discovered and studied scientifically the last 50 years. At 

this point it is estimated that more than 120 pure chemical substances extracted from higher 

plants are used in medicine throughout the world. The influence of natural products upon anticancer 

drug discovery and design cannot be overestimated. Approximately 60% of all drugs now 

in clinical trials for the multiplicity of cancers are either natural products, compounds derived 

from natural products, containing pharmacophores derived from active natural products or are 

“old drugs in new clothes,” where modified natural products are attached to targeting systems 

(Cragg and Newman, 2000). 

Most of the efforts towards the discovery of new bioactive metabolites have focused for many 

years on the easily accessible higher plants. Though in the last few decades, obscure and rare 

organisms became accessible because of the scientific advancement in the areas of chromatography, 

spectroscopy and marine technology. 

Prior to the development of reliable scuba diving techniques some 40 years ago, the collection 

of marine organisms was limited to those obtainable by free diving. Subsequently, depths from 

approximately 3–40m became routinely attainable and the marine environment has been 

increasingly explored as a source of novel bioactive agents. Deep water collections can be made 

by dredging or trawling, but these methods suffer from disadvantages, such as environmental 

damage and non-selective sampling. These disadvantages can be partially overcome by the use 

of manned submersibles or remotely operated vehicles. However, the high cost of these means 

of collecting, precludes their extensive use in routine collection operations. However, the expansion 

of rebreather techniques in the last few years has begun to open up depths of 100m to 

relatively routine collections and one-man flexible suits such as the “Nyut suit” will extend the 

limit to close to 330m in due course. 

Although the traditional sources of secondary metabolites were terrestrial higher plants, 

animals and microorganisms, marine organisms have become major targets for natural products 

research in the past decade. 

If the novelty and complexity of compounds discovered from marine sources were the only 

criteria, then the success of research in this area would be assured for there are many marine natural 

products that have no counterpart in the terrestrial world. For example the structures assigned to 

maitotoxin represents perhaps the most complex secondary metabolite described to date. The surprisingly 

large proportion of marine natural products with interesting pharmacological properties 

has coined the term “Drugs from the Sea.”

196 Vassilios Roussis et al. 

Marine organisms have exhibited an impressive spectrum of biological properties and several 

representatives have been investigated in depth as potential new biotechnological agents with 

activities including: cytotoxicity; antibiotic activity; anti-inflammatory and antispasmodic 

activity; antiviral activity; cardiotonic and cardiovascular activity; antioxidant activity; enzyme 

inhibition activity and many others. 

Macroscopic seaweeds and unicellular or colonial phytoplankton, collectively called algae and 

sea grasses are the primary producers in the sea. With the effect of solar light, they are involved 

in the fixation of carbon dioxide resulting in evolution of oxygen. Strictly speaking, the distinction 

between algae and vascular plants is very weak. Even though the cell walls of seaweeds 

lack lignins, a vascular system similar to that of the higher plants is apparent in many algae. 

Economics determine the direction of all industries today and the algal products industry is 

no exception. Where non-biological sources of compounds traditionally obtained from algae 

have been found, economics frequently dictate that these be exploited resulting in the decline 

of the algal based industry, for example, the soda ash industry. The algal products industry of 

today may be divided into two main areas; the farming of edible seaweeds and the production 

of fine chemicals and polysaccharide phycocolloids. 

Pharmaceutical compounds constitute one of the largest potential markets for algal products. 

Prior to the 1950s, the use of seaweed extracts and microalgae as drugs or drug sources was 

restricted to folk medicine. Use of algae in this context was recorded as long ago as 2700 BC in 

Chinese Materia Medica. To date there has been little commercial development of algal products 

as pharmaceutical agents. The vermifuge -kainic acid from the red algae Digenea simplex was 

marketed in the past but is no longer available in Western countries. However, there is a 

tremendous potential for the development of algae as sources of pharmaceutical compounds 

since in the recent years researchers have ascribed a wide range of biological activities to metabolites 

produced by algae. 

Isolation of pharmacologically active compounds from marine algae has been a subject of many 

intensive investigations and comprehensive account of such work in this field is given by Baslow 

(1969), Hoppe (1969), Guven et al. (1990), Pietra (1990), Lincoln et al. (1991), McConnell 

et al. (1994), Riguera (1997), Tringali (1997), Mayer (1998), Munro et al. (1999), Kerr and Kerr 

(1999), Cragg and Newman (2000), Mayer and Lehmann (2001), Faulkner (2001). 

In vivo screens for the detection of antineoplastic activity and in vitro cytotoxicity assays have 

been used in the detection of antineoplastic and cytotoxic metabolites (Margiolis and Wilson, 

1977; Hodgson, 1987; Noda et al., 1989; Boyd, 1997). Initial in vivo screens followed by in vitro 

cytotoxicity testing to monitor purification of the active compound constitute the most common 

method of investigation. Many compounds, such as polysaccharides isolated from brown 

algae, act via stimulation/activation of the immune system. 

Marine microalgae compose the majority of living species found in the oceans. There is no 

definite estimate of the total number of the existing species. New species are being discovered 

constantly, and the number is ever increasing. Currently, more than 10,000 known species are 

divided into five major divisions of marine microalgae: Chlorophyta (green algae), Chrysophyta 

(golden-brown, yellow algae and diatoms) Pyrrhophyta (dinoflagellates), Euglenophyta, and 

Cyanophyta (blue-green algae) (Shimizu, 1993). The phylogenic positions and physiologic characteristics 

of the organisms are important to consider in studying their metabolism and biochemistry. 

However, the taxonomy and phylogenic relationship of microalgae are the subjects 

on which taxonomists have never agreed (Sieburth, 1979) (Figure 4.1). 

One important issue is the handling of Cyanophyta, “Blue-green algae.” Strict disciplinarians 

place them in bacteria (cyanobacteria) and refuse to include them in the category of algae,

Cytotoxic metabolites from marine algae 197 

Chrysophyceae 

(Golden-brown algae) 

Chlorophyta 

(Green algae) 

Euglenophyta 

Prymnesiophyceae 

(Prymnesium) 

Pyrrhophyta 

(Dinoflagellates) 

Bacillariophyceae 

(Diatoms) 

(Red algae) 

Rhaeophyta 

(Brown algae) 

Cryptophyta 

Protoctista 

Rhodophyta 

(Red algae) 

Cyanophyta 

(Blue-green algae) 

Bacteria 

Eucaryote 

Procaryote 

Figure 4.1 Approximate phylogenic relationship of algae. 

because of their procaryotic nature. Nevertheless, the organisms are photosynthetic and share 

many algal characteristics with the eucaryotic counterparts. Moreover, it is generally believed 

that most photosynthetic algae have their phylogenic origin in Cyanophyta. Therefore, they are 

included in this review. 

With tens of thousands unexplored species and an infinite number of possible chemovars, 

marine microalgae seem to be a very promising source of useful compounds. Also, there is strong 

evidence that many interesting compounds found in marine environments have their origins in 

microalgae. There is widespread speculation that many of the cyclic peptides found in tunicates 

and other marine invertebrates have their origin in symbiotic blue-greens or closely related 

organisms, prochlorons (Lewin and Cheng, 1989). For example, it is speculated that the symbiotic 

prochloron in the tunicate, Didemnum sp. is totally or partially responsible for the production 

of didemnins. With a few exceptions, it is not feasible to do chemical work with material 

from natural population of marine microalgae. At present, many important organisms remain 

unculturable despite enormous efforts. 

From 1960 to 1982 some 16,000 marine organism-derived samples were screened for 

antitumor activity, mainly by the NCI. In the early 1980s, the NCI program was discontinued


because it was perceived that few novel active leads were being isolated from natural sources. Of 

particular concern was the failure to yield agents possessing activity against the solid tumor 

disease types. This apparent failure might, however, be attributed more to the nature of the 

primary screens being used at the time, rather than to a deficiency of nature. 

During 1985–90 the NCI developed a new in vitro screen based upon a diverse panel of 

human tumor cell lines (Boyd, 1997). The screen strategy comprised 60 human cancer cell lines 

derived from nine cancer types, organized into sub-panels representing leukemia, lung, colon, 

CNS, melanoma, ovarian, renal, prostate and breast. In early 1999, a pre-screen comprising 

three cell lines (MCF-7 (breast), NCI H460 (lung), SK268 (CNS)), which detected 95% of 

the materials found to exhibit activity in the 60 cell line screen was introduced. With the development 

of this new in vitro cell line screening strategy, the NCI once again turned to nature as 

a potential source of novel anticancer agents and a new natural products acquisition program was 

implemented in 1986. 

In this chapter are reviewed algal extracts and isolated metabolites with cytotoxic and 

antineoplastic activity and potential for pharmaceutical exploitation. The data concerning the 

activities exhibited from crude extracts or mixtures are summarized in Tables 4.1–4.4 organized 

on the phylogenetic basis of the source organism and brief description of the activities is 

included in the tables. Reports on the cytotoxicity or antineoplastic activity of isolated algal 

metabolites are organized in Tables 4.5–4.8 with emphasis on the chemical nature. The chemical 

structures, the exhibited activity and mode of action are briefly discussed in the text with 

reference to the original articles. This review covers the literature till February 2002. 

4.2 Cytotoxic metabolites from chlorophyta 

Dimethylmethane derivatives C-1, C-2 and C-3 isolated from the extract of Avrainvillea rawsonii 

exhibited moderate inhibition of the IMPDH enzyme, which is involved in cell proliferation. 

The IC 50 in M, was 18.0, 10.0 and 7.4, respectively. 

From the green alga Bryopsis sp. a bioactive depsipeptide, Kahalalide F (C-4), was isolated 

from the ethanolic extract. This compound shows selectivity against solid tumor cell lines. The 

IC 50 values against A-549, HT-29, LOVO, P-388, KB and CV-1 cell lines are 2.5, 0.25, 1.0, 

10, 10 and 0.25gmL 1 , respectively. 

Recent data presented at the International Conference on Molecular Targets and Cancer 

Therapeutics, suggest that Kahalalide F (KF) is a novel anticancer compound with potential in 

the treatment of refractory ovarian and prostate cancers and leukemia. KF is one of a family of 

novel dehydroaminobutyric acid-containing peptides, which have shown activity in a number of 

solid tumor models. 

At the moment an ongoing Phase I clinical and pharmacokinetic study in patients with 

advanced, metastatic, androgen-refractory prostate cancer is held. In this study, KF has been 

administered as an intravenous 1-h infusion on 5 consecutive days every 3 weeks. So far, the 

study has included 12 patients (across 6 dose levels), using an equivalent total dose of 

100–2830gm 2 . To date, the schedule has been well tolerated, though adverse events include 

rapidly reversible mild headache, fatigue, and reversible transaminitis. The only drug toxicity 

observed so far was rapidly reversible Grade 3 transaminitis at 320gm 2 day. Clinical benefit 

associated with pain relief was expressed by a decrease in prostate specific antigen (PSA) of over 

50%. Pharmacokinetic analysis has shown KF to be rapidly eliminated, with potentially active 

concentrations being reached using a dosage of 425gm 2 day during five consecutive days. 

No metabolites have been found, and the maximum tolerated dose has not yet been reached.

Table 4.1 Chlorophyta extracts 

Source Chemistry Activity Literature 

Anadyomene menziesii Aqueous extract Against KB cell line system Hodgson, 1984 

Anadyomene stellata Aqueous extract Against KB cell line system 

Chloroform extract Against PS cell culture 

Caulerpa prolifera Extract Against PS cell culture 

Caulerpa racemosa Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 

var. peltata Against Ehrlich ascites tumor systems 

Caulerpa racemosa Methanolic extract Against L-1210 mouse leukemia cell lines Harada et al., 1997 

var. laete-virense 

Caulerpa sertularioides Methanolic extract Strong in vitro telomerase inhibiting activity when Kanegawa et al., 2000 

added to MOLT-4 cell culture at a level of 1.25% (v/v) 

Extract Against PS cell culture Hodgson, 1984 

Caulerpa taxifolia Aqueous extract Lethal in mice at 1gkg 1 (winter and spring extract) Fischel et al., 1995; 

Cytotoxic activity against the fibroplastic cell line Lemée et al., 1993a 

BHK21/C13 with an IC 50 80028gmL 1 (winter 

extract) 

Methanolic extract Lethal in mice in 12h at 1gkg 1 (summer extract) 

Cytotoxic activity against the fibroplastic cell line 

BHK21/C13 with an IC 50 25020gmL 1 (winter 

extract); 15014gmL 1 (summer extract) 

Toxicity against sea urchin eggs with an IC 50 659gmL 1 

(autumn extract); 33015gmL 1 (winter 

extract) 

Dichloromethane phase Lethal in mice in 12 and 24h at 150 and 75mgkg 1 , 

respectively (autumn extract) 

Toxicity against sea urchin eggs with an IC 50 268gmL 1 

(autumn extract) 

Ether phase Lethal in mice in 12 and 24h at 200 and 150mgkg 1 , 

respectively (autumn extract) 

Toxicity against sea urchin eggs with an IC 50 163g mL 1 

(autumn extract) 

(continued)

Table 4.1 (Continued) 


Caulerpa verticillata Extract Against PS cell culture Hodgson 1984 

Cladophoropsis Methanolic extract Cytostatic activity against L-1210 and P-388 mouse Harada et al., 1997; 

vaucheriaeformis leukemia cell lines, 95% inhibition of growth rate at 50gmL 1 Harada and Kamei, 1998 

Cladophoropsis zollingeri Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 

added to MOLT-4 cell culture 

Codium pugniformis Purified aqueous extract Against Ehrlich ascites tumor systems Nakazawa et al., 1976a 

Against solid tumors produced by Elrlich carcinoma 

Against Sarcoma-180 

Enteromorpha prolifera Methanolic extract 63.7% inhibition of Trp-P-1-induced umu C gene Okai et al., 1994 

expression of Salmonella Typhimurium (TA 1535/pSK 

1002) and 90.6% inhibition of TPA-dependent ornithine 

decarboxylase induction in BALB/c 3T3 fibroblast cells 

Halicoryne wrightii Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 


Halimeda discoidea Methanolic extract Against L-1210 and P-388 mouse leukemia cell lines Harada et al., 1997; 

90% inhibition of growth rate at 12.5gmL 1 Harada and Kamei, 1998 

Halimeda macroloba Methanolic extract Against L-1210 mouse leukemia cell lines Harada et al., 1997 

Halimeda sp. Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 

Against Ehrlich ascites tumor systems 

Hizikia fusiformis Aqueous extract Strong immunomodulating activity on human Shan et al., 1999 

lymphocytes 

Meristotheca papulosa Aqueous extract Strong immunomodulating activity on human Shan et al., 1999 

lymphocytes 

Monostroma nitidium Non-dialyzable fraction Against L-1210 Leukemia Yamamoto et al., 1982 

sulfated polysaccharides In vivo, 56% inhibition on tumor growth with 400 mgkg 1 28 days Noda et al., 1982 

Tydemania expeditionis Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 

Ehrlich ascites tumor systems 

Udotea geppii Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Ulva lactuca Ulvan oligosaccharides Modification of the adhesion phase and the proliferation Kaeffer et al., 1999 

of normal colonic and undifferentiated HT-29 cells

(continued) 

Table 4.2 Rhodophyta extracts 


Ahnfeltia paradox Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 


Amphiroa zonata Methanolic extract Selective cytotoxicity to all leukemic cell lines at Harada and Kamei, 1997 

concentrations 15–375gmL 1 

Against murine leukemic cells L-1210 

Against human leukemic cells K-562, HL60, 

MOLT-4, Raji, WIL2-NS 

Acrosorium flabellatum PBS extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 


Bangia sp. Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Chondria crassicaulis Methanolic extract Against L-1210 mouse leukemia cell lines Harada et al., 1997 

Chondrus occellatus PBS extract Against L-1210 mouse leukemia cell lines Harada et al., 1997 

Cryptomenia crenulata Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Eucheuma muricatum Aqueous extract Weak immunomodulating activity on human Shan et al., 1999 

lymphocytes 

Galaxaura robusta Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 


Galaxaura falcata Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 


Gloiopeltis tenax Water extract Significantly inhibited the growth of Ehrlich ascites Ren et al., 1995 

funoran, sulfated carcinoma and solid Ehrlich, Meth-A fibrosarcoma, 

polysaccharide and Sarcoma-180 tumors 

Gracilaria salicornia Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Herposiphonia arcuata Extract Against P-388 lymphocytic leukemia 


Laurencia papillosa Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 


Laurencia yamadae Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 

added to MOLT-4 cell culture



Meristotheca coacta Methanolic extract Medium in vitro telomerase inhibiting activity when Kanegawa et al., 2000 


Meristotheca papulosa Water extract Weak immunomodulating activity on human Shan et al., 1999 

lymphocytes 

Plocamium telfairiae Methanolic extract Against L-1210 mouse leukemia cell lines Harada et al., 1997 

Porphyra tenera Methanolic extract 54.4% inhibition of Trp-P-1-induced umu C gene Okai et al., 1994 

expression of Salmonella Typhimurium 

(TA 1535/pSK 1002) and 92.4% inhibition of 

TPA-dependent ornithine decarboxylase 

induction in BALB/c 3T3 fibroblast cells 

Extracts Inhibition to mutagenicity produced by Reddy et al., 1984; Teas, 1983; 

1,2-dimethylhydrazine and other carcinogens Teas et al., 1984; Yamamoto and 

Inhibition of mammary tumors induced by Maruyama, 1985 

1,2-dimethylhydrazine Yamamoto et al., 1987 

Methanolic extract Suppressive effect on mutagen-induced umu C gene Okai et al., 1996 

mainly -carotene, expression in Salmonella Typhimurium (TA 1535/pSK 

chlorophyll- and lutein 1002) 

Additive effect of these pigments (inhibition 

19.6–30.8% at 20gmL 1 of each compound, 

inhibition 42.8% at the same final concentration of 

the combined pigments) 

Porphyra yezoensis Porphyran, phospholipid In vivo inhibition on tumor growth rate 45.3–58.4% Noda et al., 1982 

with 6.7mgkg 1 7 days 

Solieria robusta Glycoproteins In vitro against mouse leukemia cells L-1210 and Hori et al., 1988 

mouse FM 3A tumor cells 

Spyridia filamentosa Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 

Against Ehrlich ascites tumor systems

Table 4.3 Phaeophyta extracts 


Agarum crathrum Methanolic extract In vitro promoting activity of human interferon production Nakano et al., 1997 

Ascophyllum nodosum Fucoidan extract Inhibition of cell proliferation in both in vitro and in vivo Riou et al., 1996 

bronchopulmonary carcinoma models 

Chordaria flagelliformis PBS extract Against L-1210 leukemia in mice Harada et al., 1997 

Colpomenia peregrina Ethereal extract, Against He-La cell culture Biard and Verbist 1981 

containing fatty acids 

and fucoxanthin 

Dilophus okamurae Methanolic extract Strong cytotoxicity to leukemic cell lines at Harada and Kamei, 1997; 

concentrations 50gmL 1 Harada et al., 1997 

Against murine leukemic cells L-1210 and human leukemic 

cells HL60 and MOLT-4 

Ecklonia cava PBS extract Against L-1210 leukemia in mice Harada et al., 1997 

Non-dialyzable fraction Against L-1210 leukemia in mice Yamamoto et al., 1987; 

Crude fucoidin Yamamoto et al., 1982 

Eisenia bicyclis Non-dialyzable fraction Against L-1210 leukemia Takahashi, 1983; 

of aqueous extract Against Sarcoma –180 Usui et al., 1980; 

Crude fucoidin Enhanced host defense mechanism to neoplasia Yamamoto et al., 1984a, 1987 

PBS extract Against L-1210 leukaemia in mice Harada et al., 1997 



Maruyama, 1985 

Isige sinicola Methanolic extract Medium in vitro telomerase inhibiting activity Kanegawa et al., 2000 

when added to MOLT-4 cell culture 

Laminaria angustata Extracts Inhibition to mutagenicity produced by 1,2-dimethyl Reddy et al., 1984; 

hydrazine and other carcinogens Teas 1983; Teas et al., 1984; 

Yamamoto and Maruyama, 1985 

Non-dialyzed part 94.5% inhibition of Sarcoma –180 Yamamoto et al., 1974 

of aqueous extract Against P-388 lymphocytic leukemia 

Methanolic extract 31.8% inhibition of Trp-P-1-induced umu C gene Okai et al., 1994 

expression of Salmonella typhimurium (TA 1535/pSK 1002) 

and 86.6% inhibition of TPA-dependent ornithine 

decarboxylase induction in BALB/c 3T3 

fibroblast cells 

(continued)



Laminaria angustata Non-dialyzed part 92.3% inhibition of Sarcoma-180 Yamamoto et al., 1974, 1982, 1986 

var. longissima of aqueous extract 

Sulfated polysaccharide Against P-388 lymphocytic leukemia 

Fractions of aqueous Against Meth-A, B-16 Melanoma and Sarcoma-180 Suzuki et al., 1980 

extract containing Against L-1210 leukemia 

polysaccharides and In vitro against L-1210 and He-La cell lines 

nucleic acids 

Crude fucoidin Against L-1210 Leukemia in mice Maruyama et al., 1987; 

Fucoidin containing Against Sarcoma-180 Yamamoto et al., 1984a 

fractions of aqueous 

extracts 



Maruyama, 1985 

Laminaria cloustoni Sulfated and degraded Against tumors of Sarcoma-180 Fomina et al., 1966; 

laminarin Jolles et al., 1963 

Laminaria japonica Non-dialyzed part of Against L-1210 leukemia in mice Yamamoto et al., 1982, 1986 

aqueous extract Against Sarcoma-180 

Sulfated polysaccharide 

Laminaria japonica Crude fucoidin Against L-1210 Leukemia in mice Maruyama et al., 1987; 

var. ochotensis Fucoidin containing Against Sarcoma-180 Yamamoto et al., 1984a 

fractions of aqueous 

extracts 

Extracts Against mammary tumorigenesis Yamamoto et al., 1987 

Laminaria religiosa Extracts Against mammary tumorigenesis Yamamoto et al., 1987 

Macrocystis pyrifera Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 

Against Ehrlich ascites tumor systems

Sargassum fulvellum Non-dialyzable fraction 89.4% inhibition on Sarcoma-180 tumors Yamamoto et al., 1974, 1977 

of the water extract 

Polysaccharide 

components 

Acrine metabolites either 

sulfated 

epdidoglycuronoglycan or 

sulfated glycuronoglycan 

D-manno-L-gulonoglycans Neoplasm inhibitor activity Meiun, 1981 

Sodium alginate Against Sarcoma-180 in mice Fugihara et al., 1984a,b 

Against Ehrlich ascites, against IMC carcinomas 

Interferon-inducing activity 

Sargassum hemiphyllum Fractions of dialyzed Against Ehrlich ascites and Sarcoma-180 tumors Nakazawa et al., 1974, 1976b; 

water extracts containing Host-mediated effects Nakazawa and Ikeda, 1972 

polysaccharides and a 

sugar-containing protein 

Methanolic extract In vitro promoting activity of human interferon Nakano et al., 1997 

production 

Sargassum horneri Fractions of dialyzed Against Ehrlich ascites and Sarcoma-180 tumors Nakazawa et al., 1974, 1976b; 

aqueous extracts Host-mediated effects Nakazawa and Ikeda, 1972 

containing 

polysaccharides 

and a sugar-containing 

protein 

Sargassum kjellmanianum Non-dialyzable fraction Against Sarcoma-180 ascites Jiang et al., 1986; 

of water extracts Host-mediated mechanism Yamamoto et al., 1981 

Polysaccharide fraction Nagumo, 1983 

Polysulfated polysaccharide Against L-1210 tumor growth in mice Yamamoto et al., 1984b 

fractions containing 

L-fucose 

(continued)



Sargassum ringgoldianum Fucoidan, neutral lipid, Inhibition 36.1–78.1% in vivo in mice with 40mgkg 1 Yamamoto et al., 1984b 

glycolipid, phospholipid, daily 7 days 

polysaccharide 

Sargassum thunbergii Non-dialyzable fraction Antitumor effect on Ehrlich ascites carcinoma Fujii et al., 1975; Ito and 

of water extracts Enhancement of the immune response Suriura, 1976; Ito and Suriura, 1976; 

Polysaccharide fraction Against Sarcoma-180 ascites Jiang et al., 1986, Nagumo, 

Host-mediated mechanism 1983; Yamamoto et al., 1981 

Polysaccharides especially Antitumor effect on Ehrlich ascites carcinoma in mice Itoh et al., 1993 

fucoidan (sulfated Enhancement of phagocytosis 

polysaccharide, a 

hexouronic acid containing 

L-fucan sulfate) 

Fucoidan (a hexouronic Inhibition of lung metastases Itoh et al., 1995 

acid containing L-fucan Combination treatment with fucoidan and 5-fluorouracil 

sulfate) inhibits significantly the lung metastases 

Sargassum tortile Fractions of dialyzed Against Ehrlich ascites and Sarcoma-180 tumors Nakazawa et al., 1974,1976b; 

aqueous extracts Host-mediated effects Nakazawa and Ikeda, 1972 

containing 

polysaccharides and a 

sugar-containing protein 

Sargassum yendoi Methanolic extract Against L-1210 leukemia in mice Harada et al., 1997 

Scytosiphon lomentaria PBS extract Against L-1210 leukemia in mice Harada et al., 1997 

Spatoglossum schmittii Spatol Antitumor activity in the urchin egg assay Gerwick et al., 1980 

Against T242 Melanoma and 224C Astrocytoma 

neoplastic cell lines

Stypopodium zonale Chloroform and Against PS cell cultures Hodgson, 1984 

methanol extracts 

Undaria pinnantifida Ethanol precipitate Against intraperitoneally implanted Lewis lung carcinoma Furusawa and Furusawa, 1990 

of the aqueous extract (LCC) in syngeneic mice 

Partially purified 95% increase in life span (ILS) 

polysaccharide 

composed of uronic Greater ILS when combined with low doses of 

acid, fucose and galactose chemotherapeuticals (Adriamycin, cisplatin, 

at a ratio of 3:1:1 5-fluoro-uracil and vincristine) 

Water insoluble fraction Against LCC Furusawa and Furusawa, 1985 

Mainly polysaccharide Moderate prophylactic activity against LCC in allogeneic 

mice 

Enhancement of natural cytolic activity of peritoneal 

macrophages against KB cells 

Synergistic activity with standard chemotherapeuticals 

Cold water extract Against spontaneous AKR T cell leukemia in mice Furusawa and Furusawa, 1988 

80% polysaccharides Anti-LCC activity superior to that of the synthetic Furusawa and Furusawa, 1989 

immunomodulator isoprinosine 

Polysaccharides, Fucoidan Against LCC Furusawa and Furusawa, 1985; 

Noda et al., 1990 

Methanolic extract 33.0% inhibition of Trp-P-1-induced umu C gene Okai et al., 1994 

expression of Salmonella typhimurium (TA 1535/pSK 1002) 

and 93.9% inhibition of TPA-dependent ornithine 

decarboxylase induction in BALB/c 3T3 fibroblast cells

Table 4.4 Microalgae extracts 


Anacystis dimidata Mixture of extracts Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Aphanococcus biformis Mixture of extracts Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Chlorella vulgaris Extract Against Syngeneic ascites tumor cells Konishi et al., 1985; Nomoto 

Oral administration et al., 1983; Soeder, 1976; 

Tanaka et al., 1984, 1990a,b, 1997 

Chlorella vulgaris strain Glycoprotein extract Antitumor effect against both spontaneous and Konishi et al., 1996; Noda et al., 

CK22 experimentally induced metastasis in mice 1996; Tanaka et al., 1998 

Consists of 6-linked Antimetastatic activity through T cell activation 

1-6galactopyranose-rich in lymphoid organs and enhancement of 

carbohydrate (70%) and recruitment of these cells to the tumor sites. 

protein (30%) Protective effect on 5- fluorouracil-induced 

myelosuppression and indigenous infection in mice 

Chlorella sp. Carbohydrate fraction Inhibitory effect toward tumor promotion Nomoto et al., 1983; 

A-D-glucan and -L-arabino--L- Miyazawa et al., 1988 

rhamno--D-galactan Mizuno et al., 1980 

Glycoproteins In vitro against mouse lymphocytic leukemia cells Shinho, 1986, 1987 

In vivo against Sarcoma-180 

Chroococcus minor Mixture of extracts Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Entophysalis deusta Mixture of extracts Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Haslea ostrearia Pigment containing aqueous Against cell proliferation of solid tumors, lung Carbonnelle et al., 1999 

extract carcinoma (NSCLC-N6) IC 50 30.2gmL 1 , 

kidney carcinoma (E39) IC 50 34.2gmL 1 

and melanoma (M96) IC 50 57.8gmL 1 

In vivo antitumor activity on mice 

Hormothamnion Peptide Hormonothamnion A Against human lung carcinoma SW1271 Gerwick, 1989; Gerwick et al., 

enteromorphoides (IC 50 0.2gmL 1 ), carcinoma A529 1989 

(IC 50 ) 0.16gmL 1 Murine Melanoma B16-F10 

(IC 50 0.13gmL 1 ), Human colon HCT-116 

(IC 50 0.72 0.13gmL 1 )

Lyngbya confervoides Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Lyngbya gracilis Chloroform extract Against P-388 lymphocytic leukemia Mynderse et al., 1977 

Debromoaplysiatoxin 

Lyngbya majuscula Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Aplysiatoxin, Lyngbyatoxin A Tumor promoters Moore, 1982 

Lyngbya sp. Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Oscillatoria annae Extract Against P-388 lymphocytic leukemia 


Oscillatoria foreaui Mixture of extracts Against P-388 lymphocytic leukemia 


Oscillatoria nigroviridis Chloroform extract In vivo against P-388 lymphocytic leukemia Mynderse and Moore, 1978 


31-nor-debromoaplysiatoxin 

Oscillatoria sp. Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Phormidium crosbyanum Extract Against P-388 lymphocytic leukemia 


Phormidium sp. Extract Against P-388 lymphocytic leukemia 


Rivularia atra Mixture of extracts Against P-388 lymphocytic leukemia 


Schizothrix calcicola Chloroform extract In vivo against P-388 lymphocytic leukemia Mynderse and Moore, 1978 


31-nor-debromoaplysiatoxin 

Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 


Schizothrix sp. Extract Against P-388 lymphocytic leukemia 


Skeletonema costatum Organic extract In vitro inhibition of lung carcinoma Bergé et al., 1997 

(NSCLC-N6) cell line proliferation by 

inducing terminal differentiation 

Symploca muscorum Chloroform extract In vivo against P-388 lymphocytic leukemia Mynderse et al., 1977 

Tolypothrix crosbyanum Extract Against P-388 lymphocytic leukemia Kashiwagi et al., 1980 

var. chlorata Against Ehrlich ascites tumor systems


Caulerpenyne (C-5) isolated from Caulerpa taxifolia has been shown to be cytotoxic against 

KB cells and fibroblasts from hamsters. Caulerpenyne along with other drugs representative of 

the major classes of anticancer products was tested against eight cancer cell lines of human origin. 

Caulerpenyne demonstrated growth inhibitory effects in all cases with some variability 

between cell lines; this inter-cell variability was, however, less marked than that observed with 

the anticancer drug tested. Cells of colorectal cancer origin were the most sensitive to the presence 

of Caulerpenyne. The activity was of the same order or greater than that obtained from, 

cisplatinum and fotemustine. In particular, Caulerpenyne does not affect the microfilamentdependent 

processes of fertilization and cytokinesis and allows the beginning of mitosis, but 

prevents normal DNA replication and results in metaphase-like arrest of sea urchin embryos. 

Caulerpenyne (C-5) is not lethal in mice, although it displays cytotoxic activity against the 

fibroblastic cell line BHK21/C13 with an IC 50 152gmL 1 , as well as toxicity against sea 

urchin eggs with an IC 50 162gmL 1 . 

Taxifolial A (C-6) although is structurally closely related to Caulerpenyne (C-5), it is less toxic 

in the sea-urchin test with an IC 50 281gmL 1 . 

10,11-Epoxycaulerpenyne (C-8) is weakly active on the sea urchin eggs assay but lethal on 

mice at 75gkg 1 . According to the classification of Hodgson (1987) this compound is very 

toxic. 

Taxifolial D (C-7), the only example of monoterpene isolated from C. taxifolia, is not active 

on fibroblasts and has not been tested on mice. 

Clerosterol (C-9) and five oxygenated derivatives (C-10 to C-14) were isolated from the green 

alga Codium arabieum. The cytotoxicity of these compounds was tested against the cancer cell 

lines, P-388, KB, A-549 and HT-29. Clerosterol exhibited significant activity against P-388 

cells (ED 50 1.7gmL 1 ) and was the most active against A-549 cells (ED 50 0.3gmL 1 ) 

among the compounds tested. However, Clerosterol was inactive against the growth of KB and 

HT-29 cells. All oxidized products (C-10 to C-14) showed significant activity against the 

growth of the four mentioned cancer cell lines, indicating that oxidation increases the activity 

of Clerosterol. 

Cymobarbatol (C-15) and 4-isocymobarbatol (C-16) were isolated from the marine green alga 

Cymopolia barbata. Both compounds exhibited strong inhibition of the mutagenicity of 

2-aminoanthracene and ethyl methanesulfonate toward, the T-98 strain with a metabolic 

activator and T-100. 

Species of the genus Halimeda were found to contain significant amounts (~15% of the 

dichloromethane extracts) of Halimedatrial (C-17), which exhibits cytotoxic activity in laboratory 

bioassays. At 1gmL 1 , Halimedatrial completely inhibited cell division for the first 

cleavage of fertilized sea urchin eggs and the motility of sea urchin sperm. 

Three halogenated sesquiterpene (C-18 to C-20) were isolated from the green alga Neomeris 

annulata. Their cytotoxic activity was indicated by their toxicity to brine shrimp. LD 50 values 

were determined for C-18, C-19 and C-20 to be 9, 8 and 16gmL 1 , respectively. 

Sulfated cycloartanol derivatives (C-21 to C-23) from the green alga Tydemania expeditionis 

were identified as inhibitors of pp60 v-src , the oncogenic protein tyrosine kinase encoded by Rous 

sarcoma virus. Protein tyrosine kinases comprise a large family of enzymes that regulate cell 

growth and intracellular signaling pathways. Inhibitors of these enzymes may have utility in 

cancer and other hyperproliferative conditions. Cycloartanol sulfates C-21, C-22 and C-23 

showed IC 50 s of 32, 100 and 39M in the pp60 v-src assay. 

Ulvans, from Ulva lactuca, constitute a dietary fiber structurally similar to the 

mammalian glycosaminoglycans. Desulfated, reduced and desulfated-reduced polysaccharides


Table 4.5 Cytotoxic metabolites from chlorophyta 

Source Metabolite Code Literature 

Avrainvillea rawsonii Avrainvilleol C-1 Chen and Gerwick, 1994 

Rawsonol C-2 

Isorawsonol C-3 

Bryopsis sp. Kahalide F C-4 Hamann and Scheuer, 1993; 

Hamann et al., 1996; 

Garcia-Rocha et al., 1996; 

Goetz et al., 1999 

Caulerrpa taxifolia Caulerpenyne C-5 Fischel et al., 1994, 1995; 

Pesando et al., 1996, 1998 

Caulerpenyne C-5 Lemée et al., 1993b 

Taxifolial A C-6 

Taxifolial D C-7 

10,11-Epoxy-caulerpenyne C-8 

Codium arabieum Clerosterol C-9 Sheu et al., 1995 

Oxygenated Clerosterols C-10 to C-14 

Cymopolia barbata Cymobarbatol C-15 Wall et al., 1989 

4-Isocymobarbatol C-16 

Halimeda sp. Halimedatrial C-17 Paul and Fenical, 1983 

H. tuna 

H. opuntia 

H. incrassata 

H. simulans 

H. scabra 

H. copiosa 

Neomeris annulata Halogenated C-18 to C-20 Barnekow et al., 1989 

sesquiterpenes 

Tydemania Sulfated C-21 to C-23 Govindan et al., 1994 

expeditionis cycloartanols 

Ulva lactuca Ulvan oligosaccharides Kaeffer et al., 1999 

were examined on the adhesion, proliferation and differentiation of normal or tumoral colonic 

epithelial cells cultured in conventional or rotating bioreactor culture conditions. In conventional 

culture conditions, Ulvan modified the adhesion phase and the proliferation of normal 

colonic sells and undifferentiated HT-29 cells. 

4.3 Cytotoxic metabolites from rhodophyta 

The brine shrimp toxicity bioassay was used to direct the fractionation of the red alga 

Ceratodictyon spongiosum extract. This process afforded two stable conformers of a cyclic heptapeptide, 

cis,cis- and trans,trans- Ceratospongamide (R-1 and R-2). 

Five oxygenated Desmosterols (R-3 to R-7) were isolated from the red alga Galaxaura 

marginata, which exhibited significant cytotoxicity to P-388, KB, A-549 and HT-29 cancer 

cell lines. Even though Desmosterol was not cytotoxic, the oxidized products were quite


Cytotoxic metabolites from chlorophyta 

OH 

Br 

CH 2 OH 

OH 

OH 

Br 

OH 

C-1 

Br 

CH 2 OMe 

OH 

OH 

Br 

OH 

Br 

OH 

OH 

Br 

C-2 

HO 

Br 

HO 

CH 2 OH 

OH 

Br 

Br 

OH 

OH 

OH 

Br 

C-3 

H2N 

D-Pro 

Val-3 

L-Orn 

O 

H 

N 

O 

N 

H 

O 

O 

N 

O N O 

H Val-1 N 

H 

Val-4 H 

N O 

Z-Dhb 

Thr-2 

O 

HO H 

N 

O 

N 

H 

O 

N 

H 

Val-5 

L-Phe 

O 

D-alloIleu-2 

O 

N 

H Thr-1 

O 

N 

H 

O D-alloIleu-1 

N 

H 

H 

N 

O 

Val-2 

C-4 

AcO 

C-5 

H B 

OAc 

H A 

CHO 

C-6 

OAc 

OAc 

OAc 

AcO 

H 

O 

C-7 

C-8 

O 

OAc 

OAc 

HO 

R 1 

R 1 

OOH H 

R 2 

H H 

R 2 

O O 

OH H 

C-9 

C-10 

C-11 

C-12 

O 

OH 

C-13 

Br 

O 

C-14 

HO 

H 

Br 

C-15 

HO 

OOH


Br 

HO 

O 

H 

Br 

C-16 

H 

CHO 

CHO 

H C-17 

CHO 

Br 

Br 

HO H C-18 

OH 

C-19 

Br 

C-20 

H 

O 

C-21 

OH 

NaO 3 SO 

H 

OSO 3 Na 

H 

OH 

H 

H 

C-22 

H 

O 

C-23 

NaO 3 SO 

H OSO3 Na 

NaO 3 SO 

H 

OSO 3 Na 

cytotoxic, indicating that oxidation increases the activity. Four additional oxygenated 

desmosterols (R-8 to R-11) were isolated from the same organism and exhibited significant 

cytotoxicity against P-388, KB, A-549 and HT-29 cancer cell lines, with ED 50 values within 

the range of 0.11–2.37gmL 1 . 

From the red algae Gigartina tenella a sulfolipid (R-12) that belongs to the class of 

sulfoquinovosyldiacyl glycerol was isolated. The compound potently inhibited the activities 

of mammalian DNA polymerase and and terminal deoxynucleotidyl transferase (TdT), and 

enhanced the cytotoxicity of bleomycin. Complete inhibition doses of each were achieved at 

1.0–2.0M for polymerase and TdT and 7.5M for polymerase . 

Three new Malyngamides: Malyngamide M (R-13), Malyngamide N (R-14) and 

Malyngamide I acetate (R-15) were isolated from the Hawaiian red alga Gracilaria coronopifolia. 

Malyngamide N and Malyngamide I acetate showed moderate cytotoxicity to mouse neuroblastoma 

(NB) cells in the tissue culture. The IC 50 values of R-14 and R-15 were 12M 

(4.9gmL 1 ) and 12M (7.1gmL 1 ), respectively. In contrast Malyngamide M showed 

rather weak cytotoxicity to NB cells (IC 50 20M). Malyngamides are known as metabolites 

of blue green algae, in particular Lyngbya majuscula. Furthermore it has been reported that epiphytes 

such as blue green algae grow on Gracilaria. Therefore the true origin of R-13 to R-15 

is likely a blue green alga that grows on Gracilaria coronopifolia. 

A cytotoxic oxysterol, 16-hydroxy-5a-cholestane-3,6-dione (R-16) was isolated from the red 

alga Jania rubens and was found to be significantly cytotoxic towards the KB tumor cell line with 

an ID 50 value 0.5gmL 1 .


Callicladol (R-17), a brominated metabolite has been isolated from the red alga Laurencia 

calliclada. This compound displayed cytotoxic activity in vitro against P-388 murine leukemia 

cell with IC 50 value 1.75gmL 1 . 

Six chamigrane derivatives (R-18 to R-23) isolated from Laurencia cartilaginea, were screened 

for toxicity. All metabolites have shown remarkable results against various cancer cell lines at low 

concentrations, especially to HT-29. The IC 50 values for the compounds R-18 to R-23 were 1.0, 

1.0, 1.0, 1.0, 5.0 and 5.0gmL 1 for the P-388 cell line, 0.1, 1.0, 1.0, 1.0, 5.0 and 1.0gmL 1 

for the A-549 cell line, 0.1, 0.025, 0.025, 0.25, 0.5 and 0.25gmL 1 for the HT-29 cell line 

and 0.1, 1.0, 1.0, 1.0, 10.0 and 1.0gmL 1 for the MEL-28 cell line, respectively. 

Majapolene A (R-24), a dioxabicyclo[2.2.2]-alkene, was isolated from the red alga Laurencia 

majuscula. It displayed modest mean response parameter values for all NCI 60-cell lines of 

0.4M for GI 50 (50% net growth inhibition, relative to controls), 0.9M for TGI (net total 

growth inhibition) and 2.8M for LC 50 (50% net cell death). 

Thyrsiferyl 23-acetate (R-25) has been isolated from the red alga Laurencia obtusa, which 

showed strong cytotoxicity against mammalian cells. Actually, TF23A is a specific inhibitor of 

protein phosphatase 2A (PP2A) activity. 

Red seaweeds of genus Laurencia is known to produce interesting active polyether 

squalene-derived metabolites, which possess strong cytotoxic properties. Mechanisms of 

growth inhibition by the novel marine compound Dehydrothyrsiferol (DHT) (R-26), isolated 

from the red alga Laurencia viridis and Laurencia pinnatifida, were investigated in a sensitive 

and an MDR human epidermoid cancer cell line. DHT was found to circumvent 

multidrug resistance mediated by P-glycoprotein. Cell cycle analysis revealed an accumulation 

in S-phase. Growth inhibition in KB cancer cells is not mediated by apoptosis but by 

growth retardation. The IC 50 values of DHT in all investigated cell lines were, although in 

the M range, found to be higher than the ones determined for the clinically established 

chemotherapeutic compound Doxorubicin and the cytotoxic compound Colchicine. The IC 50 

values determined in tumor cell lines derived from different primary tissues support the 

notion that the cytotoxicity mediated by DHT may be more tissue related than correlated to 

a single mechanism of growth inhibition throughout the various cancer systems. 

Screening for cytotoxicity was performed on compounds R-26 to R-36 with a battery of 

cultured tumor cell lines: P-388, suspension culture of a lymphoid neoplasm from a DBA/2 

mouse; A-549, monolayer culture of a human lung carcinoma; HT-29, monolayer culture of a 

human colon carcinoma; MEL-28, monolayer culture of a human melanoma. This assay proved 

them to possess a potent and selective activity against P-388 cells. 

Compounds Thyrsiferol (R-27), Dehydrothyrsiferol (R-26), Dehydrovenustatriol (R-28), 

Isodehydrothyrsiferol (R-31) and Thyrsenol B (R-36) had IC 50 0.01gmL 1 . This activity 

was significantly higher than that of 15–16-dehydrovenustatriol (R-29), Thyrsenol A (R-35), 

(IC 50 0.25gmL 1 ), 16-hydroxydehydrothyrsiferol (R-32), 10-epi-15–16-dehydrothyrsiferol 

(R-33), (IC 50 0.50gmL 1 ), 10-epidehydrothyrsiferol (R-34) (IC 50 1.00gmL 1 ) and 

predehydrovenustatriol acetate (R-30) (IC 50 1.20gmL 1 ), establishing that small chemical 

changes in the molecule greatly affect the cytotoxicity. Moreover compound R-31 showed 

selective activity against P-388 mouse lymphoid neoplasm. 

Martiriol (R-37) along with three other derivatives of dehydrothyrsiferols (R-38 to R-40) were 

isolated from Laurencia viridis and tested for their cytotoxicity against different cancer cell lines. 

The results showed that Martiriol (R-37) was inactive at concentrations lower than 10gmL 1 

and compounds R-38 to R-40 were inactive at concentrations lower than 1gmL 1 .


From the tropical marine red alga Plocamium hamatum two polyhalogenated monoterpenes 

(R-41, R-42) were isolated. Compound R-41 was moderately cytotoxic (IC 50 : 

Lu1 12.9gmL 1 , KB 13.3gmL 1 , ZR-75–1 7.8gmL 1 ) as was compound R-42 

(IC 50 : KB-V (-VBL) 5.3gmL 1 , KB 12.4gmL 1 , LNCaP 14.8gmL 1 ). An array of 

similar halogenated monoterpenes has been isolated by other researchers from Plocamium sp. 

According to Mynderse and Faulker (1978) the observed chemical variability is not caused 

from extraction decompositions but is depended on the algae geographic location. 

The polyhalogenated acyclic monoterpene Halomon, (R-43) was obtained as a major 

component of the organic extract of the red algae Portieria hornemannii. It exhibited highly differential 

cytotoxicity against the NCI’s new in vitro human tumor cell line screening panel; brain 

tumor, renal, and colon tumor cell lines were most sensitive, while leukemia and melanoma cell 

lines were relatively less sensitive. On the basis of its unprecedented cytotoxicity profile on the 

NCI primary screen this compound has been selected by the NCI Decision Network Committee 

for preclinical drug development. Pharmacological studies of Halomon have been conducted 

concerning the in vitro metabolism, pharmacokinetics, bioavailability and tissue distribution 

in mice. 

A second collection of Portieria hornemannii yielded a monocyclic 3-halogenated 

monoterpene (1-[3-(1-chloro-2(E)-propenyl)]-2,4-dichloro-3,3-dimethylcyclohex-5-ene, 

R-44), which proved to be one order of magnitude less potent than R-43 and devoid of 

differential activity. 

Isohalomon R-45, an isomer of Halomon, R-43, with a diatropic rearrangement of the halogens 

at C-6 and C-7, dehydrobromo derivative of isohalomon R-46, dehydrochloro derivative of 

Halomon R-47 and the monocyclic halogenated monoterpene R-48 uniformly exhibited the 

unique differential cytotoxicity profile reported earlier for Halomon against the NCI panel of 

60 human tumor cell lines, with comparable panel-averaged potency. 

The monocyclic halogenated monoterpene R-48 was more comparable in overall (panel-averaged) 

potency to Halomon, however, there was little differential response of the cell lines, and 

consequently no significant correlation to the profile of the Halomon R-43. Mean panel response 

(Values10 6 M): R-43 GI 50 0.676, LC 50 11.5; R-44 GI 50 20.0, LC 50 100; R-45 

GI 50 1.32, LC 50 16.2; R-46 GI 50 0.741, LC 50 17.0; R-47 GI 50 0.691, LC 50 13.5; 

R-48 GI 50 1.15, LC 50 20.0. 

A structure/activity relationship study with compounds R-43, and R-45 to R-48 exhibited a 

similar cytotoxicity profile, displaying higher activity than R-49 to R-53. These results suggest 

that halogen on C-6 is essential for this characteristic activity profile. 

Three agglutinins have been isolated from the aqueous ethanolic extract of the marine red 

alga Solieria robusta. These proteins, designated solnins A, B and C, were monomeric glycoproteins 

with a similar MW and they share predominant amino acids as Gly, Asx and Glx. Solnins 

showed mitogenic activity for mouse splenic lymphocytes, while they inhibited the growth in 

vitro of mouse leukemia cells L-1210 and mouse FM3A tumor cells. 

Four sulfated triterpenoids R-54 to R-57 were isolated from brine shrimp-toxic fractions of 

the methanolic extract of the red alga Tricleocarpa fragilis. Compounds R-54 and R-55 were the 

most active, showing 55.78.7% and 47.115.1% immobilization of brine shrimp respectively, 

at 17gmL 1 . Compounds R-56 and R-57 showed 39.111.0% and 35.512.8% 

immobilization respectively, at 50gmL 1 . Toxicity toward P-388, A-549, MEL-28 and HT- 

29 cell lines was also evaluated. IC 50 values for R-54 and R-55 were10gmL 1 and for 

R-56 and R-571gmL 1 against all cell lines tested.

Table 4.6 Cytotoxic metabolites from rhodophyta 


Ceratodictyon spongiosum cis,cis-Ceratospongamide R-1 Tan et al., 2000a 

trans,trans-Ceratospongamide R-2 

Galaxaura marginata Oxygenated desmosterols R-3 to R-7 Sheu et al., 1996 

R-8 to R-11 Sheu et al., 1997a 

Gigartina tenella Sulfoquinovosyldiacyl glycerol R-12 Ohta et al., 1999 

Gracilaria coronopifolia Malyngamide M R-13 Kan et al., 1998 

Malyngamide N R-14 

Malyngamide I acetate R-15 

Jania rubens 16-Hydroxy-5a-cholestane-3,6-dione R-16 Ktari et al., 2000 

Laurencia calliclada Callicladol R-17 Suzuki et al., 1995 

Laurencia cartilaginea Chamigrane deriv. R-18 to R-21 Juagdan et al., 1997 

Ma’ilione R-22 

Allo-isoobtusol R-23 

Laurencia majuscula Majapolene A R-24 Erickson et al., 1995 

Laurencia obtusa Thyrsiferyl 23-acetate R-25 Matsuzawa et al., 1994 

Laurencia viridis Dehydrothyrsiferol (DHT) R-26 Pec et al., 1998, 1999 

Dehydrothyrsiferol (DHT) R-26 Fernández et al., 1998 

Thyrsiferol R-27 

Dehydrovenustatriol R-28 

15–16 Dehydrovenustatriol R-29 

Predehydrovenustatriol acetate R-30 

Isodehydrothyrsiferol R-31 

16-Hydroxydehydrothyrsiferol R-32 

10-epi-15,16 Dehydrothyrsiferol R-33 

10-epi-Dehydrothyrsiferol R-34 

Thyrsenol A R-35 Norte et al., 1996, 1997 

Thyrsenol B R-36 

Martiriol R-37 Manriquez et al., 2001 

Dehydrothyrsiferol derivatives R-38 to R-40

Plocamium hamatum Polyhalogenated monoterpenes R-41, R-42 Coll et al., 1988 

Koenig et al., 1999 

Portieria hornemannii 6(R)-Bromo-3(S)-(bromomethyl)-7- R-43 Fuller et al., 1992 

methyl-2,3,7-trichloro-1-octene 

(Halomon) 

1-[3-(1-chloro-2(E)-propenyl)]-2,4- R-44 

dichloro-3,3-dimethylcyclohex-5-ene 

Portieria hornemannii Isohalomon R-45 Fuller et al., 1994 

Dehydrobromo derivative of Egorin et al., 1996, 1997 

Isohalomon R-46 

Dehydrochloro derivative of Halomon R-47 

Monocyclic halogenated monoterpene R-48 

Acyclic halogenated monoterpene R-49 




Monocyclic halogenated monoterpene R-53 

Solieria robusta Isoagglutinins Hori et al., 1988 

Solnins A-C 

Tricleocarpa fragilis Triterpenoid sulfates R-54 to R-57 Horgen et al., 2000


Cytotoxic metabolites from rhodophyta 

R 

Phe-2 

Pro-2 

N 

O 

Phe-1 

S 

N 

NH 

O 

O 

N 

H 

N 

O 

Ile 

H 

N 

O 

N 

O 

Pro-1 

cis-cis 

trans-trans 

R-1 

R-2 

HO 

R= 

R= 

R= 

OOH 

OOH 

OH 

R-3 

R-4 

R-5 

R= 

OH 

R-6 

O 

R 

R-7 

R= 

OOH 

R-8 

O 

OH 

O 

OH 

OOH 

R-9 

O 

R 

O 

H C 

OOH 

O 

H C O 

R-10 

H C H O 

R= 

O 

O 

OOH R-11 

H 2 C 

O 

S O 

O 

OH 

CH 3 CH 3 

OCH 3 O 

HO 

OCH 3 O 

O 

R-13 

N 

N 

O 

Me Cl 

Me Cl 

CH H 

3 H 

OCH O 

3 O 

OAc 

R-15 

N 

OH 

O 

Me Cl 

O 

H 

O 

OH 

OH 

OH 

R-12 

R-14 

R-16 

Br 

O 

H 

O 

O 

H H 

OH 

O 

H 

OH 

O H R-17 

HO 

Br R-18 

Cl 

HO 

Br 

Br 

R-19 

HO 

Br 

Br 

R-20 

HO 

HO 

Br 

R-21 

Br 

O 

R-22


Br 

HO 

CH 3 

Br 

Cl 

Me 

R-23 

O 

O 

CH 3 R-24 

Br 

HOH 2 C 

Br 

O 

H 

O 

OH 

O 

H H 

OH 

H 

H 

O 

OAc 

R-25 

Br 

O 

H 

O 

O 

H H 

OH H 

O 

H 

OH 

R-26 

Br 

O 

O 

H H 

O H OH H 

O 

HO OH 

R-27 

H 

Br 

O 

O H 

O 

H H 

H 

OH 

O 

H 

OH 

R-28 

Br 

O H 

H 

O 

O 

R-29 HO 

O 

OH 

H H 

OH 

O H 

O 

H H 

OAc 

O 

H 

OH 

R-30 

Br 

O 

O H 

O 

H H 

H H OH 

O 

HO R-31 

Br 

O 

O H 

O 

H H 

H 

O 

OH 

OH OH 

R-32 

Br 

H 

O H 

O 

OH 

O R-33 

O 

OH 

H H 

Br 

O 

O H 

O 

H H 

H 

O 

OH 

OH R-34 

Br 

O 

HOCH 2 

O 

O 

H H 

H 

OH 

OH 

O 

H 

OH 

R-35 O 

Br 

HO CH 2 OH 

O 

H 

O 

OH 

O H 

H H 

OH 

R-36 

HO 

O 

H 

H 

O 

O 

H 

O 

H 

OH 

OH 

R-37 

HO 

H 

H 

O 

O 

OH 

H R-38 

O 

OH 

O 

H H 

H 

Br 

H 

O 

O 

H 

O H 

O 

OH 

H 

OH 

R-39 

Br 

O 

H 

O 

H 

HO H OH OH 

O 

H H 

R-40


Br 

Cl 

R-41 

BrH 2 C 

Cl 

Cl 

CH 2 Cl 

R-42 

BrH 2 C 

Cl 

Cl 

Br 

Br 

Cl 

Cl 

Br 

Cl 

Cl 

R-43 

R-44 

Br 

Cl 

Cl 

Br 

Cl 

Br 

R-45 

Cl 

Br 

R-46 

Cl 

Cl 

Cl 

Cl 

Cl 

Br 

Cl 

Cl 

R-47 

R-48 

Br 

Cl 

Br 

Cl 

Cl 

Br 

R-49 

Br 

R-50 

H 

Cl 

Cl 

Cl 

Cl 

Br 

R-51 

Cl 

Br 

R-52 

Br 

Br 

Cl 

R-53 

– O3 SO 

HOH R 1 R 2 

CH 3 COOCH 3 R-54 

CH 3 CH 2 OH R-55 

H COOCH 3 R-56 

R 1 

R 2 

O 

– O3 SO 

COOCH 3 

R-57

4.4 Cytotoxic metabolites from phaeophyta 


From the brown algae Bifurcaria bifurcata five linear diterpenes (B-1 to B-5) and two terminally 

cyclized derivatives (B-6, B-7) were isolated and revealed potent cytotoxicity to fertilized sea urchin 

eggs. Bifurcanol (B-4) and bifurcane (B-6) were the most active from the compounds tested with 

an ED 50 4 and 12gmL 1 , respectively. Eleganediol (B-1), 12-(S)-hydroxygeranylgeraniol (B-2) 

and 12-(S)-hydroxy-geranylgeranic acid (B-3) exhibited an ED 50 36, 18 and 60gmL 1 , respectively, 

while the two compounds (B-5 and B-7) did not exhibit significant cytotoxic activity. 

The Et 2 O extract of Cystoseira mediterranea, containing meroterpenoids, possess antineoplastic 

activity attributable to Mediterraneol A, one of its major components. Mediterraneol A (B-8), 

Mediterraneone (B-9) and Cystoseirol (B-10) were tested by the crown-gall potato disc bioassay, 

as a high correlation between this test and the mouse P-388 leukemia protocol has been demonstrated. 

While Didemnin B, a potent antitumor cyclic depsipeptide, inhibited 100% the tumor 

growth (number of tumors per leaf disc), Mediterraneol A, Mediterraneone and Cystoseirol 

inhibited tumor growth by 88%, 76% and 73%, respectively. 

Four meroterpenes have been isolated from the brown alga Cystoseira usneoides, Usneoidone E (B- 

11), Usneoidone Z (B-12), Usneoidol E (B-13) and Usneoidol Z (B-14). The antitumoral activity of 

compound B-11 and B-12 was tested against P-388, A-549, HeLa and B-16 cell lines with an IC 50 

0.8, 1.25, 1.0 and 1.0gmL 1 and 1.5, 1.4, 1.3 and 1.5gmL 1 , respectively. The other two compounds 

were tested against P-388, L-1210 and A-549 cell lines and were also found to be cytotoxic. 

Bicyclic diterpenes, which possess a decalin skeleton, have been isolated from the brown algae 

Dictyota dichotoma and Pachydictyon coriaceum and their cytotoxicity was tested against murine 

B16 melanoma cells. It was found that Dictyotin A (B-15), Dictyotin B (B-16), Dictyotin C 

(B-17), Dictyotin B methyl ether (B-32) and Dictyotin D methyl ether (B-33) had IC 50 values 

8, 3, 15, 10 and 19gmL 1 , respectively. 

Xenicane and norxenicane diterpenes (B-18 to B-21) have been isolated from the brown alga 

Dictyota dichotoma and their cytotoxicity was tested against murine B16 melanoma cells. It was 

found that 4-acetoxydictyolactone (B-18), Dictyotalide A (B-19), Dictyotalide B (B-20) and 

nordictyotalide (B-21) had IC 50 values 1.57, 2.57, 0.58 and 1.58gmL 1 , respectively. 

Four Dolabellane (B-22 – B-25) and one hydroazulenoid (B-26) diterpenes, isolated from 

Dictyota dichotoma, were tested against the following cancer cell lines: P-388 mouse lymphoma, 

A-549 Human Lung Carcinoma, HT-29 Human Colon Carcinoma and MEL-28 Human 

Melanoma. Compounds B-23 to B-26 were mildly active with ED 50 5gmL 1 in all cases, whereas 

B-22 exhibited the greatest activity with ED 50 equal to 1.2gmL 1 against P-388 and A-549 

tumor cell lines and 2.5gmL 1 against HT-29 and MEL-28 tumor cell lines. Dolabellane B-27 

was found to possess interesting bioactivities among them cytotoxicity against KB cancer cells. 

Metabolites Dilopholide (B-28), hydroxyacetyldictyolal (B-29), acetylcoriacenone (B-31), 

and isoacetylcoriacenone (B-30) were isolated from the brown alga Dilophus ligulatus. These 

metabolites displayed cytotoxic activity to several types of mammalian cells in culture (KB, 

P-388, P-388/DOX, and NSCLC-N6). Especially, Dilopholide (B-28) showed significant cytotoxic 

activity (ED 50 4gmL 1 ) against KB (human nasopharynx carcinoma), NSCLC-N6 

(human lung carcinoma) cells, and P-388 (murine leukemia) cells. 

24-Hydroperoxy-24 –vinyl cholesterol (B-34) was isolated from the dichloromethane extract 

of the brown alga Padina pavonica and was found to be cytotoxic toward the KB tumor cell line. 

The ID 50 was approximately 6.5gmL 1 (14. 10 3 M). 

Fucoidan (GIV-A) B-35, a hexouronic acid containing L-fucan sulfate was isolated from 

Sargassum thunbergii and showed antimetastatic effect when examined on an experimental model 

of lung metastases induced by LLC in mice.


It is speculated that the antitumor action of GIV-A may be correlated with the activation of 

complement C3 macrophages and reticuloendothelial system, and the enhancement of antibobyproducing 

capacity and cell-mediated immunity. This seems to be favorable for cancer 

immunotherapy. 

Bioassay-directed fractionation of the methanolic extract of the marine brown alga Sargassum 

tortile has led to the isolation and characterization of eight compounds which include 

the chromenes Sargaol (B-36), Sargadiol-I (B-37), Sargadiol-II (B-38), Sargasal-I (B-39), 

Sargasal-II (B-40), hydroxysargaquinone (B-41), Kjellmanianone (B-42) and Fucosterol (B-43). 

Among them, hydroxysargaquinone (B-41) and Sargasals-I and II (B-37, B-38) demonstrated 

significant (ED 50 0.7gmL 1 ) and marginal (ED 50 5.8 and 5.7gmL 1 ) cytotoxicity 

against cultured P-388 lymphotic leukemia cells, respectively, while the other compounds 

showed moderate activity. 

Spatol (B-44) was isolated from the brown seaweed Spatoglossum schmittii and showed 

an ED 50 1.2gmL 1 in the urchin egg assay. Further, at the preliminary cell culture testing 

concentration of 16gmL 1 of Spatol completely inhibits cell division in human T242 

melanoma and 224C astrocytoma neoplastic cell lines. 

14-Keto-stypodiol diacetate (SDA) (B-45) was isolated from the brown alga Stypopodium 

flabelliforme and its effect on the cell growth and tumor invasive behavior of DU-145 human 

prostate cells was studied. SDA at concentrations of 45M decreased cell growth by 61%. This 

compound induces mitotic arrest of tumor cells, an effect that could be associated to alterations 

in the normal microtubule assembly process. SDA disrupts the normal organization of the 

microtubule cytoskeleton in the DU145 cell line as revealed by immunofluorescence studies. 

It affects protease secretion and the in vitro invasive capacity, both properties of cells from 

metastases. 

The different effects of SDA, the microtubule assembly inhibition together with its cellular 

effects in arresting mitosis and blocking protease secretion mechanisms and cell invasion, suggest 

that SDA interferes with the tumoral activity of these prostatic cancer cells. 

(-)-Stypoldione (B-46) was isolated from the brown algae Stypodium zonale and proven to be 

an interesting cytotoxic metabolite. Stypoldione inhibits microtubule polymerization, and 

sperm motility, in contrast to the properties of other microtubule assembly inhibitors. This 

metabolite seems to prolong the survival time of mice injected with tumor cells, showing relatively 

little cytotoxicity itself. Actually, using tumor cells derived from P-388 lympholytic 

leukemia cells injected into BDF1 or CDF1 mice, and drug treatment up to 30 days, a 42% 

increase in survival time in mice treated with stypoldione was observed. 

Four oxygenated Fucosterols were isolated from the brown alga Turbinaria conoides and were 

tested for cytotoxicity against P-388, KB, A-549 and HT-29 cancer cell lines. Steroid B-50 

exhibited significant cytotoxicity against the above four cancer cell lines (ED 50 2gmL 1 ). 

Compounds B-47 to B-49 exhibited significant activity against the growth of P-388, A-549 

and HT-29 cancer cells, and moderate cytotoxicity toward KB cells. 

Turbinaric acid, a secosqualene carboxylic acid, (B-51) isolated from the brown alga 

Turbinaria ornate exhibited cytotoxicity against murine melanoma and human colon carcinoma 

cells at 26.6gmL 1 and 12.5gmL 1 , respectively. 

Two hydroperoxysterols (B-34 and B-52) and Fucosterol (B-43) were isolated from 

the extracts of Turbinaria ornata. The cytotoxic activities of these metabolites against KB, P-388, 

A-549 and HT-29 cell lines were assayed by a modification of the MTT colorimetric method. 

The results showed that steroids B-34, B-52 and B-43 were active against the growth of P-388 

cells. Fucosterol B-43 was not cytotoxic against KB, A-549 and HT-29 cells, however 

oxygenated sterols B-34 and B-52 were moderately cytotoxic.

(continued) 

Table 4.7 Cytotoxic metabolites from phaeophyta 


Bifurcaria bifurcata Eleganediol B-1 Valls et al., 1993 

12-(S)-Hydroxygeranylgeraniol B-2 

12-(S)-Hydroxygeranylgeranic acid B-3 

Bifurcanol B-4 

Eleganolone B-5 

Bifurcane B-6 Valls et al., 1995 

Epoxyeleganolactone B-7 

Cystoseira mediterranea Mediterraneol B-8 Fadli et al., 1991 

Cystoseirol B-9 

Mediterraneone B-10 

Cystoseira usneoides Usneoidone E B-11 Urones et al., 1992a 

Usneoidone Z B-12 

Usneoidol E B-13 Urones et al., 1992b 

Usneoidol Z B-14 

Dictyota dichotoma Dictyotin A B-15 Ishitsuka et al., 1990a 

Dictyotin B B-16 

Dictyotin C B-17 

4-Acetoxydictyolactone B-18 Ishitsuka et al., 1988, 1990b 

Dictyotalide A B-19 

Dictyotalide B B-20 

Nordictyotalide B-21 

Dolabellane and B-22 to B-25 Durán et al., 1997 

Hydroazulenoid diterpenes B-26 

Dolabellane B-27 Piattelli et al., 1995 

Dilophus ligulatus Dilopholide B-28 Bouaicha et al., 1993a,b 

Hydroxyacetyldictyolal B-29 

Isoacetylcoriacenone B-30 

Acetylcoriacenone B-31 

Pachydictyon coriaceum Dictyotin B methyl ether B-32 Ishitsuka et al., 1990a 

Dictyotin D methyl ether B-33 

Padina pavonica 24-Hydroperoxy-24-vinyl-cholesterol B-34 Ktari and Guyot, 1999



Sargassum thunbergii Fucoidan B-35 Itoh et al., 1993; 1995; Zhuang et al., 1995 

Sargassum tortile Sargaol B-36 Numata et al., 1992 

Sargadiol-I B-37 

Sargadiol-II B-38 

Sargasal-I B-39 

Sargasal-II B-40 

Hydroxysargaquinone B-41 

Kjellmanianone B-42 

Fucosterol B-43 

Spatoglossum schmittii Spatol B-44 Gerwick et al., 1980 

Stypopodium flabelliforme 14-Keto-stypodiol diacetate B-45 Depix et al., 1998 

Stypopodium zonale Stypoldione B-46 Mori and Koga, 1992; Gerwick and 

Fenical, 1981 

Stypoldione B-46 O’Brien et al., 1984 

Turbinaria conoides Oxygenated fucosterols B-47 to B-50 Sheu et al., 1999 

Turbinaria ornata Turbinaric acid B-51 Asari et al., 1989 

24-Hydroperoxy-24-vinyl-cholesterol B-34 Sheu et al., 1997b 

29-Hydroperoxystigmasta-5,24(28)- B-52 

dien-3b-ol 

Fucosterol B-43


Cytotoxic metabolites from phaeophyta 

OH 

OH B-1 

OH 

OH 

B-2 

OH 

O 

OH 

B-3 

OH 

HO B-4 

O 

OH 

B-5 

OH 

O 

B-6 

OH 

O 

O 

O 

B-7 

OH 

O 

OH 

OH 

B-8 

OH 

OH 

OCH 

OCH 3 

OH 

OCH 3 O 

O O 

O 

O 

B-9 

O 

O 

B-11 

O 

OH 

B-13 

HO 

OCH3 

OH 

OCH 3 

O 

O 

O 

O 

O 

B-10 

OH 

O 

O 

B-12 

O 

O 

OH B-14 

OH 

OH 

H OH 

H 

OH 

H 

B-15 

R 

H 1 

R2 

H H 

H 

R 1 = Me, R 2 =OH 

R 1 = OH, R 2 =Me 

R 1 = Me, R 2 = OMe 

B-16 

B-17 

B-32 

OMe 

H 

OAc 

B-33 

B-18 

H 

H 

H 

O 

O


CHO 

O 

O 

B-19 

OAc 

O 

O 

B-20 

O 

O 

O 

B-21 

R 1 O 

H 

R 2 

H 

H 

R 1 R 2 

Ac OH 

Ac H 

B-22 

B-25 

HO 

H 

HO 

OAc 

B-23 H 

O 

H 

B-24 

H 

HO 

B-26 

H 

O 

O 

B-27 

OAc 

O 

C 

B-28 

OAc 

OHC OH 

B-29 

O 

R 

O 

R 

C 

R R 

OAc H 

H OAc 

B-30 

B-31 

HOO 

B-34 

HO 

H 3 C 

O 

OH 

O 

– O3 SO 

H 3 C 

HO 

O 

O 

– O3 SO 

H 3 C 

HO 

O 

HO 

O 

n 

O 

R 

H 3 C 

– O3 SO 

O 

O 

OH 

OH 

H 3 C O 

OH 

O 

a 

B-35 

HO 

R: H 

R: OH 

B-36 

B-37 

O 

H 3 C 

– O3 SO 

O 

H 

OH 3 C 

– O3 SO 

OH 

O 

HO 

OH 

b


HO 

O 

OH 

B-38 

HO 

O 

R 

R= B-39 

CHO 

R= 

CHO B-40 

O 

OH 

HO 

O 

B-41 

MeO 

C 

B-42 

O 

O 

OMe 

OH 

B-43 

H 

O 

O 

B-44 

HO 

O 

O 

OAc 

OAc 

B-45 

HO 

H 

H 

O 

O 

O 

B-46 

O 

O 

R 

R= 

HOO 

B-47 

B-48 

O 

OH 

R 

R= 

HOO 

B-49 

B-50 

COOH 

HOO 

B-51 

B-52 

HO 

4.5 Cytotoxic metabolites from microalgae 

Amphidinolides A (M-1), B (M-2), C (M-3) and D (M-4) have been isolated from the 

cultured cells of the marine dinoflagellate Amphidinium sp., a symbiotic microalga. These potent 

cytotoxic 25-membered macrolides exhibited strong antineoplastic activity against L-1210 

murine leukemia cells in vitro with IC 50 values of 2.4, 0.00014, 0.0058 and 0.019gmL 1 , 

respectively.


Amphidinolide B is the most active and 10,000 times more potent than Amphidinolide A. 

It is worth noting that these macrolides isolated from the same dinoflagellate are quite different 

in substitution patterns and activities. 

Amphidinolide R (M-5) and S (M-6), isolated from the cultured dinoflagellate Amphidinium 

sp., showed cytotoxicity against murine lymphoma L-1210 (IC 50 : 1,4 and 4.0gmL 1 ) and 

human epidermoid carcinoma KB cells (IC 50 : 0.67 and 6.5gmL 1 ) in vitro, respectively. 

Amphidinolide V (M-7) exhibited cytotoxicity against murine lymphoma L-1210 (IC 50 : 

3.2gmL 1 ) and epidermoid carcinoma KB cells (IC 50 : 7gmL 1 ) in vitro. 

Carbenolide (M-8) isolated from Amhidinium sp. was assessed against the human colon 

carcinoma cell line HCT-116 by XTT assay and the IC 50 found to be 1.6nM. Further, in vivo 

studies found that when P-388 mouse leukemia was implanted intraperitoneally, a dose of 

0.03mgkg 1 day produced a 50% increase in life span. 

A cytotoxic carbohydrate-conjugated ergosterol (Astasin) (M-9) was found in cells of the colorless 

euglenoid Astasia longa. When cells of HL 60, human lymphoma, were cultured with 

Astasin, 50% of the cell growth was inhibited at 5.0g Astasin mL 1 medium. With 10.0g 

Astasin mL 1 medium the cell growth was inhibited completely and 50% of the initial cells 

were killed. 

Cell extracts from photoautrophic cultures of two cyanobacterial Calothrix isolates inhibited 

the growth in vitro of a chloroquine-resistant strain of the malaria parasite, Plasmodium falciparum, 

and of human HeLa cancer cells, in a dose-dependent manner. Bioassay-directed fractionation 

of the extracts led to the isolation and structural characterization of calothrixins 

A(M-10) and B (M-11), pentacyclic metabolites with an indolo[3,2-j]phenanthridine ring 

system unique amongst natural products. Calothrixins exert their growth-inhibitory effects at 

nanomolar concentrations moreover M-10 and M-11 inhibited in vitro the growth of HeLa 

human servical cancer cells with IC 50 40nM and 350nM, respectively. 

Two antitumor promoters, monogalactosyl diacylglycerols (M-12, M-13) were isolated from 

the freshwater green alga, Chlorella vulgaris, along with three other monogalactosyl diacylglycerols 

(M-14 to M-16) and two digalactosyl diacylglycerols (M-17, M-18). The monogalactosyl 

diacylglycerol containing (7Z,10Z)-hexadecadienoic acid (M-13) showed a more potent 

inhibitory effect toward tumor promotion [on the Epstein–Barr virus-associated early antigen 

(EBV-EA) activation on Raji cells induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)], 

than the other metabolites. 

Increases in the cytotoxic activity of peritoneal macrophages has been attributed to the action 

of -Carotene (M-19) which has also been reported to increase the number of tumor necrosis 

factor positive cells considered by many to be endogenous antineoplastic agents. -Carotene 

(M-19) has been isolated from Dunaliella sp. as well as from cyanobacteria such as Spirulina sp. 

In addition carotenoids, which were detected in cyanobacterial extracts, have been found to be 

mitogenic and to enhance the cytotoxic action of thymus derived cells. 

-Carotene-rich alga Dunaliella bardawil has been found to inhibit spontaneous mammary 

tumorigenesis of mice and the results strongly suggest that this is performed by increasing the 

homeostatic potential of the host animals as well as by the well-known antioxidant function of 

-Carotene. 

Welwitindolinones are a family of novel alkaloids recently isolated from the blue-green alga 

Hapalosiphon witschii. Incubation of SK-OV-3 human ovarian carcinoma cells and A-10 vascular 

smooth muscle cells with welwistatin (M-20), results in dose-dependent inhibition of cell 

proliferation, which is correlated with increases in the percentage of cells in mitosis. Treatment 

of A-10 cells with welwistatin resulted in reversible depletion of cellular microtubules but did


not affect microfilaments. Pretreatment of A-10 cells with paclitaxel prevented microtubule 

depolymerization in response to welwistatin. Welwistatin (M-20), inhibited the polymerization 

of purified tubulin in vitro but did not alter the ability of tubulin to bind [3H]colchicine or to 

hydrolyze GTP. Also, welwistatin (M-20) did not induce the formation of topoisomerase/DNA 

complexes. These results indicate that welwistatin is a new antimicrotubule compound that circumvents 

multiple drug resistance and so may be useful in the treatment of drug-resistant 

tumors. 

Hormothamnione (M-21) is a cytotoxin isolated from the marine cyanophyte Hormothamnion 

enteromorphoides. This metabolite was found to be a potent cytotoxic agent to P-388 lymphocytic 

leukemia (ID 50 4.6 ng mL 1 ) and HL-60 human promyelocytic leukemia cell lines 

(ID 50 0.1ngmL 1 ) and appears to be a selective inhibitor of RNA synthesis. 

Debromoaplysiatoxin (M-22) isolated from Lynbya gracilis, Oscillatoria nigroviridis, Schizothrix 

calcicola and Symploca muscorum, as well as from deep and shallow specimens of Lynbya majuscula 

exhibited T/C (Ratio of the survival time of Treated compared to Control diseased mice) 186 and 

140 with 1.8gkg 1 and 0.6mgkg 1 doses, respectively. From the same organism was 

Aplysiatoxin (M-23) originally isolated. 

Curacins A, B and C were isolated from the marine cyanobacterium Lyngbya majuscula. 

Curacin A (M-24) is an extremely potent antimitotic agent, which is under examination for its 

potential anticancer utility. Also Curacin B (M-25) and C (M-26) are both toxic to brine shrimp, 

demonstrate strong cytotoxicity against murine L-1210 leukemia and human CA46 Burkitt 

lymphoma cell lines, inhibit the polymerization of purified tubulin in vitro, and the NCI in vitro 

60-cell line assay, show potent antiproliferative activity to many cancer-derived cell lines in a 

manner characteristic of antimitotic agents. Even though Curacin D (M-27) was found to be 

comparable active to Curacin A (M-24) as a potent inhibitor of colchicine binding, it was 7-fold 

less active than Curacin A in its ability to inhibit tubulin polymerization, 10-fold less active in 

inhibiting MCF-7 breast cancer cell growth and 13-fold less active as a brine shrimp toxin. 

The marine cyanobacterium Lyngbya majuscula has yielded also two toxic natural products 

Hermitamides A (M-28) and B (M-29). Metabolites M-28 and M-29 exhibited LD 50 values 

of 5M and 18M in the brine shrimp bioassay, and IC 50 values of 2.2M and 5.5M to 

Neuro-2a neuroblastoma cells in tissue culture, respectively. 

Dolastatin 3 (M-30) previously reported from the sea hare Dolabella auricularia was isolated 

from an extract of the macroscopic cyanophyte Lyngbya majuscula. 

Dolastatin 12 (M-31) and Lyngbyastatin 1 (M-32), a new cytotoxic analogue of Dolastatin12, 

were isolated as inseparable mixtures with their C-15 epimers from extracts of Lyngbya 

majuscula/Schizothrix calcicola assemblages collected near Guam. Both metabolites proved toxic 

with only marginal or no antitumor activity when tested against colon adenocarcinoma #38 or 

mammary adenocarcinoma #16/C. Both compounds were shown to be potent disrupters of 

cellular microfilament networks. 

The lipopeptide Microcolin A (M-33) was also isolated from the marine blue green alga 

L. majuscula. Microcolin A suppressed concavalin A, phytohemagglutinin and lipopolysaccharideinduced 

proliferation of murine splenocytes. Mixed lymphocyte reaction, anti-IgM, and phorbol 

12-myristate 13-acetate plus ionomycin stimulation of murine splenocytes were all similarly 

suppressed by Microcolin A. The inhibitory activity of Microcolin A was time-dependent and 

reversible and was not associated with a reduction in cell viability. These results indicated that 

Microcolin A is a potent immunosuppressive and antiproliferative agent. 

Apratoxin A (M-34) a potent cytotoxin with a novel skeleton has been isolated from 

L. majuscula. This cyclodepsipeptide of mixed peptide–polyketide biogenesis bares a thiazoline


ring flanked by polyketide portions, one of which possesses an unusual methylation pattern. 

Apratoxin A possesses IC 50 values for in vitro cytotoxicity against human tumor cell lines ranging 

from 0.36 to 0.52nM; however it was only marginally active in vivo against a colon tumor 

and ineffective against a mammary tumor. 

The cytotoxic depsipeptides Lyngbyabellin A (M-35) and Lyngbyabellin B (M-36) were 

isolated from a Guamanian strain of L. majuscula. Both metabolites found to be cytotoxic with 

M-36 being slightly less active in vitro than M-35. The IC 50 values for M-35 and M-36 were 

0.03gmL 1 and 0.10gmL 1 against KB cells and 0.5gmL 1 and 0.83gmL 1 against 

LoVo cells, respectively. Lyngbyabellin A was proved to be potent microfilament-disrupting 

agent and the same mode of action is speculated for Lyngbyabellin B. 

From extracts of the same cyanobacterium two new lipopeptides; Malyngamides D (M-37) and 

Malyngamide H (M-38) were isolated by bioassay-guided fractionations. Malyngamide D was 

mildly cytotoxic with an ID 50 30gmL 1 to KB cells in tissue culture, while Malyngamide 

H exhibited an ichthyotoxic effect with an LC 50 5gmL 1 and EC 50 2gmL 1 . End points 

in this assay were death and inability to swim against a manually induced current. 

The novel lipopeptides Laxaphycin A (M-39) and Laxaphycin B (M-40) were isolated from 

L. majuscula extracts during screening against three cell lines. The cytotoxicity of Laxaphycins 

were evaluated for the parent drug-sensitive CCRF-CEM human leukemic lymphoblasts, 

CEM/VLB100 vinblastine-resistant subline which presents a MDR phenotype7 and CEM/VM-1 

subline usually referred to as atypical MDR cells8. Laxaphycin A was not active when tested at 

a concentration of 20mM. Laxaphycin B showed pronounced cytotoxic activities on the drugsensitive 

cells with IC 50 of 1.1mM and was practically equally active against the drug-sensitive 

cells and the drug-resistant cells. Both sublines showed no resistance to Laxaphycin B whereas 

those lines showed a 62- and 9-fold resistance to adriamycin. So, unlike the clinically used antitumor 

antibiotic adriamycin, Laxaphycin B preserved equal cytotoxicity on Pgp-MDR cells and 

altered DNA-topoisomerase II-associated MDR cells. 

Yanucamide A (M-41) and Yanucamide B (M-42) were isolated from the lipid extract of 

L. majuscula and Schizothrix sp. assemblage collected at Yanuca island, Fiji. Both Yanucamides 

exhibited strong brine shrimp toxicity with a LD 50 5ppm. 

Grenadadiene (M-43) and grenadamide are structurally unique cyclopropyl-containing 

metabolites isolated from the organic extract of a Grenada collection of Lyngbya majuscula. These 

were the first reported cyclopropyl-containing fatty acid derivatives from a Lyngbya sp. 

Grenadadiene (M-43) has an interesting profile of cytotoxicity in the NCI 60 cell line assay, 

while grenadamide exhibited modest brine shrimp toxicity (LD 50 5gmL 1 ). 

Kalkipyrone (M-44), a novel -methoxy-,-dimethyl--pyrone possessing an alkyl 

side chain, was isolated from an assemblage of Lyngbya majuscula and Tolypothrix sp. Kalkipyrone 

(M-44) is toxic to brine shrimp (LD 50 1gmL 1 ) and gold fish (LD 50 2gmL 1 ) and is structurally 

related to the actinopyrones that were previously isolated from Streptomyces sp. 

Microcystilide A (M-45) was isolated from the methanolic extract of the cyanobacterium 

Microcystis aeruginosa NO-15-1840. The compound was found to be only weakly cytotoxic 

against HCT116 and HCTVP35 cell lines (IC 50 0.5mgmL 1 ), but found to be active in the cell 

differentiation assay using HL-60 cells at a concentration of 0.5mgmL 1 . 

The lipophilic extract of a marine strain of Nostoc linckia was found to display appreciable 

cytotoxicity against LoVo (MIC 0.066gmL 1 ) and KB (MIC 3.3gmL 1 ). This algal extract 

was among the most LoVo-cytotoxic found in screening extracts of 665 blue-green algae. 

Bioassay-directed chromatography led to the isolation of Borophycin (M-46). 

Cryptophycin A (M-47) was initially isolated from cyanobacterium Nostoc sp. ATCC 53789 

and demonstrated antitumor activity. In vitro testing showed tumor selective cytotoxicity, that


is, higher cytotoxicity for tumor cells (leukemia and solid tumor cells) compared to a low 

malignant potential fibroplast cell line. The in vitro cytotoxicity spectrum of the Cryptophycins 

included tumors of non-human (L-1210 and P-388 leukemias, colon adenocarcinoma 38, 

pancreatic ductual adenocarcinoma 03, mammary adenocarcinoma 16/C) and human (colon 

adenocarcinomas: LoVo, CX-1, HCT-8 and H-116; mammary adenocarcinomas: MX-1 and 

MCF-7; lung adenosquamous carcinoma: H-125; ovarian adenocarcinoma: SKOV-3; and 

nasopharyngeal carcinoma: KB) origin. 

Six other Cryprophycins were isolated from the same species in minor amounts and 

structure–activity relationship studies were conducted. The cytotoxicities of epoxides 

Cryptophycin A (M-47) and Cryptophycin B (M-48) were the two strongest and were surprisingly 

identical in potency, implying that the chloro substituent on the O-methyltyrosine was 

unnecessary for exhibiting cytotoxicity. Removal of the epoxide oxygen or hydroxy groups from 

C-7 and C-8 of unit A as in Cryptophycin C (M-49) and Cryptophycin D (M-50) resulted in 

100-fold decrease in cytotoxicity. The leucic acid unit was clearly required for the potent activity, 

since Cryptophycin F methyl ester (M-52) and Cryptophycin G (M-53) were only weakly cytotoxic. 

The ester bond connecting 3-amino-2-methylpropionic acid and leucic acid was also 

clearly necessary for optimal activity. Cryptophycin E methyl ester (M-51) was 1000-fold less 

cytotoxic than M-47 and M-48. 

In addition, potent in vitro cytotoxicity was demonstrated against cells that were known to 

have multiple drug resistance (mammary 17/C/ADR, MCF-7/ADR, SKVLB1). Thus, 

Cryptophycin A (M-47) belongs to a class of compounds with a broad spectrum of in vitro 

antitumor activity, which is clearly maintained when administered in vivo by a route different 

from the tumor inoculation. Growth of L-1210 cells was inhibited by 85% upon exposure 

to Cryptophycin A. Cryptophycin A binds strongly with tubulin and disrupts the assembly 

of microtubules especially needed for mitotic spindle formation and cell proliferation. 

Because of the impressive in vitro and in vivo activities exhibited by Cryptophycin A, 

a number of analogues were synthesized by Eli Lilly & Co. The synthetic derivative 

Cryptophycin-145 (M-54) had an IC 50 of 0.015pM against the GC3 human colon carcinoma 

cell line. 

From the extract of Oscillatoria acutissima Acutiphycin (M-55) was isolated and showed 

antineoplastic activity with a T/C186 with a dose treatment of 50gkg 1 . Acutiphycin and 

the 20, 21didehydroacutiphycin (M-56) showed ED 50 1gmL 1 against KB and N1H/3T3 

cell lines, respectively. 

From a mixed culture of Oscillatoria nigroviridis and Schizothrix calcicola, metabolite 

Oscillatoxin A (M-57) was isolated, and showed antineoplastic activity level, T/C140 with a 

dose 0.2gkg 1 . 

The nucleoside Tubercidin–5--D glucopyranoside (M-58) was isolated from the 

cyanophyceae Plectonema radiosum and Tolypothrix distorta and showed cytotoxicity on KB cells 

with MIC 3gmL 1 . 

The cytotoxic macrolide Prorocentrolide (M-59) was isolated from the dinoflagellate 

Prorocentrum lima and exhibited cytotoxicity against L-1210 with an IC 50 20gmL 1 . 

The structurally related macrolide Prorocentrolide B (M-60) was isolated from Prorocentrum 

macolosum and the pharmacological evaluation is under investigation. 

Tolytoxin (M-61), the most potent of the Scytophycin compounds, has been shown to inhibit 

cell proliferation, induce morphological changes, and disrupt stress fiber organization in 

cultured mammalian cells. These effects are manifested rapidly (less than 15min) and at 

concentrations significantly lower than other F-actin disrupting agents such as Cytochalasins B 

or D, Latrunculin A, or Swinholide A. Tolytoxin also inhibits G-actin polymerization and


induces F-actin depolymerization in vitro. Tolytoxin has been also isolated from the cyanophyta 

Tolypothrix conglutinata, Scytonema mirabile and S. ocellatum. The Scytophycins (M-62 to M-65) are 

antifungal, cytotoxic macrolides produced by cyanobacteria of the genera Tolypothrix and 

Scytonema. 

The nucleoside Tubercidin (M-66), isolated from Tolypothrix byssoidea and Scytonema 

saleyeriense, was tested on KB and N1H/3T3 cell lines in vivo and the levels of toxicity were found 

to be high. The MIC on KB cells was found to be 2gmL 1 . Tubercidin is an inhibitor of 

DNA, RNA and protein synthesis in growing KB cells, acting by disruption of nucleic acid 

structure following incorporation. Synthesis of messenger RNA was found to be particularly 

susceptible. 

Symbioramide (M-67), a sphingosine derivative, isolated from the cultured dinoflagellate 

Symbiodinium sp. exhibits antileukemic activity against L-1210 murine leukemia cells in vitro 

with an IC 50 value of 9.5gmL 1 . The -hydroxy---dehydro fatty acid contained in 

Symbioramide is seldom found from natural sources. 

A new solid tumor selective cytotoxic analogue of Dolastatin 10, Symplostatin 1 (M-68) has 

been isolated from the marine cyanobacterium Symploca hydnoides, collected near Guam. 

Symplostatin 1 exhibited a cytotoxicity IC 50 value of 0.3ngmL 1 against KB cells (an epidermoid 

carcinoma line), as opposed to 0.1ngmL 1 for Dolastatin 10. Since M-68 induced 80% 

microtubule loss at 1ngmL 1 when tested on A-10 cells, its mechanism of action must be similar, 

if not identical, to that of Dolastatin 10. Dolastatin 10 appears to be one of the most potent 

antineoplastic compounds known to date and is in phase I trials as an anticancer agent. A second 

metabolite Symplostatin 2 (M-69) an analogue to Dolastatin 13 was also isolated from the 

same cyanobacterium. It has been suggested that Dolastatins isolated from Dolabella auricularia, 

probably have a cyanobacterial dietary origin. The sequestration of algal metabolites by sea hares 

is well documented in the ecological literature. 

Tolyporphin (M-70), a porphyrin extracted from the cyanobacteria Tolypothrix nodosa, was 

found to be a very potent photosensitizer of EMT-6 tumor cells grown both in vitro as suspensions 

or monolayers and in vivo in tumors implanted on the backs of C.B17/Icr severe combined 

immunodeficient mice. Thus, during photodynamic treatment (PDT) of EMT-6 tumor cells 

in vitro, the photokilling effectiveness of TP measured as the product of the reciprocal of D 50 (the 

light dose necessary to kill 50% of cells) and the concentration of TP is ~5000 times higher than 

that of Photofrin II (PII), the only PDT photosensitizer thus far approved for clinical trials. 

The outstanding PDT activity of TP observed in vivo may be due to its unique biodistribution 

properties, in particular low concentration in the liver, resulting in a higher delivery to the other 

tissues, including tumor. 

Tolyporphins J and K (M-71 and M-72) were tested for biological activity in MDR reversal 

and [ 3 H]vinblastine accumulation assays alone with Tolyporphin as a comparison. In the MDR 

reversal assay Tolyporphin J (M-71) exhibited virtual identical activity to M-70. Both 

compounds sensitized MCF-7/ADR cells to actinomycin D, reversing MDR and verifying their 

abilities to enhance drug accumulation. Tolyporphin K (M-72) exhibited little activity. In contrast 

to M-70 and M-71, Tolyporphin K promoted only modest increases in [ 3 H]vinblastine 

accumulation, consistent with its poor ability to sensitize these cells to cytotoxic drugs. 

Cyano nucleoside Toyocamycin-5--D-glucopyranoside (M-73), closely related to 

Tubercidin-5-D glucopyranose (M-58), was isolated from Tolypothrix tenuis and was assayed on 

KB and HL-60 cell lines showing MICs 12 and 6gmL 1 , respectively.

(continued) 

Table 4.8 Cytotoxic metabolites from microalgae 


Amphidinium sp. Amphidinolide A M-1 Ishibashi et al., 1987; Ishiyama et al., 1996; 

Amphidinolide B M-2 Kobayashi, 1989 

Amphidinolide C M-3 Kobayashi et al., 1986, l988a, 1989a 

Amphidinolide D M-4 

Amphidinolide R, S M-5, M-6 Ishibashi et al., 1997 

Amphidinolide V M-7 Kubota et al., 2000 

Carbenolide M-8 Shimizu, 1996 

Astasia longa Astasin M-9 Kaya et al., 1995 

Calothrix sp. Calothrixins A, B M-10, M-11 Rickards et al., 1999 

Chlorella vulgaris Glyceroglycolipids M-12 to M-18 Morimoto et al., 1995, Soeder, 1976 

Dunaliella sp. B-Carotene and other M-19 Nagasawa et al., 1989, 1991; Schwartz et al., 1986; 

carotenoids 1993; Schwartz and Shklar, 1989; Shklar and 

Schwartz, 1988; Tomita et al., 1987 

Hapalosiphon witschii Welwistatin M-20 Zhang and Smith, 1996 

Hormothamnione Hormothamnione M-21 Gerwick et al., 1986, 1989 

enteromorphoides 

Lyngbya gracilis Debromoaplysiatoxin M-22 Mynderse et al., 1977; Mynderse and Moore, 1978 

Lyngbya majuscula Debromoaplysiatoxin M-22 Moore, 1982 

Aplysiatoxin M-23 

Curacin A M-24 Blokhin et al., 1995; Bonnard et al., 1997, Gerwick et al., 

Curacin B M-25 1987, 1994; Graber and Gerwick, 1998; 

Curacin C M-26 Harrigan et al., 1998a; Luesch et al., 2000a,b, 

Curacin D M-27 2001; Marquez et al., 1998; Mitchell et al., 2000; 

Hermitamides A M-28 Nagle et al., 1995; Orjala et al., 1995; Pettit et al., 1987; 

Hermitamides B M-29 Sitachitta and Gerwick, 1998; Sitachitta et al., 2000; 

Dolastatin 3 M-30 Tan et al., 2000b; Verdier-Pinard et al., 1998; 

Dolastatin 12 M-31 Yoo and Gerwick, 1995; Zhang et al., 1997 

Lyngbyastatin 1 M-32 

Microcolin A M-33 

Apratoxin A M-34 

Lyngbyabellin A M-35 

Lyngbyabellin B M-36 

Malyngamide D M-37



Malyngamide H M-38 

Laxaphycin A M-39 

Laxaphycin B M-40 

Yanucamide A M-41 

Yanucamide B M-42 

Grenadadiene M-43 

Kalkipyrone M-44 

Microcystis aeruginosa Microcystilide A M-45 Tsukamoto et al., 1993 

NO-15-1840 

Nostoc sp. ATCC 53789 Borophycin M-46 Foster et al., 1999 

Cryptophycin A M-47 Golakoti et al., 1994, 1995 

Cryptophycin B M-48 Hemscheidt et al., 1994 

Cryptophycin C M-49 Valeriote et al., 1995 

Cryptophycin D M-50 Smith et al., 1994a 

Cryptophycin E methyl ester M-51 

Cryptophycin F methyl ester M-52 

Cryptophycin G M-53 

Cryptophycin-145 M-54 Eli Lilly & Co et al., 1998 

Oscillatoria acutissima Acutiphycin M-55 Barchi et al., 1984 

20,21 Didehydroacutiphycin M-56 

Oscillatoria nigroviridis Oscillatoxin A M-57 Moore, 1982 

Debromoaplysiatoxin M-22 Mynderse and Moore, 1978; Mynderse et al., 1977 

Plectonema radiosum Tubercidin-5-D glucopyranose M-58 Stewart et al., 1988 

Prorocentrium lima Prorocentrolide M-59 Torigoe et al., 1988 

Prorocentrium Prorocentrolide B M-60 Hu et al., 1996 

maculosum 

Schizothrix calcicola Oscillatoxin A M-57 Harrigan et al., 1998a; Moore, 1982 

Debromoaplysiatoxin M-22 Mynderse and Moore 1978; Mynderse et al., 1977 

Dolastatin 12 M-31 Sitachitta et al., 2000 

Lyngbyastatin 1 M-36 

Yanucamide A and B M-41 and M-42

Scytonema conglutinata Tolytoxin M-61 Stewart et al., 1988 

Scytonema mirabile Tolytoxin M-61 Carmeli et al., 1990; Stewart et al., 1988 

Scytonema ocellatum Tolytoxin M-61 Stewart et al., 1988 

Scytonema Scytophycins A – D M-62 to M-65 Barchi et al., 1984; Patterson et al., 1993 

pseudohofmanni Smith et al., 1993 

Scytonema saleyeriense Tubercidin M-66 Stewart et al., 1988 

Symbiodinium sp. Symbioramide M-67 Kobayashi et al., 1988b 

Symploca hydnoides Symplostatin 1 M-68 Harrigan et al., 1998b, 1999; Poncet, 1999 

Symplostatin 2 M-69 

Symploca muscorum Debromoaplysiatoxin M-22 Mynderse et al., 1977 

Tolypothrix nodosa Tolyporphin M-70 Mayer, 1998; Minehan et al., 1999 

Tolyporphin J M-71 Morlière et al., 1998; Prinsep et al., 1992, 1995, 1998 

Tolyporphin K M-72 Smith et al., 1994b 

Tolypothrix tenuis Toyocamycin-5-D glucopyranose M-73 Renau et al., 1994; Stewart et al., 1988 

Tolypothrix byssoidea Tubercidin M-66 Barchi et al., 1983; Furusawa et al., 1983 

Tolypothrix conglutinata Tolytoxin M-61 Moore, 1981 

Tolypothrix distorta Tubercidin-5-D glucopyranose M-60 Stewart et al., 1988


Cytotoxic metabolites from microalgae 

HO 

HO 

HO 

OH 

O 

O 

O 

M-1 

O 

OH OH O 

HO 

* 

OH 

O 

O 

Srereoisomers at *C21 M-2 

M-4 

O 

OH 

OH 

O 

O 

O 

O 

OH 

M-3 

HO 

O 

OH 

M-5 

OH 

O 

O 

O 

O 

O 

OH 

M-6 

H 

O H 

OH O 

M-7 

O 

HO 

HO 

HO 

O 

O 

O 

O 

CH 2 

O OH O 

CH 3 

M-8 

O 

O O 

HO O O 

O 

H 

M-9 

N 

H 

O 

O 

+ O – 

N 

M-10 

N 

H 

O 

O 

N 

M-11 

HO 

CH 2 OH 

O 

HO 

O 

CH 2 

HO 

H C OR 2 

CH 2 OR 1 

R 1 = (7Z,10Z,13Z)-hexadecatrienoyl, 

R 2 = (7Z,10Z)-hexadecadienoyl 

R 1 , R 2 = (7Z,10Z)-hexadecadienoyl 

R 1 = linolenoyl, 

R 2 = (7Z,10Z,13Z)hexadecatrienoyl 

R 1 = linolenoyl, R 2 = (7Z,10Z)-hexadecadienoyl 

R 1 , R 2 = linoleoyl 

M-12 

M-13 

M-14 

M-15 

M-16 

HO CH 2 OH 

O 

HO 

HO 

O CH 2 

HO 

O 

O 

HO CH 2 

HO 

H C OR 2 

CH 2 OR 1 

R 1 = linolenoyl, R 2 = (7Z,10Z)-hexadecadienoyl 

R 1 = linolenoyl, R 2 = (7Z,10Z,13Z)-hexadecatrienoyl 

M-17 

M-18


Cl 

M-19 

SCN 

O 

N 

H 

H 

O 

M-20 

H 2 C 

H 2 C 

R 

OCH 3 

OH O 

HO 

CH 3 O 

CH 3 

O 

O R R: H M-22 

O 

O O 

N 

OH 

N 15 

N O R 

H 

O O H 

O 

H M-31 

H O 

CH 

O 

2 CH(CH 3 ) 2 N 

H O H H OCH 

N 

N N N 

N N N N 

3 M-32 

N 

O 

OAc 

O O 

O 

M-33 

CH 3 O O 

OH M-21 O O O 

R: Br M-23 

CH 3 O 

O 

OH 

OH 

OH 

R 

OCH 

S 

3 

OMe 

H N CH 3 

H S 

2 C 

N 

H H 

CH H 3 CH 3 M-25 

R: Me 

R: H 

M-24 

M-27 

H H 

H 3 C 

S 

OCH 3 O 

H N CH 3 

M-26 

N 

M-28 

H H 

H 

Val 

Pro 

O 

N 

OCH 3 

N 

OCH 3 O 

NH 

S 

N 

H O 

HN O 

N 

M-29 

M-30 

H 

O 

Leu 

Gly 

NH 

O 

N 

S 

NH 

CONH 2 

Gln 

O O O 

MeO 

O-Me-Tyr 

N-Me-Ala 

N 

N 

H 

N 

O 

O 

O 

O 

N 

moCys 

S 

N 

O 

O 

OH 

Dtena 

M-34 

S 

HN 

N 

O H 

N 

H 

O 

S 

N 

O O O 

Cl Cl 

M-35 

N-Me-Ile 

Pro 

HO 

O


O 

HO 

S 

HN 

N 

O 

N 

H 

O S 

N 

O O O 

Cl Cl 

M-36 

OMe 

O 

N 

H 

H 

Cl O 

OH 

M-37 

OMe 

O 

N 

H 

O 

H 

O 

M-38 

(2S)-Leu 

(2R,3S)-Ile HN 

(2S, 3S)-Ile 

HN 

(2R)-Leu 

O 

O 

Gly 

H 

O 

N 

N 

O 

H 

NH 

H 

N 

O 

O 

O 

N 

H 

O 

O 

HN 

(2R)-β-Aoc 

(2S)-Hse 

NH 

O N 

NH 

OH 

E-Dhb 

OH 

O (2S, 4R)-Pro(4HO) 

M-39 

(2R)-Phe 

OH 

(2S)-Hse 

(2S)-Val 

(2S,3S)-Leu(3-OH) 

(3R)-β-Ade 

O 

H 

OH 

HN N 

N 

(2S)-Thr 

H 

D-N-MePhe 

O 

H 

HO O 

O NH 

(2S)-Ala 

β-Ala N 

O NH 

O 

N 

(2R)-Leu 

OH 

L-Hiv 

HN 

NH M-40 O 

O 

O 

(2R, 3S),-Leu(3-OH) 

O 

HN O 

O O O O 

(2S)-Pro 

Dhoya 

N O O 

O O 

NH 2 

H 

L-Val 

N 

N N NCH 3 O 

(2S)-Thr 

H 

H 

OH 

NH 2 

(2S)-Gln 

HO 

O 

N-Me-(2S, 3S)-Ile 

(2R, 3R)-Asn(3-OH) 

M-41 

β-Ala 

O 

Dhoya 

O 

H 

N 

O 

D-N-MePhe 

N 

L-Hiv 

O 

O 

O O 

L-allo-Ile 

N 

H 

M-42 

H 

H 

O 

O 

H 

H 

H 

O 

Br 

O 

M-43 

OH 

O 

O 

OMe 

M-44 

HO 

OH 

L-Tyr 

Ahp 

OH 

O 

H 2 N O 

N 

NH 

O O NH 

O 

NH 

NH 

O L-Leu 

H 3 C N 

O NH 

OH O 

O 

D-p-OH-PLac L-Gln L-Thr O 

L-Ile CH 3 

OH 

L-N-Me-Tyr 

M-45


O 

O 

O HO 

O 

O Na + O 

_ 

B 

O O 

O 

OH 

O 

O 

M-46 

O 

O 

O O 

O 

HN 

N 

H 

O 

O 

R 

OCH 3 

R: Cl 

R: H 

M-47 

M-48 

O 

O 

O O 

O 

O 

HN 

N O 

H 

R 

OCH 3 

R: Cl 

R: H 

M-49 

M-50 

O 

O 

O 

OH 

CH 3 O 

O 

HN 

N 

H 

O 

O 

Cl 

OCH 3 

M-51 

OH 

OH OH 

CH 3 O 

O 

HN 

N 

H 

O 

O 

Cl 

OCH 3 

M-52 

OH 

OH 

OH 

O 

HN 

HO O 

Cl 

OCH 3 

M-53 

OH 

CH 3 

O 

OH 

Br O 

CH 3 

H 3 C 

O 

O 

O 

CH 3 

HN 

N 

H 

O 

Cl 

OCH 3 O O 

M-54 O 

OH 

R 

OH 

O 

R: Bu 

R: CH 2 CH = CHCH 3 

M-55 

M-56 

HO 

O 

O O O 

O 

OH 

O 

OCH 3 

OH 

M-57 

CH 2 OH 

O 

OH 

HO O 

OH 

HO 

O 

NH 2 

N 

N N 

OH 

M-58 

OH 

OH 

OH 

OH 

N 

Me 

Me Me 

O 

O 

OH 

Me 

OH 

Me O O 

OH 

O 

HO 

OH 

OH 

M-59 

N 

O 

OH 

OH 

HO 

OH O 

OH 

O 

O 

O 

OSO 3H 

OH 

M-60


O 

OMe 

O OMe OMe 

OH 

O OH 

OMe O 

O 

OMe 

N 

O 

H 

M-61 

O 

OMe 

16 

O OMe OMe 

O OH 

OH 

O 

27 

R 

O 

N H 

OMe 

R: C27 –OH 

R: C27 = O 

R: C16 –Me 

R: C16 –Me, –OH 

M-62 

M-63 

M-64 

M-65 

N 

OH 

HO 

NH 2 

O 

N 

N 

M-66 

HO 

HN 

OH 

M-67 

HO 

OH 

O 

N 

Val Dil Dap Doe 

O 

H 

N N N 

O OCH 3 

O 

H 

N 

OCH 3 O 

S 

N 

N-Me-TYR VAL THR MET(O) ILE 

O 

O O 

O 

HO 

H 

N 

N 

H 

N 

N 

O NMe O 

M-68 H 

H 

O H HN 

O 

N O 

N 

S O 

HO 

O 

PHE AHP ABU 

M-69 

Me 

HO 

O 

Me 

OAc 

Me 

O 

N 

H 

N 

Me 

N 

H 

N Me 

AcO 

O 

O 

M-70 

Me 

OH 

Me 

HO 

Me 

O 

N 

H 

N 

Me 

N 

H 

N 

OH 

Me 

O 

M-71 

Me 

Me 

N 

H 

N 

N 

H 

N 

Me 

HO 

Me 

O 

O 

Me 

OH 

CH 2 OH 

O 

NC 

NH 2 

OH 

N 

M-72 HO O N 

OH 

O 

N 

M-73 

HO 

OH 

Conclusions 

In the last 25 years, marine organisms (algae, invertebrates and microbes) have provided key 

structures and compounds that proved their potential in several fields, particularly as new therapeutic 

agents for a variety of diseases. The interest in the field is reflected by the number of scientific 

publications, the variety of new structures and the wide scope of the organisms 

investigated. As indicated in a review (Bongiorni and Pietra, 1996) covering the patents on different 

aspects of marine natural products applications, filed during the last 25 years, human 

health, health food and cosmetics account for more than 80% of the applications. As reported


by Bongiorni and Pietra (1996), approximately 200 patents on marine natural products had 

been recorded between 1969 and 1995. In the period from 1996 until April 1999, close to 

100 new patents had been issued in this area. 

As yet, no compound isolated from a marine source has been approved for commercial 

use as a chemotherapeutic agent, though, Ziconotide® which is conotoxin VII from Conus 

magnus is awaiting final approval from the US FDA as a non-narcotic analgesic. In the 

antitumour area, several compounds are in the various phases of clinical development as 

potential agents. 

Seaweeds have afforded, to date the highest number of compounds within a single group of 

marine organisms. A high percentage of recent reports concern bioactive metabolites with interesting 

biological properties. The reported pharmacological activities in this review have focused 

on the cytotoxicity against tumoral cells. 

Algae were some of the first marine organisms that were investigated and proven to be rich 

sources of extraordinary chemical structures. Up to date only a small percentage of algae has 

been studied and the fact that many species exhibit geographic variation in their chemical composition 

shows the huge potential algae still hold as sources of interesting bioactive metabolites. 

Also since some of the investigations on the algal chemistry preceded the development of many 

of the current pharmacological bioassays it is well profitable to reexamine the pharmacological 

potential of these algal metabolites as well. 

On the basis of the reviewed literature, it can be predicted that further intense research on 

bioactive algal metabolites will be stimulated from the advancement of sophisticated NMR 

techniques and the development of new faster and more efficient pharmacological evaluation 

assays.

Appendix 

Chemical structures of selected 

compounds 

List of compounds 

1 1,4-Naphthoquinone .............................................................................................. 244 

2 Isoretinoin .............................................................................................................. 244 

3 2-Hydroxy-4-methoxybenzaldehyde ....................................................................... 245 

4 22-Hydroxytingenone ............................................................................................ 245 

5 5-Fluorouracil ......................................................................................................... 245 

6 9-Methoxycanthin-6-one ........................................................................................ 246 

7 Adenosine diphosphate ........................................................................................... 246 

8 Ammonium phosphate monobasic .......................................................................... 246 

9 Aflatoxin B1 ........................................................................................................... 247 

10 Aluminum isopropoxide ......................................................................................... 247 

11 Allamandin ............................................................................................................ 247 

12 Allamcin ................................................................................................................ 248 

13 Angelicin ................................................................................................................ 248 

14 Arachidonic acid ..................................................................................................... 248 

15 Arachidonic acid ..................................................................................................... 249 

16 Vitamin C .............................................................................................................. 249 

17 Baicalein ................................................................................................................. 249 

18 Benzo[a]pyrene ....................................................................................................... 250 

19 Benzylisothiocyanate .............................................................................................. 250 

20 -Carotene ............................................................................................................. 250 

21 Biochanin A ........................................................................................................... 250 

22 Caffeine .................................................................................................................. 251 

23 Canthin-6-one ........................................................................................................ 251 

24 Carbamylcholine chloride ....................................................................................... 251 

25 5-Isopropyl-2-methylphenol ................................................................................... 251 

26 Catechin ................................................................................................................. 252 

27 Cisplatin ................................................................................................................. 252 

28 Colchicine .............................................................................................................. 252 

29 Curcumin ............................................................................................................... 253 

30 Cyclophosphamide .................................................................................................. 253 

31 D-Galactose ............................................................................................................. 253 

32 Desoxypodophyllotoxin .......................................................................................... 254

Appendix 243 

33 Dichloromethane .................................................................................................... 254 

34 Dihydrofolate ......................................................................................................... 254 

35 7,12-Dimethyl benz[a]anthracene .......................................................................... 255 

36 Taxotere .................................................................................................................. 255 

37 Ellagic acid ............................................................................................................. 255 

38 Eupatorin ............................................................................................................... 256 

39 Fagaronine .............................................................................................................. 256 

40 Falcarinol ................................................................................................................ 256 

41 Tabun ..................................................................................................................... 256 

42 N-acetyl-D-Galactosamine ...................................................................................... 257 

43 Alantolactone ......................................................................................................... 257 

44 Genistein ................................................................................................................ 257 

45 Glycyrrhetinic acid ................................................................................................. 258 

46 Glycyrrhizic acid .................................................................................................... 258 

47 Goniothalamicin ..................................................................................................... 259 

48 Helenalin ................................................................................................................ 259 

49 Hexane ................................................................................................................... 259 

50 Hydroquinone ........................................................................................................ 259 

51 Hypericin ............................................................................................................... 260 

52 Indole ..................................................................................................................... 260 

53 Isoflavone ............................................................................................................... 260 

54 Dodecyl benzenesulfonic acid, sodium salt .............................................................. 261 

55 Levodopa ................................................................................................................ 261 

56 L-()-Arabinose ...................................................................................................... 261 

57 -L-Rhamnose ........................................................................................................ 262 

58 D-()-Lactose ......................................................................................................... 262 

59 Lapachol ................................................................................................................. 262 

60 All cis--9,12,15-Octadecatrienoate ........................................................................ 262 

61 Maytansine ............................................................................................................. 263 

62 Methotrexate .......................................................................................................... 263 

63 Methyl methanesulfonate ........................................................................................ 264 

64 Mitomycin C .......................................................................................................... 264 

65 N-methyl-N-nitro-N-nitrosoguanidine .................................................................. 264 

66 N-Acetylgalactosamine ........................................................................................... 265 

67 N-nitrosopyrrolidine ............................................................................................... 265 

68 Naringenin ............................................................................................................. 265 

69 4,5,7-Trihydroxyflavanone ..................................................................................... 265 

70 Neurolanin ............................................................................................................. 266 

71 Nickel chloride ....................................................................................................... 266 

72 Norepinephrine ...................................................................................................... 266 

73 Oleic acid ............................................................................................................... 266 

74 Parthenolide ........................................................................................................... 267 

75 Phloroglucinol ........................................................................................................ 267 

76 Phyllanthoside ........................................................................................................ 267 

77 Picrolonic acid ........................................................................................................ 268 

78 Piperidine ............................................................................................................... 268 

79 Plumbagin .............................................................................................................. 268

244 Appendix 

80 Plumericin .............................................................................................................. 268 

81 Podophyllotoxin ..................................................................................................... 269 

82 Psoralen .................................................................................................................. 269 

83 Quercetin ............................................................................................................... 269 

84 L-Malic acid, sodium salt ........................................................................................ 270 

85 Paclitaxel ................................................................................................................ 270 

86 Tetrahydrofuran ...................................................................................................... 270 

87 Thymol .................................................................................................................. 271 

88 Tricine .................................................................................................................... 271 

89 Tubulosine .............................................................................................................. 271 

90 S-(–)-Tyrosine ......................................................................................................... 271 

91 Urethane ................................................................................................................ 272 

92 Valtrate .................................................................................................................. 272 

93 Vinblastine ............................................................................................................. 272 

94 22-oxovincaleukoblastine ........................................................................................ 273 

95 Viscotoxin A 3 ......................................................................................................... 273 

O 

O 

1,4-Naphthoquinone 

Synonyms: 1,4-Naphthalenedione; 1,4-dihydro-1,4-diketonaphthalene; -naphthoquinone. 

O 

HO 

Isoretinoin 

Synonyms: Accutane; 13-cis-Vitamin A acid; 13-cis-Retinoic acid; cis-retinoic acid; neovitamin A 

acid; 13-RA; ro-4-3780; retinoic acid, 9Z form; 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)- 

2,(E),4,6,8(Z,Z,Z)-nonatetraenoic acid; Isotretinoin; Accure; IsotrexGel; Roaccutane; Isotrex; 

Teriosal; 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)2-cis-4-trans-6-trans-8-trans-nonatetraenoic 

acid; Tasmar.

Appendix 245 

O 

H 

O 

HO 

2-Hydroxy-4-methoxybenzaldehyde 

Synonyms: 4-Methoxysalicylaldehyde. 

29 30 

O 

HO 

3 

2 

4 

1 

11 

25 

10 

9 

5 

6 

12 

8 

7 

R 1 

19 

27 

18 

13 

H 

14 

15 

26 

R 2 

21 O 

20 

22 

17 

R 3 

28 

16 

23 

R 1 R 2 R 3 

1 H CH 3 OH 

22-Hydroxytingenone 

O 

HN 

F 

O 

N 

H 

5-Fluorouracil 

Synonyms: Fluorouracil, FU; 5-FU; 5-fluoro-2,4(1H,3H)-Pyrimidinedione; Adrucil; Efudex; Fluoroplex; 

Ro 2-9757; Arumel; Carzonal; Effluderm (free base); Efudix; Fluoroblastin; Fluracil; Fluri; Fluril; 

Kecimeton; Timazin; U-8953; Ulup; 5-Fluoro-2,4-pyrimidinedione; 5-Fluoropyrimidine-2,4-dione; 

5-Ftouracyl; efurix; fluracilum; ftoruracil; queroplex; 50fluoro uracil; Fluorouracil (Topical); 

Fluroblastin.

246 Appendix 

R 3 

10 

11 

1 

12 14 2 

R 2 

B 

N 

16 R 1 

9 13 15 

N 

6 4 

O 

5 

R 1 R 2 R 3 

– OMe H 

9-Methoxycanthin-6-one 

N 

NH 2 

N 

O 

O 

N 

N 

HO 

P 

OH 

O 

P 

OH 

O 

H 

OH 

O 

H 

H 

OH 

Adenosine diphosphate 

Synonyms: ADP; adenosine 5-diphosphate. 

NH 4 

– O 

O 

P 

OH 

OH 

Ammonium phosphate monobasic 

Synonyms: Ammonium biphosphate; Ammonium Dihydrogen Phosphate; ADP; Ammonium 

phosphate; Phosphoric acid, monoammonium salt; Monoammonium phosphate.

Appendix 247 

H 

O 

O 

O 

H 

O 

O 

O 

Aflatoxin B1 

Synonyms: AFB1; AFBI aflatoxin b; 2,3,6a,9a-tetrahydro-4-methoxycyclopenta(c)furo(3,2:4,5)furo- 

(2,3-h)(1)benzopyran-1,11-dione; Aflatoxin B1, crystalline. 

O 

O 

AI 

O 

Aluminum isopropoxide 

Synonyms: AIP; 2-Propanol, aluminum salt; Aluminum(III)isopropoxide. 

O 

OH 

O 

H 

H 

O 

H 

O 

O 

H 

O 

Allamandin

248 Appendix 

OH 

H 

H 

O 

H 

O 

O 

H 

O 

Allamcin 

O 

O 

O 

Angelicin 

Synonyms: Furo(2,3-h)coumarin. 

O 

OH 

Arachidonic acid 

Synonyms: 5,8,11,14-icosatetraenoic acid; 5,8,11,14-Eicosatetraenoic acid, (all-Z)-; Eicosa- 

5Z,8Z,11Z,14Z-tetraenoic acid.

Appendix 249 

HO 

O 

Arachidonic acid 

Synonyms: all cis-Delta-5,8,11,14-icosatetraenoate. 

HO 

HO 

O 

O 

HO 

Vitamin C 

OH 

Synonyms: L-ascorbic acid; L-3-ketothreohexuronic acid; Ascorbicap; Cebid; Cecon; Cevalin; Cemill; 

Sunkist; L-()-Ascorbic Acid; Acid Ascorbic; antiscorbic vitamin; antiscorbutic vitamin; cevitamic 

acid; 3-keto-L-gulofuranolactone; L-3-ketothreohexuronic acid lactone; laroscorbine; L-lyxoascorbic 

acid; 3-oxo-L-gulofuranolactone; L-xyloascorbic acid; adenex; allercorb; cantan; proscorbin; vitacin; 

AA; arco-cee; ascoltin; ascorb; ascorbajen; ascorbicab; ascor-b.i.d.; ascorbutina; ascorin; ascorteal; 

ascorvit; cantaxin; catavin c; cebicure; cebion; cee-caps td; cee-vite; cegiolan; ceglion; celaskon; 

ce lent; Celin; cemagyl; ce-mi-lin; cenetone; cereon; cergona; cescorbat; cetamid; cetemican; cevatine; 

Cevex; cevibid; cevimin; ce-vi-sol; cevital; cevitamin; cevitan; cevitex; Cewin; ciamin; Cipca; citriscorb; 

c-level; C-Long; colascor; concemin; C-Quin; C-Span; c-vimin; dora-c-500; davitamon c; duoscorb; L- 

threo-hex-2-enonic acid, -lactone; Hicee; hybrin; IDO-C; lemascorb; liqui-cee; Meri-c; natrascorb 

injectable; 3-oxo-L-gulofuranolactone (enol form); planavit c; redoxon; ribena; roscorbic; scorbacid; 

scorbu-c; secorbate; testascorbic; vicelat; Vicin; vicomin c; viforcit; viscorin; vitace; vitacee; vitacimin; 

vitamisin; vitascorbol; Xitix; Ascorbic Acid. 

OH 

O 

HO 

HO 

O 

Baicalein 

Synonyms: 5,6,7-Trihydroxyflavone.

250 Appendix 

Benzo[a]pyrene 

Synonyms: 6,7-Benzopyrene; B[A]P; BP; 3,4-Benzopyrene; Benzo[d,e,f]chrysene; 3,4-Benzpyrene; 

Benzpyrene; 3,4-benzylpyrene; 3,4-benz[a]pyrene; 3,4-BP; Benzo[a]pyrene. 

N 

S 

Benzylisothiocyanate 

Synonyms: Benzene, (isothiocyanatomethyl)-. 

β-Carotene 

Synonyms: Solatene; trans--Carotene; Carotene; ,-Carotene. 

OH 

O 

O 

HO 

O 

Biochanin A 

Synonyms: 5,7-dihydroxy-4-methoxyiso-flavone;olmelin.

Appendix 251 

O 

N 

N 

O 

N 

N 

Caffeine 

Synonyms: 1,3,7-Trimethylxanthine; 3,7-dihydro-1,3,7-trimethyl-1H-Purine-2,6-dione; 1,3,7- 

Trimethyl-2,6-dioxopurine; 7-Methyltheophylline; Alert-Pep; Cafeina; Cafipel; Guaranine; Koffein; 

Mateina; Methyltheobromine; No-Doz; Refresh’n; Stim; Theine; 1-methyltheobromine; methyltheobromide; 

eldiatric c; organex; 1,3,7-trimethyl-2,6-dioxo-1,2,3,6-tetrahydropurine; caffenium. 

R 11 1 

3 

12 14 

2 

10 

9 13 15 N 

R 2 N 

8 

16 R 1 

6 4 

O 5 

R 1 

O 

R 2 

H 

R 3 

H 

Canthin-6-one 

H 2 N O 

N 

O 

Carbamylcholine chloride 

Cl – 

Synonyms: Carbachol chloride; 2-[(aminocarbonyl)oxy]-N,N,N-trimethyl-Ethanaminium chloride; 

Carbachol; (2-Hydroxyethyl)trimethylammonium chloride carbamate; (2-Carbamoyloxyethyl)trimethylammonium 

chloride. 

OH 

5-Isopropyl-2-methyl-phenol 

Synonyms: carvacrol; Phenol, 2-methyl-5-(1-methylethyl)-; Cymenol; Hydroxy-p-cymene; Isopropylo-cresol; 

Isothymol; Methyl-5-(1-methylethyl)phenol.

252 Appendix 

OH 

OH 

HO 

O 

OH 

OH 

Catechin 

Synonyms: Cianidanol; ()-CATECHIN. 

NH 3 

NH 3 

Cl 

Pt 

Cl 

Cisplatin 

Synonyms: cis-Diaminedichloroplatinum(II); cis-Platinous Diamine Dichloroplatin; CACP; CDDP; 

CPDD; Platinol; cis-Platinous diamine dichloride; dCDP; cis Pt II; cis-Diaminedichloroplatinum; 

DDP; DDPt; Platiblastin; cis-Dichlorodiamineplatinum(II); (SP-4-2)-diaminedichloroplatinum; cisdiaminodichloroplatinum(II); 

cis-platinum(II) diamine dichloride; cisplatyl; CPDC; cis-ddp; neoplatin; 

peyrone’s chloride; platinex; PT-01; diaminedichloroplatinum; cis-dichlorodiaminoplatinum(II); 

cis-dichlorodiamineplatinum; cis-platinous diaminodichloride; 2-Deoxycytidine diphosphate; 

cis-Diammine dichloroplatinum(II); cis-Dichlorodiammine platinum (II); CISPLATIN (CIS- 

DIAMINEDICHLOROPLATIUM (II)). 

O 

O 

O 

O 

O 

HN 

O 

Colchicine 

Synonyms: (S)-N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)acetamide; 

N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)-acetamide; 

N-acetyltrimethylcolchicinic acid methyl ether; 7-acetamido-6,7-dihydro-1,2,3,10-tetramethoxybenzo[a]heptalen-9(5H)-one; 

7--H-colchicine; colchineos; colchisol; colcin; colsaloid; condylon; 

colchiceine methyl ether; Colgout; COLCHICINE CRYSTALLINE.

Appendix 253 

O 

O 

HO 

OH 

O 

Synonyms: C.I. 75300; 1,6-Heptadiene-3,5-dione, 1,7-bis(4-hydroxy-3-methoxyphenyl)-, (E,E)-; 

tumeric yellow; 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione; C.I. natural yellow 3; 

curouma; diferuloylmethane; gelbwurz; Haidr; Halad; haldar; Halud; indian saffron; kachs haldi; merita 

earth; safra d’inde; souchet; terra merita; yellow ginger; yellow root; YO-KIN; Natural Yellow 3; 

E-100. 

O 

Curcumin 

Cl 

O 

O 

P 

N 

NH 

Cl 

Cyclophosphamide 

Synonyms: N, N-Bis(2-Chloroethyl)tetrahydro-2H-1,3,2-Oxazaphosphorin-2-Amine, 2-Oxide; Cytoxan; 

Cyclophosphane; B 518; Procytox; Neosar; Cyclophosphamides; Cyclophosphoramide; Sendoxan; 

bis(2-Chloroethyl)phosphamide cyclic propanolamide ester; bis(2-Chloroethyl)phosphoramide cyclic 

propanolamide ester; N,N-bis(beta-Chloroethyl)-N,O-propylenephosphoric acid ester diamide; N- 

bis(-Chloroethyl)-N,O,trimethylenephosphoric acid ester diamide; Cytophosphane; 2-(bis(2- 

Chloroethyl)-amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide; Cycloblastin; Cyclostin; 

()-Cyclophosphamide; Asta B 518; Clafen; Claphene; Cyclophosphamidum; cb 4564; Endoxan R; 

Endoxan-Asta; Endoxana; Endoxanal; Endoxane; Enduxan; Genoxal; Mitoxan; N,N-Bis(-chloroethyl)- 

N,O-trimethylenephosphoric acid ester diamide; N,N-Bis(2-chloroethyl)-N,O-propylenephosphoric 

acid ester diamide; N,N-Di(2-chloroethyl)-N,O-propylene-phosphoric acid ester diamide; Semdoxan; 

Senduxan; sk 20501; tatrahydro-2-(Bis(2-chloroethyl)amino)-2H-1,3,2-oxazaphosphorine 2-oxide; 

2-(di(2-chloroethyl)amino)-1-oxa-3-aza-2-phosphacyclohexane 2-oxide; ASTA; N,N-bis(2- 

chloroethyl)-N-(3-hydroxypropyl)phosphorodiamidic acid intramol. ester; tetrahydro-N,N-bis(2- 

chloroethyl)- 2H-1,3,2-oxazaphosphorin-2-amine 2-oxide; 1-(bis(2-chloroethyl)amino)-1-oxo-2-aza- 

5-oxaphosphoridine. 

HO 

O 

OH 

HO 

OH 

Synonyms: D-()-Galactose; Galactose; Gal; -Galactose(D); D()GALACTOSE SIGMA GRADE. 

OH 

D-Galactose

254 Appendix 

O 

O 

O 

O 

O 

O 

Synonyms: (5S)-5,8,8a,9-Tetrahydro-5-(3,4,5-trimethoxyphenyl)-6H-furo[3,4:6,7]-naphtho[2,3-d]- 

1,3-dioxol-6-one. 

O 

Desoxypodophyllotoxin 

H 

H 

Dichloromethane 

Synonyms: Methylene dichloride; Methane dichloride; R 30; Aerothene MM; Refrigerant 30; Freon 30; 

DCM; narkotil; solaesthin; solmethine; Methylene chloride; Plastisolve; METHYLENE CHLORIDE 

(DICHLOROMETHANE); Dichloromethane. 

Cl 

Cl 

HO 

O 

O 

N 

H 

N 

HN 

H 2 N N N 

H 

N 

H 

Dihydrofolate 

Synonyms: 7,8-dihydrofolic acid. 

O 

O 

OH

Appendix 255 

7,12-Dimethylbenz[a]anthracene 

Synonyms: 9,10-Dimethyl-1,2-benzanthracene; DMBA; Dimethylbenzanthracene; dimethylbenz[a]anthracene; 

7,12-dimethylbenzanthracene; 9,10-dimethyl-benzanthracene; 9,10-dimethylbenz[a]anthracene; 

dimethylbenzanthrene; 1,4-dimethyl-2,3-benzophenanthrene; 7,12-dmba; 

7,12-dimethyl-1,2-benzanthracene. 

O 

HO 

O 

NH 

O 

O 

OH 

O 

OH 

HO 

O 

O 

O 

O 

Taxotere 

Synonyms: docetaxel; N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol. 

O 

O 

OH 

HO 

OH 

HO 

O 

Ellagic acid 

O 

Synonyms: 4,4,5,5,6,6-hexahydrodiphenic acid 2,6,2,6-dilactone; 2,3,7,8-tetrahydroxy(1)benzopyrano(5,4,3-cde)(1)benzopyran-5,10-dione; 

alizarine yellow; benzoaric acid; elagostasine; eleagic acid; 

gallogen; lagistase; C.I. 55005; C.I. 75270; Ellagic acid dihydrate.

256 Appendix 

OH 

OCH 3 

CH 3 O 

O 

CH 3 O 

OH 

O 

Eupatorin 

Synonyms: 5-Hydrohy-2-(3-hydroxy-4-methoxy-phenyl)-6,7-dimethoxy-4H-1-benzopyran-4-one; 

3,5-dihydroxy-4,6,7-trimethoxyflavone. 

O 

O 

O 

O 

N 

Fagaronine 

HO 

Falcarinol 

O 

O 

P 

N 

H 

Tabun 

Synonyms: Ethyl N,N-dimethylphosphoramidocyanidate; Ethyl dimethylphosphoramidocyanidate; 

Dimethylaminoethoxy-cyanophosphine oxide; Dimethylamidoethoxyphosphoryl cyanide; 

Ethyldimethylaminocyanophosphonate; Ethyl ester of dimethylphosphoroamidocyanidic acid; 

Ethylphosphorodimethylamidocyanidate; GA; EA1205; O-Ethyl N,N-dimethyl phosphoramidocyanidate; 

dimethylphosphoramidocyanidic acid ethyl ester; O-ethyl dimethylamidophosphorylcyanide.

Appendix 257 

OH 

HO 

OH 

O 

O 

Synonyms: 2-Acetamido-2-deoxy-D-galactopyranose; N-Acetyl-D-chondrosamine; 2-Acetamido-2- 

deoxy-D-galactose; GalNAc. 

N 

H 

OH 

N-acetyl-D-Galactosamine 

O 

O 

Alantolactone 

Synonyms: [3aR-(3aa,5b,8ab,9aa)]-3a,5,6,7,8,8a,9,9a-Octahydro-5,8a-dimethyl-3-methylenenaphtho- 

[2,3-b]furan-2(3H)-one; 8b-hydroxy-4aH-eudesm-5-en-12-oic acid; -lactone; Helenin; Alant 

camphor; Elecampane camphor; Inula camphor; Eupatal. 

O 

OH 

HO 

Synonyms: 4,5,7-Trihydroxyisoflavone. 

O 

Genistein 

OH

258 Appendix 

O 

O 

H 

OH 

H 

HO 

H 

Glycyrrhetinic acid 

Synonyms: 18beta-Glycyrrhetinic acid; Enoxolone; 18-beta-Glycyrrhetinic acid, (Titr., on the 

anhydrous basis). 

O 

OH 

O 

H 

H 

O 

H 

O 

O 

O 

OH 

HO 

O 

OH 

OH 

HO 

OH 

OH 

Glycyrrhizic acid 

Synonyms: Glycyrrhizinate; Glycyrrhizin.

Appendix 259 

OH 

O 

OH 

Goniothalamicin 

OH 

OH 

O 

O 

O 

HO 

O 

O 

Helenalin 

Synonyms: 3,3a,4,4a,7a,8,9,9a-Octahydro-4-hydroxy-4a,8-dimethyl-3-methyleneazuleno[6,5-b]furan- 

2,5dione; 6,8-dihydroxy-4-oxoambrosa-2,11(13)-dien-12-oic acid 12,8-lactone. 

Hexane 

Synonyms: Normal hexane; Hexyl hydride; n-Hexane; skellysolve B; dipropyl; gettysolve-b; Hex; 

n-Hexane. 

OH 

HO 

Hydroquinone 

Synonyms: Dihydroquinone; 1,4-Dihydroxybenzene; Quinol; 1,4-benzenediol; p-Benzendiol; 

Benzoquinol; para-Hydroxyphenol; Dihydroxybenzene; 1,4-Hydroxybenzene; p-Hydroquinone; 

p-Dihydroxybenzene; 1,4-Benzendil; Aida; Black and White Bleaching Cream; Eldoquin; Elopaque; 

quinnone; Tecquinol; Hydroquinol; p-Diphenol; Hydrochinon; hydrokinone; p-benzenediol; 

p-dioxobenzene; -hydroquinone; benzohydroquinone; -quinol; arctuvin; eldopaque; tenox hq; 

tequinol; Benzene-1,4-diol; HYDROQUINONE BAKER; Hydroquinone.

260 Appendix 

OH O OH 

HO 

HO 

OH O OH 

Hypericin 

Synonyms: 1,3,4,6,8,13-Hexahydroxy-10,11-di-methylphenanthro(1,10,9,8,opqra)perylene-7,14- 

dione; Hypericum red; Cyclo-Werrol; Cyclosan; Vimrxyn. 

H 

N 

Indole 

Synonyms: 2,3-Benzopyrrole; 1-Benzazole; Benzopyrrole; 1H-indole; Indoles; 1-Benzol beta pyrrol. 

O 

Synonyms: 3-Phenylchromone. 

O 

Isoflavone

Appendix 261 

O 

S 

O 

O – Na+ 

Dodecyl benzenesulfonic acid, sodium salt 

Synonyms: Sodium Laurylbenzenesulfonate; sodium dodecyl benzenesulfonate; sodium dodecylphenylsulfonate; 

AA-9; AA-10; abeson nam; bio-soft D-40; bio-soft D-60; bio-soft D-62; bio-soft 

D-35x; calsoft f-90; calsoft L-40; calsoft L-60; conco aas-35; conco aas-40; conco aas-65; conco aas- 

90; conoco c-50; conoco c-60; conoco sd 40; detergent hd-90; mercol 25; mercol 30; naccanol nr; 

naccanol sw; nacconol 40f; nacconol 90f; nacconol 35SL; neccanol sw; pilot hd-90; pilot sf-40; pilot 

sf-60; pilot sf-96; pilot sf-40b; pilot sf-40fg; pilot SP-60; richonate 1850; richonate 45b; richonate 60b; 

santomerse 3; santomerse no. 1; santomerse no. 85; solar 40; solar 90; sulfapol; sulframin 85; sulframin 

90; sulframin 40; sulframin 40ra; sulframin 1238 slurry; sulframin 1250 slurry; ultrawet k; ultrawet 

60k; ultrawet kx; ultrawet sk; stepan ds 60; ultrawet 1t; marlon a 350; marlon a; maranil; marlon 

a 375; siponate ds 10; trepolate f 40; conoco c 550; kb (surfactant); nansa sl; santomerse me; merpisap 

ap 90p; nansa ss; trepolate f 95; nansa hs 80; deterlon; ultrawet 99ls; sulfuril 50; F 90; elfan 

wa; sandet 60; steinaryl nks 50; sinnozon; NANSA HS 85S; C 550; KB; HS 85S; nansa hf 80; arylan 

sbc; marlon 375a; X 2073; conco aas 35H; neopelex 05; richonate 40b; DS 60; pelopon a; sulframin 

1240; 35SL; SDBS; Nacconol; Santomerse; Sulframin 1238; Ultrawet XK; Arylsulfonat; SODIUM 

DODECYLBENZENE SULFONATE. 

O 

HO 

OH 

HO 

NH 2 

Levodopa 

Synonyms: Dopar; Larodopa; Sinemet; [3-(3,4-Dihydroxyphenyl)-L-Alanine]; L-3,4-dihydroxyphenylalanine; 

3-hydroxy-L-tyrosine; L-Dihydroxyphenyl-L-alanine; 3,4-Dihydroxy-L-phenylalanine; L--(3,4- 

Dihydroxyphenyl)alanine; L-3-(3,4-Dihydroxyphenyl)alanine. 

O 

OH 

HO 

OH 

L-(+)-Arabinose 

Synonyms: L-Arabinopyranose; Arabinose(L); L-()-ARABINOSE CRYSTALLINE. 

OH

262 Appendix 

O 

OH 

OH 

OH 

α-L-Rhamnose 

OH 

Synonyms: -L-rhamnopyranose; 6-deoxy-L-mannose; L-rhamnose; L-Mannomethylose; -6-Deoxy-Lmannose; 

-L-Mannomethylose; rhamnose. 

OH OH 

H 

HO 

H 

H 

H O 

OH 

H 

H OH 

O 

HO 

H 

H 

D-(+)-Lactose 

H O 

OH 

OH 

H 

Synonyms: Milk sugar; 4-O--D-galactopyranosyl-D-glucose; -lactose; -D-Lactose; Lactose; Lac; 

lactin; 4-(-D-galactosido)-D-glucose; lactobiose; saccharum lactin; ()--D-lactose. 

O 

O 

OH 

Lapachol 

Synonyms: 2-Hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthalenedione. 

O 

All cis-δ-9,12,15-Octadecatrienoate 

OH 

Synonyms: Linolenic acid; -linolenic acid; all-cis-9,12,15-octadecatrienoic acid; cis,cis,cis-9,12,15-octadecatrienoic 

acid; cis--9,12,15-octadecatrienoic acid; cis-9,12,15-octadecatrienoic acid; 9,12,15-all-cisoctadecatrienoic 

acid; (Z,Z,Z)-9,12,15-Octadecatrienoic acid; (9Z,12Z,15Z)-9,12, 15-Octadecatrienoic 

acid.

Appendix 263 

O 

O 

O 

HO NH 

O 

O 

O 

N 

O 

O 

N 

Cl 

O 

Maytansine 

Synonyms: Alanine, N-acetyl-N-methyl-, 6-ester with 11-chloro-6,21-dihydroxy-12,20-dimethoxy- 

2,5,9,16-tetramethyl-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1(10,24).0(3,5)]hexacosa- 

10,12,14[26],16,18-pentaene-8,23-dione; N-acetyl-N-methyl-L-Alanine, [1S-(1R*,2S*,3R*,5R*, 

6R*,16E,18E,20S*,21R*)]-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo- 

4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl ester; 

Maitansine; Maysanine; MTS. 

H 2 N 

N 

N 

N 

N 

N 

O 

O 

OH 

NH 2 

HN 

O 

Methotrexate 

HO 

Synonyms: N-4-( (2,4-Diamino-6-Pteridinyl) Methyl Methylamino Benzoyl)-L-Glutamic Acid; 

Amethopterin; MTX; Hdmtx; Methyl-aminoopterin; Rheumatrex; 4-Amino-N10-methyl-pteroylglutamic 

acid; 4-Amino-10-methylfolic acid; Methylaminopterin; Emtexate; N-(p(((2,4-Diamino-6- 

pteridinyl)methyl)-methylamino)-benzoyl)-L-glutamic acid; cl-14377; emt 25,299; Metatrexan; 

Methopterin; R 9985; L-()-amethopterin dihydrate; 4-amino-4-deoxy-N(sup 10)-methylpteroylglutamate; 

N-bismethylpteroylglutamic acid; N-(p-( ( (2,4-diamino-6-pteridyl)methyl)methylamino) 

benzoyl)glutamic acid; 4-amino-4-deoxy-N(sup 10)-methylptero ylglutamic acid; 4-amino- 

N(sup 10)-methylpteroylglutamic acid; methotextrate; antifolan; L-()-N-(p-( ( (2,4-diamino-6- 

pteridinyl)methyl)methylamino)benzoyl)glutamic acid; ledertrexate; methylaminopterinum; 

Methotrexate dihydrate; MTX dihydrate; L-()-4-Amino-N10-methylpteroylglutamic acid dihydrate; 

Amethopetrin; Folex; Folex PFS; Methoblastin; Mexate; ()-4-Amino-10-methylfolic acid; Mexate 

(disodium salt of Methotrexate); Folex (disodium salt of Methotrexate); L-()-N-; Abitrexate; 

Brimexate; Emthexate; Farmitrexat; Maxtrex; Methotrexato; Metotrexato; Neotrexate; Tremetex.

264 Appendix 

O 

O 

S 

O 

Methyl methanesulfonate 

Synonyms: MMS; Methanesulfonic acid methyl ester; Methyl mesylate; as-dimethyl sulfite; methyl 

ester of methanesulfonic acid; methyl methansulfonate; Methylsulfonic acid, methyl ester. 

O 

NH 2 

O 

O 

O 

NH 2 

HN 

N 

O 

Mitomycin C 

Synonyms: MMC; Mitomycin; Mutamycin; 6-amino-8-[[(aminocarbonyl)oxy]methyl]-1,1a,2,8,8a,8bhexahydro 

-8a-methoxy-5-methyl, [1aS-(1a,8,8a,8b)]-azirino[2,3:3,4]pyrrolo[1,2a]indole-4,7- 

dione; [1aR-(1a,8,8a,8b)]-6-amino-8-[[(aminocarbonyl)oxy]methyl]-1,1a,2,8,8a,8b-hexahydro-8amethoxy-5-methylazirino[2,3:3,4]pyrrolo[1,2-]indole-4,7-dione; 

Ametycin; Mit-C; Mito-C; Mitocin-C; 

Mitomycinum; Mytomycin; 7-Amino-9-methoxymitosane; Azirino[2,3:3,4]pyrrolo[1,2-a]indole- 

4,7-dione, 6-amino-8-[[(aminocarbonyl)oxy]methyl]-1,1a,2,8,8a,8b-hexahydro-8a-methoxy-5-methyl-, 

[1aS-(1a,8,8a,8b)]-; 6-amino-1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methylazirino[2,3:3,4]pyrrolo[1,2-a]indole-4,7-dione, 

carbamate (ester); (1ar)-6-amino-8-(((aminocarbonyl) 

oxy)methyl)-1,1a,2,8,8a,8b-hexahydro-8a-methoxy-5-methylazirino[2,3:3,4]pyrrolo[1,2-a]indole-4,7- 

dione. 

O – 

NH 

O 

N 

N 

H 

N 

N 

O 

N-methyl-N-nitro-N-nitrosoguanidine 

Synonyms: MNNG; N-methyl-N-nitroso-N-nitroguanidine; N-nitro-N-nitroso-N-methylguanidine; 

1-methyl-3-nitro-1-nitrosoguanidine; methylnitronitrosoguanidine; N-nitroso-N-methylnitroguanidine; 

1-methyl-1-nitroso-N-methylguanidine; 1-nitro-N-nitroso-N-methylguanidine; MNG; Methyl- 

N-nitro-N-nitrosoguanidine; N-Methyl-N-Nitroso-N-Nitroguanidine, 97% - Carc.

Appendix 265 

OH 

HO 

OH 

O 

O 

Synonyms: N-Acetylchondrosamine; 2-Acetamido-2-deoxygalactose; N-Acetyl--D-galactosamine; 

N-Acetyl-D-galactosamine. 

N 

H 

OH 

N-Acetylgalactosamine 

O 

N 

N 

N-Nitrosopyrrolidine 

Synonyms: 1-nitroso-Pyrrolidine; Nitrosopyrrolidine; NPYR; N-N-PYR; No-pyr; Pyrrole, tetrahydro- 

N-nitroso-; N-Nitrosopyrrolidine. 

O 

OH 

HO 

O 

Naringenin 

OH 

Synonyms: 5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one; 4[,5,7-Trihydroxyflavanone. 

OH 

O 

HO 

O 

4,5,7-Trihydroxyflavanone 

OH 

Synonyms: Naringenin.

266 Appendix 

O 

O 

O 

O 

OH 

OR 1 

OR 2 

O 

O 

O 

1 

2 

3 

4 

5 

O 

O 

R 1 R 1 6 

Ac 

i-Val 

H 

Ac 

Ac 

i-Val 

H 

i-Val 

i-But 

2-Me-but 

Neurolanin 

O 

O 

Cl – Ni 2 Cl – 

Nickel chloride 

Synonyms: Nickel (II) Chloride; Nickelous Chloride; Nickel dichloride; Nickel (II) chloride, ultra dry, 

anhydrous, 99.9% (metals basis); Nickel chloride. 

OH 

HO NH 2 

HO 

Norepinephrine 

Synonyms: NE; NA; noradrenalin; Arterenol; Levophed. 

O 

Oleic acid 

OH 

Synonyms: cis--9-octadecanoate; 9-Octadecenoic acid (Z)-; cis-9-Octadecenoic acid; cis-octadec-9- 

enoic acid; century cd fatty acid; emersol 210; emersol 213; emersol 6321; emersol 233ll; glycon ro; 

glycon wo; cis-(sup 9)-octadecanoic acid; 9-octadecenoic acid; wecoline oo; tego-oleic 130; vopcolene 

27; groco 2; groco 4; groco 6; groco 5l; hy-phi 1055; hy-phi 1088; hy-phi 2066; K 52; neo-fat 

90-04; neo-fat 92-04; hy-phi 2088; hy-phi 2102; Metaupon; red oil; (Z)-9-Octadecenoic acid; 

Octadecenoic acid; oleoate.

Appendix 267 

O 

O 

O 

Parthenolide 

Synonyms: [1aR-(1aR*,4 E .7aS*,10aS*,-10bR*)]-2,3,6,7,7a,8,10a,10b-Octahydro-1a,5-dimethyl-8- 

methyleneoxireno[9,10]cyclodeca[1,2-b]furan-9(1aH)-one; 4,5-epoxy-6-hydrohy-germacra- 

1(10),11(13)-dien-12-oic acid,-lactone. 

OH 

HO 

Phloroglucinol 

OH 

Synonyms: 1,3,5-Benzenetriol; 1,3,5-trihydroxybenzene; 1,3,5-THB; 1,3-Trihydroxybenzene. 

HO 

O 

O 

O 

O 

O 

O 

O 

O 

O 

HO 

O 

OH 

O 

O 

O 

O 

Phyllanthoside 

Synonyms: Phyllantoside.

268 Appendix 

O 

N 

O – 

O 

N 

N 

O 

N 

O – 

Picrolonic Acid 

Synonyms: 3H-Pyrazol-3-one-2,4-dihydro-5-methyl-4-nitro-2-(4-nitrophenyl). 

H 

N 

Piperidine 

Synonyms: Hexahydropyridine; Pentamethyleneimine; Azacyclohexane; cyclopentimine; cypentil; 

hexazane. 

O 

OH O 

Plumbagin 

Synonyms: 5-Hydroxy-2-methyl-1,4-naphthoquinone. 

O 

O 

H 

H 

O 

H 

O 

O 

H 

Synonyms: [3aS-(3E,3a,4a;,7a,9aR*,9b)]-3-Ethylidene-3,3a,7a,9b-tetrahydro-2-oxo-2H,4aH- 

1,4,5-trioxadicyclopent[a,hi]indene-7-carboxylic acid methyl ester. 

O 

Plumericin

Appendix 269 

OH 

O 

O 

O 

O 

O 

O 

Synonyms: 5,8,8a,9-Tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)furo[3,4:6,7]naphthol[2,3-d]-1,3- 

dioxol-6(5aH)-one; 1-hydroxy-2-hydroxymethyl-6,7-methylenedioxy-4-(3,4,5-trimethoxyphenyl)- 

1,2,3,4-tetrahydronaphthalene-3-carboxylic acid lactone; podophyllinic acid lactone; podofilox; 

Condyline; Condylox; Martec; Warticon 

O 

Podophyllotoxin 

O 

O 

O 

Psoralen 

Synonyms: 7H-Furo[3,2-g][1]benzopyran-7-one; 6-hydroxy-5-benzofuranacrylic acid -lactone; 

furo[3,2-]-coumarin; ficusin. 

OH 

OH 

HO 

O 

OH 

OH 

O 

Quercetin 

Synonyms: 3,3,4,5,7-pentahydroxyflavone; 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran 

-4-one; 3,5,7,3,4-pentahydroxyflavone; 3,4,5,7-tetrahydroxyflavon-3-ol; cyanidelonon 1522; C.I. 

natural yellow 10; C.I. natural yellow 10 & 13; C.I. natural red 1; C.I. 75670; meletin; quercetol; 

quertine; sophoretin; t-gelb bzw. grun 1; xanthaurine.

270 Appendix 

O 

Na 

– O 

O – 

OH O 

L-Malic acid, sodium salt 

Na 

Synonyms: Hydroxybutanedioic acid; hydroxy-succinic acid. 

O 

O 

O 

NH 

O 

O 

OH 

O 

OH 

HO 

O O O 

O 

O 

Paclitaxel 

Synonyms: Taxol; Taxal; Taxol A; 7,11-Methano-5H-cyclodeca[3,4]benz[1,2-b]oxete,benzenepropanoic 

acid deriv.; TAX; 5-,20-epoxy-1,2-,4,7-,10-,13--hexahydroxy-tax-11-en-9-one 4,10- 

diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenyl-isoserine. 

O 

Tetrahydrofuran 

Synonyms: THF; 1,4-Epoxybutane; Butylene oxide; Cyclotetramethylene; tetramethylene oxide; 

oxacyclopentane; Cyclotetramethylene oxide; Furanidine; Hydrofuran; oxolane.

Appendix 271 

OH 

Thymol 

Synonyms: 6-Isopropyl-m-cresol; 3-Hydroxy-p-cymene; Isopropyl cresol; 5-Methyl-2-(1- 

methylethyl)phenol; 5-Methyl-2-isopropyl-1-phenol; 3-p-Cymenol; 2-Isopropyl-5-methyl phenol; 

THYMOL CRYSTALS USP. 

HO 

O 

HO 

HN 

Tricine 

OH 

OH 

Synonyms: N-(tris(hydroxymethyl)methyl)glycine; Glycine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]-. 

R 3 

N 

R 2 

R 1 

HN 

CH 2 

H 

N 

R 1 

OH 

R 2 

OCH 3 

R 3 

OCH 3 

Tubulosine 

tubulosine 

O 

OH 

HO 

NH 2 

(S)-(–)-Tyrosine 

Synonyms: p-tyrosine; Tyr; Y; Tyrosine; L-Tyrosine; L-(-)-tyrosine; 2-Amino-3-(4-hydroxyphenyl)- 

propanoic acid; 3-(4-Hydroxyphenyl)-L-alanine; 3-(p-hydroxyphenyl)alanine; 2-amino-3-(p-hydroxyphenyl)propionic 

acid; L-TYROSINE FREE BASE.

272 Appendix 

O 

O 

Urethane 

NH 2 

Synonyms: Ethyl carbamate; Carbamic acid ethyl ester; Ethyl urethane; o-ethylurethane; ethyl ester of 

carbamic acid; leucethane; leucothane; pracarbamin; a 11032; u-compound; X 41; o-Ethyl carbamate; 

Ethyl carbamate. 

O 

O 

O 

O 

O 

O 

O 

O 

Valtrate 

Synonyms: Valtrate. 

HO 

N 

H 

N 

N 

H 

O 

O 

O 

N 

O 

OOH 

O 

O 

Vinblastine 

Synonyms: Vincaleukoblastine.

Appendix 273 

HO 

N 

H 

N 

N 

H 

O 

O 

O 

O 

N 

O 

OH 

O 

O 

O 

22-Oxovincaleukoblastine 

Synonyms: Vincristine; Oncovin; Vincasar; Vincrex; Leurocristine; VCR; LCR; Kyocristine; PES; 

Vincosid; Vincasar PES; Vincasar (Vincristne sulfate); Oncovin (Vincristne sulfate); Kyocristine 

(Vincristine sulfate); Vincrex (Vincristine sulfate). 

- Tyr 

- Pro 

Lys - Asp 

42 

43 

- Ser 

44 

45 

46 

Lys - Ser 

- Pro 

41 

1 2 

- Cys 

40 

38 

- Cys 

39 

37 

- Thr 

- Ser 

- Gly 

- 

3 

 

- Cys 

ser 

36 

4 

Ile 

- 

 

5 

- 

- Lys 

Ile 

- 

6 7 

Pro 

35 

- Cys 

8 

- Asm - Thr 

33 

34 

9 

- Thr 

- Oly - Ser 

3231 

30 

10 

11 

- Gly - Arg - Asn 

- Leu - Lya - Ala 

29 

28 

27 

12 

- 

26 

lie 

- Cys 

25 

13 

- Tyr - Asn 

24 

- Thr - 

- Ala 

Pro 

14 

15 

16 

- 

- Arg 

23 

17 18 

Cys - Arg 

- 

Pro 

22 

- Leu 

- 

- Ala 

19 

- Thr 

21 

20 

Viscotoxin A3

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Anonymous (2000) Loss of loved one affects cancer risk and survival. Healthcentral News. 

Asari, F., Kusumi, T. and Kakisawa, H. (1989) Turbinaric acid, a cytotoxic secosqualene carboxylic acid 

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Aulas, J.J. (1996) Alternative cancer treatments. Sci. American 275, 126–7. 

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World Wide Web sites 

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http://www.bali-travelnews.com Bali Travel News 

http://biotech.icmb.utexas.edu/botany BioTech 

http://www.botany.com Botany.com 

http://www.chemfinder.com ChemFinder.com 

http://www.colciencias.gov.co/simbiosis/ingles/projects.html Colciencias 

http://www.desert-tropicals.com Desert-Tropicals.com 

http://django.harvard.edu Django 

http://.epnws1.ncifcrf.gov.2345 

http://ericir.syr.edu 

http://www.floridata.com Floridata 

http://www.gi.alaska.edu Geophysical Institute 

http://healthcentral.com Health Central 

http://www.hortpix.com Horticopia ® Plant Information 

http://www.hort.purdue.edu Horticulture and Landscape Architecture 

http://www.ird.nc IRD 

http://lamington.nrsm.uq.edu.au Lamington National Park Website 

http://www.ncbi.nlmnih.…/query.fcgicmd National Centre for Biotechnology Information 

http://www.npwrc.usgs.gov Northern Prairie Wildlife Research Centre 

http://www.pasificrimginseng.com/world.html 

http://www.pfc.cfs.nrcan.gc.ca/ecosystem/yew/taxol.html Pacific Forestry Centre 

http://www.pubmed Pubmed 

http://www.rsnz.govt.nz Royal Society of New Zealand 

http://www.sare.org Sustainable Agriculture Network 

http://scisun.nybg.org 

http://www.streetside.com Streetside.com 

http://stuartxchange.org Stuart Xchange 

http://www.Taxol.com/timeli.html Taxol 

http://www.tropilab.com Tropilab ® Inc 

http://uvalde.tamu.edu Agriculture Research & Extension Center-Uvalde 

http://www.uog.edu University of Guam 

http://www.vedamsbooks.com/no13147.htm Vedams 

http://wiscinfo.doit.wisc.edu/herbarium University of Wisconsin

Index 

Acacia catechu 104, 166 

Acacia confusa 30, 167 

Acacia lenticularis 104 

Acetogenins 78–80, 109, 193, 194 

13-Acetyl-9-dihydrobaccatin III 62 

N-Acetylgalactosamine 54 

Aclarubicin 7 

Aconitine 161 

Aconitum napellus L. 21, 160, 161 

Acronychia baueri 21, 73 

Acronychia haplophylla 21, 73 

Acronychia laurifolia 28, 73 

Acronychia oblongifolia 72 

Acronychia pedunculata 73 

Acronychia porteri 23, 73, 194 

Acrosorium flabellatum 201 

Adrenocorticoids 7 

Agrimonia pilosa 74–5 

Agrimoniin 74–5 

Ahnfeltia paradox 201 

Ajmalicine 48 

Aldehydes 19–20 

Alkaloids 5, 7, 17–21, 30, 48, 49, 51, 55, 58, 

72–4, 78, 79, 81–3, 86, 89, 94, 99, 102–3, 

122, 161–6, 169, 171–3, 178, 180, 182, 188, 

191, 228, 275, 276 

Alkylating agents 5, 7 

Allamandin 247 

Amphidinium sp. 227, 228, 233 

Amphiroa zonata 201 

Amsacrine 7 

Anacystis dimidata 208 

Anadyomene menziesii 199 

Anadyomene stellata 199 

Angelica acutiloba 29, 77 

Angelica archangelica L. 76 

Angelica decursiva 28 

Angelica gigas 28, 77 

Angelica keiskei 23, 28, 77 

Angelica radix 77 

Angelica sinensis 29, 68, 77, 132 

Annona bullata 22, 80 

Annonaceous acetogenins 19, 22, 78–80, 193 

Annona cherimola 78 

Annonacin 110 

Annona densicoma 23, 80 

Annona muricata 22, 79–80 

Annona purpurea 21, 79 

Annona reticulata 23, 79, 80 

Annona senegalensis 79 

Annona squamosa 22 

Anthracyclines 7 

Anthraquinone 26 

Anti-androgens 7 

Antibiotics 5, 7, 67, 285 

Antiestrogens 7 

Antimetabolites 5, 7 

Aphanococcus biformis 208 

Aristolochia elegans 168 

Aristolochia rigida 168 

Aristolochia tagala 168 

Aristolochia versicolar 31, 168 

Aryltetralin 45 

Ascites 11, 12, 24–6, 29, 58, 75, 77, 96, 104, 

126–7, 134, 136, 141, 144, 150, 160, 163, 

192, 199–202, 204–6, 208, 209 

Asimicin 193 

L-Aspariginase 7 

Astasia longa 228, 233 

Astragalus membranaceus 68, 132, 153 

Atraclylodes macrocephala 68, 132 

Avrainvillea rawsonii 198, 211 

Azathioprin 7 

B16 11, 23, 28, 57, 63, 110, 119, 120, 134, 143, 

144, 163, 208, 221 

Baccatin III 62, 65, 66 

Baccatin VI 33, 162 

Bacillus 8, 179 

Baicalin 70, 151–3 

Bangia sp. 201 

Benzyl glucosinolate 186, 187 

Bicyclic hexapeptides 143 

Bifurcaria bifurcata 221, 223

290 Index 

Bioassays 12 

Biotechnology 32–4 

Bitetrahydroanthracene 85 

Bladder 2, 4, 6, 21, 37, 178, 192 

Bleomycin 7, 50, 213 

Bletilla striata 132 

Bone cancer 1, 2, 5, 6, 37, 49, 59, 69, 70, 104, 

108, 153 

Botany 35–6 

Brain cancer 3, 6, 9, 11, 29, 82, 83, 215 

Breast cancer 1, 2, 4–6, 8, 9, 11, 22, 37, 50, 56, 

58, 63, 64, 65, 79, 80, 109, 116, 117, 134, 

135, 139, 172, 173, 198, 229 

Brucea antidysenterica 21, 31, 81 

Brucea javanica 29, 82 

Bruceantinoside C 81, 83 

Brucea sp. 25 

Bruceoside C 81 

Bryopsis sp. 198, 211 

Bursera klugii 85 

Bursera microphylla 85 

Bursera morelensis 85 

Bursera permollis 84 

Bursera schlechtendalii 85 

Bursera simaruba 84 

Busulfan 7 

Caesalpinia sappan 132 

Calothrix sp. 228, 233 

Calycodendron milnei 21, 182 

Camptotheca acuminata 36, 37 

Cancer: causes 1–3; classification of cancer types 

3–4; genetic background 1–3; incidence 1; 

malignant tumor 1; metastases 1; survival 

rates 3–4; tumor development 1 

Carmustine 7 

Casearia sylvestris Sw. 31, 172 

Casearins A-F 172 

Cassia acutifolia 85 

Cassia angustifolia 29, 86 

Cassia leptophylla 21, 86 

Cassia marginata 104 

Cassia torosa 85 

Catechin 23, 111 

Catechu nigrum 166 

catharanthine 33, 48, 52 

Catharanthus roseus 33, 47, 52 

Catharanthus sp. 43 

Caulerpa prolifera 199 

Caulerpa racemosa 199 

Caulerpa sertularioides 199 

Caulerpa taxifolia 199, 211 

Centranthus ruber 189 

Cephalomannine 62, 64 

Cephalotaxus harringtonia 64 

Cephalotaxus sp. 43 

Ceratodictyon spongiosum 211, 216 

Chalcones 23, 76, 77 

Chamaecyparis lawsonianna 169 

Chamaecyparis sp. 21 

Chaparrinone 112 

Chelidonine 86, 87 

Chelidonium majus L. 21, 31, 86, 87 

Chlorambucile 7 

Chlorella sp. 208 

Chlorella vulgaris 208, 228, 233 

Chondria crassicaulis 201 

Chondrus occellatus 201 

Chroococcus minor 208 

Chrysanthemum morifolium 107 

Chrysanthemum sp. 93 

Cicer arietinum 104 

Cinnamaldehydes 92 

Cinnamomum camphora 90 

Cinnamomum cassia 19, 68, 91, 92, 132 

Cisplatin 7, 40, 42, 68, 70, 141, 207, 210, 252 

Claopodium crispifolium 23, 80 

Clerodane diterpenes 172–80 

Clinical trials 12–13 

Codium arabieum 210, 211 

Colchicine 93, 94, 140, 189, 229, 252 

Colchicum autumnale 21, 93, 94 

Colchicum speciosum 94 

Colon cancer 2, 4, 5, 11, 12, 22, 29, 37, 56, 57, 

63, 68–70, 80, 82, 112, 113, 116, 117, 139, 

140, 148, 153, 155, 158, 172, 173, 181, 196, 

198, 200, 208, 211, 214, 215, 221, 222, 228–31 

Colorectal 1, 4, 6, 210 

Concanavalin A 46, 167 

Conophylline 99 

Conus magnus 241 

Crataegus monogyna 56 

Crinum asiaticum 170, 171 

Crocin 96, 97 

Crocus sativus 31, 93, 95, 96, 97, 127 

Crotolaria juncea 104 

Cryptomenia crenulata 201 

Cyclopentenyl cytosine 27, 157 

Cyclophosphamide 7, 59, 68, 75, 152, 253 

Cymopolia barbata 210, 211 

Cyperus rotundus 132 

Cystoseira mediterranea 221, 223 

Cystoseira usneoides 221, 223 

Cytosine arabinoside 7 

Dacarbazine 7, 50 

Dactinomycin 7 

Dalton’s lymphoma ascites (DLA) 11, 24, 25, 58, 

96, 126, 127, 136 

Daphnoretin 160 

Daunorubicin 7 

Deacetyleupaserrin 100 

Decursin 76, 77 

Delphinidin 156

Index 291 

3-O-Demethyldigicitrin 72, 194 

15-Demethylplumieride 139 

Dendropanax arboreus 98 

Deoxylapachol 176 

Deoxypodophyllotoxin 84, 85, 87 

10-Desacetylbaccatin III 

5-Desmethoxydeoxypodophyllotoxin 84 

Des-N-methyl acronycine 73 

3-Diacetylvilasinin 123 

Dichloromethane 174, 210, 221 

Dictyota dichotoma 221, 223 

Didemnum sp. 197 

Digenea simplex 196 

Digicitrin 72, 194 

9-Dihydrobaccatin III 33, 62 

5,3-Dihydroxy-3,6,7,8,4-pentamethoxyflavone 

72, 140 

Dihydroxysargaquinone 149, 150 

Dilophus ligulatus 221, 223 

1,11-Dimethoxycanthin-6-one 81, 83 

3,9-Dinitrofluoranthene 74 

1,6-Dinitropyrene 75 

Diphyllin 44 

Diptheriotoxin 8 

Dithymoquinone 126 

DMBA 11, 12, 77, 97, 108, 109, 127, 134, 135, 

255 

Dolabella auricularia 229, 232 

Doxorubicin 7, 126, 214 

Dunaliella bardawil 228 

Dunaliella sp. 228, 233 

Dysosma pleianthum 45 

Ehrlich 11, 12, 24, 26, 29, 58, 76, 77, 96, 104, 

126, 127, 134, 141, 149, 150, 160, 163, 

199–202, 204–6, 208, 209 

Ellagitannin arjunin 185 

Entophysalis deusta 208 

Enzymes 5, 7, 12, 15, 17, 29, 30, 52, 58, 66, 72, 

75, 107, 210 

10-Epi-olguine 141, 142 

Epirubicin 7, 167 

Eriophyllum confertiflorum 100 

Eriophyllum sp. 99 

Ervatamia divaricata 99 

Ervatamia heyneana 99 

Ervatamia microphylla 21, 99 

Erythroleukemia 11, 102 

Estrogens 7 

Ethyl gallate 185 

Etoposide 7, 33, 44, 45, 47, 126 

Eucheuma muricatum 201 

Eupatorin 100 

Eupatoriopicrin 100 

Eupatorium altissimum 23, 100 

Eupatorium cannabinum 22, 100 

Eupatorium cuneifolium 22, 100 

Eupatorium formosanum 100 

Eupatorium rotundifolium 100, 101 

Eupatorium semiserratum 22, 100 

Eurycoma longifolia 21, 172, 173 

Eurycomanone 172 

Fagara macrophylla 21, 101, 102 

Fagara xanthoxyloides 102 

Fagaronine 102 

Falcarinol 98 

Ficus carica L. 103 

Ficus cunia 30, 103, 104 

Ficus racemosa 104 

Flavonoids 23 

Flavonols 23, 73, 194 

5-Fluorouracile 7 

Fucoidan polysaccharides 149 

Fulvoplumierin 139 

Galactose 33, 54, 56, 57, 86, 207, 

253 

Galangin 128, 129 

Galaxaura falcata 201 

Galaxaura marginata 211, 216 

Galaxaura robusta 201 

Garcinia hombrioniana 105 

Garcinia hunburyi 106 

Germacranolides 100 

Gigartina tenella 213, 216 

Ginsan 134, 135 

Ginsenosides 135 

Glandular 6, 35, 87 

Glioblastoma 2, 119, 158 

Glioma 2, 3, 9, 12, 119, 153, 158 

Gloiopeltis tenax 201 

Glycosides 24 

Glycyrrhiza glabra L. 106 

Glycyrrhiza inflata 23, 108 

Glycyrrhiza sp. 31, 93, 107 

Glycyrrhiza uralensis 30, 68, 107, 132 

Glycyrrhizic acid 107 

Glyptopetalum sclerocarpum 22, 173 

Gnidimacrin 154, 155 

Goniodiol-7-monoacetate 109 

Goniothalamus amuyon 109 

Goniothalamus gardneri 109 

Goniothalamus giganteus 109 

Goniothalamus sp. 22, 109 

Gossypium herbaceum L. 110, 111 

Gossypium indicum 23, 28, 104, 111 

Gracilaria 213 

Gracilaria coronopifolia 213, 216 

Gracilaria salicornia 201 

Halimeda copiosa 211 

Halimeda incrassata 211 

Halimeda opuntia 211

292 Index 

Halimeda scabra 211 

Halimeda simulans 211 

Halimeda sp. 200, 210, 211 

Halimeda tuna 211 

Hannoa chlorantha 111, 112 

Hannoa klaineana 111, 112 

Haslea ostrearia 208 

Head 2, 36, 64, 114 

Hedyotis diffusae 132 

HeLa 23, 30, 64, 96, 108, 130, 141, 147, 167, 

221, 228 

Helenalin 113–15 

Helenium microcephalum 22, 112, 114 

Helixor 54, 61 

HEp-2 11, 56, 119, 120, 130 

Hepatocellular 11, 44, 70, 115, 136, 165 

Herposiphonia arcuata 201 

Hinokiflavone 183 

Hinokitiol 169 

Hormones 5, 7, 16 

Hormothamnion enteromorphoides 208, 229, 233 

Hydroquinone 128, 130, 192, 259 

10-Hydroxyangustine 178 

11-Hydroxycanthin-6-one 81, 83 

2-Hydroxycinnamaldehyde 90, 91 

4-Hydroxy-2-cyclopentenone 179, 180 

22-Hydroxytingenone 173, 245 

Hydroxyurea 7 

Hypericum drummondii 117 

Hypericum perforatum L. 26, 115, 116 

Idarubicine 7 

Ifosfamide 7 

Immunomodulators 6, 7, 19, 21, 25, 29, 47, 54, 

68, 74, 75, 86, 90, 92, 133, 138, 171, 184, 

185, 207, 277 

Indole 17, 20, 33, 49, 51–3, 162, 260 

Interferons 7, 8, 60, 129, 131, 145, 203, 205, 

283 

Interleukins 7, 8, 68 

Intermedine 164 

Iscador 54–60 

Isoflavone biochanin A 156 

Isorel 55, 59 

Jania rubens 213, 216 

Juniperus chinensis 118 

Juniperus virginiana L. 25, 117, 118 

KB 11, 21, 23–6, 31, 58, 63, 73, 82, 84–6, 101, 

110, 114, 117, 120, 123, 127, 139, 172, 173, 

181, 183, 194, 198, 199, 207, 210, 211, 

213–15, 221, 222, 228, 230–2 

Kidney 2, 3, 6, 35, 68, 93, 113, 114, 132, 144, 

182, 186, 208 

Kigelia pinnata 26, 174 

Kinase 2, 7, 12, 27, 31, 69, 77, 113, 119, 120, 

149, 155, 175, 210, 278 

Koelreuteria henryi 26, 174, 175 

L5 11 

L5178Y 11, 57, 119, 120, 143, 144 

Lactose 54, 57, 262 

Laminaria angustata var. longissim 203, 

204 

Laminaria cloustoni 204 

Laminaria japonica var. ochotensis 204 

Laminaria religiosa 204 

Landsburgia quercifolia 26, 176 

Lapachol 174 

Larynx 11, 56, 119, 120, 130 

Laurencia 214 

Laurencia calliclada 214, 216 

Laurencia cartilaginea 214, 216 

Laurencia majuscula 214, 216 

Laurencia obtusa 214, 216 

Laurencia papillosa 201 

Laurencia pinnatifida 214 

Laurencia viridis 214, 216 

Laurencia yamadae 201 

Lectins 33, 54–60, 104, 125 

Lentinan 8 

Leukemia 2, 4–6, 8, 10, 11, 21–4, 29–31, 36, 

37, 44, 49, 50, 57, 59, 63, 64, 82, 84, 85, 93, 

94, 96, 99, 101–4, 107, 109, 110, 112, 114, 

117, 119–21, 135–7, 139–41, 144, 146, 147, 

150, 154, 155, 160, 169, 172, 173, 176, 179, 

181, 187, 198–204, 206–9, 214, 215, 221, 

222, 227–9, 231, 232 

Leurosidine 48 

Levamisol 8 

LHRH 7, 132 

Lignans 24 

Ligustrum lucidum 153 

Lipids (saponifiable) 25 

Lipids (unsaponified) 26 

Liqusticum wallichii 68, 132 

Liver cancer 1, 4, 9, 11, 21, 24, 25, 36, 37, 60, 

68, 69, 74, 113, 114, 118, 129, 136, 143, 153, 

163, 165, 192, 193, 232 

Lochnera rosea 47 

Lomustine 7 

Lung cancer 1–4, 6, 8, 9, 11, 21, 26, 29, 31, 

37–9, 44, 45, 51, 57, 58, 63, 64, 82, 83, 87, 

96, 100, 113, 116, 117, 119, 120, 135, 139, 

140, 142–4, 147–9, 152–5, 165, 172, 173, 

181, 187, 198, 206–9, 214, 221, 231 

Luteinizing hormone 7 

Lycorine 171 

Lymphocytes 6, 8, 12, 49, 58, 66, 70, 71, 88, 89, 

104, 114, 124, 125, 127, 152, 165, 169, 

200–2, 215

Index 293 

Lynbya gracilis 229 

Lynbya majuscula 229 

Lyngbya confervoides 209 

Lyngbya majuscula 209, 213, 229, 230 

Lyngbya sp. 209 

Macrocystis pyrifera 204 

Macrophages 6, 8, 56–8, 66, 68, 69, 88, 150, 

207, 222, 228 

Magnolia grandiflora 177 

Magnolia officinalis 25, 177 

Magnolia virginiana L. 176 

Magnolol 177 

Mallotophenone 119 

Mallotus anomalus 31, 120 

Mallotus japonicus 26, 120 

Mallotus philippinensis 119 

Maytenin 121 

Maytenus boaria 121 

Maytenus guangsiensis 121 

Maytenus ovatus 121 

Maytenus senegalensis 121 

Maytenus sp. 31 

Maytenus wallichiana 121 

Mechlorethamine hydrochloride 7 

Melanoma 1, 2, 4, 8, 11, 23, 26, 28, 29, 37, 55, 

57, 58, 63, 82, 110, 116, 117, 119, 120, 130, 

134, 139, 140, 143, 144, 148, 155, 163, 

172–4, 198, 204, 206, 208, 214, 215, 221, 

222 

Meletia ovalifolia 104 

Melia azedarach 122, 123 

Melia composita 104 

Melia sp. 31 

Melia toosendan 123 

Melia volkensii 123 

Meliavolkinin 123 

Melphalan hydrochloride 7 

Menispermum dehiricum 31 

6-Mercaptopurine 7 

Meristotheca coacta 202 

Meristotheca papulosa 200, 202 

Methotrexate 7, 44, 263 

9-Methoxycanthin-6-one 172, 246 

Microcystis aeruginosa 230, 234 

Microhelenin-E 113, 114 

Mistletoe alkaloids 54 

Mitomycin 7, 38, 68, 69, 71, 133, 264 

Mitoxantrone 7 

MOLT-4 11, 57, 158 

Momordica charantia 30, 124 

Momordica indica 30 

Mondia whitei 19, 183 

Naphthohydroquinones 143 

Nauclea orientalis 21, 178 

Neck 2, 45, 64 

Neomeris annulata 210, 211 

Neuroblastoma 2, 213, 229 

Neurolaena lobata 31, 178, 179 

Nigella sativa L. 25, 26, 96, 97, 125, 126, 127 

Nitidine chloride 102 

Nitrosoureas 7 

NK cells 31, 45, 68, 87, 125, 137 

Noracronycine 72, 73 

Nostoc sp. 230, 234 

Nucleic acids 27 

Nucleotides 17, 18, 27 

Oldenlandia diffusa 153 

Oncogenes 2 

Oridonin 141 

Origanum majorana 128, 129, 130 

Origanum vulgare 127, 129, 130 

Oscillatoria acutissima 231, 234 

Oscillatoria annae 209 

Oscillatoria foreaui 209 

Oscillatoria nigroviridis 209, 229, 231, 234 

Oscillatoria sp. 209 

Ovarian cancer 2–4, 6, 11, 26, 37–42, 44, 63, 64, 

82, 88, 130, 134, 135, 140, 187, 198, 228, 231 

P-388 10, 11, 21, 22, 24–6, 31, 59, 63, 69, 70, 

82, 85, 101, 102, 107, 110, 112, 114, 117, 

120, 136, 137, 139, 141, 147, 150, 154, 155, 

160, 169, 172, 173, 176, 179, 181, 183, 198, 

210, 211, 213–15, 221, 222, 228, 229, 231 

Pachydictyon coriaceum 221, 223 

Padina pavonica 221, 223 

Paeonia alba 132 

Paeonia lactiflora 68, 132 

Paeonia officinalis L. 131 

Paeonia suffruticosa 132 

Palomia sp. 31 

Panax ginseng 68, 132, 134, 135 

Panax notoginseng 107 

Panax quinquefolium 133 

Panax quinquefolius 135 

Panax vietnamensis 135 

Pancreas 2 

Pancreatic cancer 2, 3, 6, 11, 22, 30, 31, 37–40, 

79, 123, 231 

Passiflora tetrandra 22, 179 

PC-13 11, 119, 120 

Peltophorum ferrenginium 104 

Phases 13 

Phenols 27–8 

Phlomis armeniaca 24, 152 

Phormidium crosbyanum 209 

Phormidium sp. 209 

Phosphinesulfide 86, 87 

Phyllanthoside 136, 137

294 Index 

Phyllanthostatin 136, 137 

Phyllanthus acuminatus 137 

Phyllanthus amarus 31, 136, 137 

Phyllanthus emblica 31, 136, 137 

Phyllanthus niruri 136, 137 

Phyllanthus sp. 24 

Phyllanthus urinaria 136 

Picro-beta-peltatin methyl ether 84 

Piperidine 20, 21, 86 

Plant cell 15–18; chemical constituents 16; 

primary metabolites 16–17; secondary 

metabolites 17–18; structure 15–16 

Plasmodium falciparum 173, 179, 228 

Plectonema radiosum 231, 234 

Plicamycin 7 

Plocamium 215 

Plocamium hamatum 215, 217 

Plocamium telfairiae 202 

Plumeria rubra 24, 138 

Plumeria sp. 25, 138 

Plumericin 139 

Podophyllotoxin 33, 44–6, 118 

Podophyllum emodi 45, 46 

Podophyllum hexandrum 32, 45 

Podophyllum peltatum 43, 45 

Polanisia dodecandra L. 140 

Polyacetylenic alcohols 134 

Polyalthia barnesii 31, 180 

Polysaccharides 15, 27–9, 56, 57, 86, 149, 150, 

196, 200, 204–7, 210 

Polytrichum obioense 8, 23 

Poria cocos 68, 132 

Porphyra tenera 202 

Porphyra yezoensis 202 

Portieria hornemannii 215, 217 

Preclinical tests 10–12 

Procarbazine 7, 50 

Progestogens 7 

Prorocentrium lima 234 

Prorocentrium maculosum 234 

Prostate 1, 2, 4–6, 11, 22, 30, 31, 79–81, 123, 

198, 222 

Proteins 29–30 

Protocols 13–14 

Protooncogenes 2 

Provitamin 97 

Prunus persica 132 

Pseudohypericin 116, 117 

Pseudolarix kaempferi 181 

Pseudolarolides 181 

Psorospermum febrifugum 23, 80 

Psychotria sp. 21, 181 

Pyranocoumarins 27, 76, 77 

Pyrrolidine 20 

Pyrrolizidine 20, 164, 165 

Quassinoids 112 

Quercetin 128, 129 

Rabdophyllin G 141 

Rabdosia rubescens 141, 142 

Rabdosia macrophylla 141 

Rabdosia ternifolia 22, 141 

Rabdosia trichocarpa 31, 141 

Rehmannia glutinosa 68, 132 

Retinoblastoma 2 

L-Rhamnose 86, 262 

Rhus succedanea 23, 182, 183 

Rhus velgaus 19 

Rhus vulgaris 183 

Rivularia atra 209 

Robina fertilis 156 

Rosane 119, 120 

Rottlerin 119, 120 

RPMI 11, 82, 110 

Rubia akane 143 

Rubia cordifolia L. 26, 30, 142, 144 

Rubia tinctorum L. 144 

Rubidazone 7 

Safranal 96 

Salvia canariensis L. 147 

Salvia miltiorrhiza 26, 148 

Salvia officinalis 147 

Salvia przewalskii 148 

Salvia sclarea 145, 146 

Saponine 8 

Sarcomas 2, 3, 6, 11, 79, 97, 127 

Sargassum bacciferum 149 

Sargassum fulvellum 29, 150, 205 

Sargassum hemiphyllum 205 

Sargassum horneri 205 

Sargassum kjellmanianum 150, 205 

Sargassum ringgoldianum 206 

Sargassum thunbergii 29, 150, 206, 221, 224 

Sargassum tortile 26, 150, 206, 222, 224 

Sargassum yendoi 206 

Schizothrix calcicola 209, 229, 231, 234 

Schizothrix sp. 209, 230 

Sclerocarya caffra 19, 183 

Scutellaria baicalensis 151, 152, 153 

Scutellaria barbata 151, 152, 153 

Scutellaria salviifolia 24, 152 

Scytonema conglutinata 235 

Scytonema mirabile 232, 235 

Scytonema ocellatum 232, 235 

Scytonema pseudohofmanni 235 

Scytonema saleyeriense 232, 235 

Scytosiphon lomentaria 206 

Seselidiol 183 

Seseli mairei 31, 183

Index 295 

Sesquiterpene lactones 100, 114, 115, 178 

Sho-saiko-to, Juzen-taiho-to 25, 68, 69, 70 

Skeletonema costatum 209 

Skin cancer 2, 4, 6, 8, 12, 24, 25, 28, 29, 48, 50, 

59, 76, 77, 97, 107, 108, 119, 120, 126, 127, 

134, 147, 151, 160, 177 

Small-cell lung cancer 2, 37, 39, 41, 44, 45, 82, 

140, 154 

Smilax glabrae 132 

Solieria robusta 202, 215, 217 

Spatoglossum schmittii 206, 222, 224 

Spirulina sp. 228 

Spyridia filamentosa 202 

Standardization of anticancer extracts 32 

Stellera chamaejasme 31, 154, 155 

Stomach cancer 2, 6, 36, 37, 87, 90, 107, 134, 

135, 143, 154, 155 

Streptozocin 7 

Strychnopentamine 163, 168 

Strychnos Nux-vomica 162 

Strychnos usabarensis 21, 162, 163 

Stypopodium flabelliforme 222, 224 

Stypopodium zonale 207, 224 

Styrylpyrone 109 

Supply of anticancer drugs 32 

Symbiodinium sp. 232, 235 

Symphytine 164 

Symphytum officinale L. 164, 165 

Symploca hydnoides 232, 235 

Symploca muscorum 209, 229, 235 

Tamarindus indica 29, 184, 185 

Tamarinus officinalis 184 

Taraxacum mongolicum 132 

Taxane 65 

Taxol 32, 33, 38, 62–7, 126 

Taxotere 62, 66 

Taxus baccata 62, 65 

Taxus brevifolia 32, 33, 64, 65, 66 

Taxus canadensis 65, 66 

Taxus cuspidata 65, 66 

Taxus marei 65 

Taxus spp. 43, 65 

Taxus sumatriensis 65 

Taxus wallachiana 65 

Teniposide 7, 33, 44, 45 

Terminalia arjuna 185 

Terpenoids 30–1 

Testing procedures 10–14 

5,7,2,3-Tetrahydroxyflavone 151 

TG671 11, 110 

Therapy 4–10; chemotherapy 5–6; conventional 

treatments 4–6; radiation 5; surgery 4–5 

6-Thioguanine 7 

Thiotepa 7 

Thymoquinone 126 

Thymus 8, 114, 153, 228 

Thyroid 2, 55 

Tolypothrix byssoidea 232, 235 

Tolypothrix conglutinata 232, 235 

Tolypothrix crosbyanum var. chlorata 209 

Tolypothrix distorta 231, 235 

Tolypothrix nodosa 232, 235 

Tolypothrix tenuis 232, 235 

Toosendanal 123 

Topoisomerase 5, 7, 37, 38, 42, 45, 97, 229, 

230 

Topoisomerase inhibitors 5, 7 

Treatments, advanced 6–9; angiogenesis 

inhibition 9; immunotherapy 6–9; tissue 

specific cytotoxic agents 9 

Treatments, alternative 9–10; antineoplastons 

10; herbal extracts 10; hydrazine sulfate 10 

Trichillin H 123 

Tricleocarpa fragilis 215, 217 

Trifolium pratense L. 31, 155, 156 

Trifolium repens 156 

Tropaeolum majus 186, 187 

Tropane 17, 18, 20 

Trypsin 124, 167 

Tumor suppressor genes 2 

Turbinaria conoides 222, 224 

Turbinaria ornata 222, 224 

Tydemania expeditionis 200, 210, 211 

Tyrosine 7, 175, 210, 231, 261, 271, 278 

Ulva lactuca 200, 210, 211 

Undaria pinnantifida 207 

Unidentified compounds 31 

Uronic acid 76, 77, 128, 150 

Valeriana officinalis 188, 189, 190 

Valeriana wallichii 189 

Valerianella locusta 189 

Valerianic acid 188 

Versicolactone A. 168 

Vinblastine 7, 33, 48–50, 52, 53, 230, 232, 

272 

Vinca major 51 

Vinca minor 51 

Vinca rosea Linn. 33, 43, 47 

Vincristine 7, 33, 48, 50, 144, 207, 

273 

Vindesine 7 

Vindoline 48, 33, 51–3 

Viola odorata 27, 157 

Viscotoxin 54, 55, 158 

Viscum album 33, 54, 56, 57, 58, 59, 60 

Viscum alniformosanae 56 

Viscum cruciatum 56

296 Index 

Viscumin 56 

Vitamin 8, 137, 249 

Wikstroelides 160 

Wikstroemia foetida 25, 160 

Wikstroemia indica 24, 26, 159, 160 

Wikstroemia uvaursi 160 

Xanthatin 192 

Xanthium strumarium 192 

Xanthoangelol 76, 77 

Xylomaticin 193 

Xylopia aromatica 193 

Zieridium pseudobtusifolium 23, 194

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