Introduction:

Cancer (malignant tumour) is an abnormal growth & proliferation of cells. It is a

frightful disease because the patient suffers pain, disfigurement & loss of many physiological processes. [1] It may be uncontrollable, & may occur at any time at any age in any part of the body. Cancer is a major public health burden in both developed and developing countries and the number of individuals living with cancer, is expanding continuously. According to the American Cancer Society [2], deaths arising from cancer constitute 23% of the annual deaths worldwide. A large number of chemo-preventive agents are used to cure various cancers, but they produce side-effects that prevent their extensive usage. Although more than 1500 anticancer drugs are in active development with over 500 of the drugs under clinical trials, there is an urgent need to develop much effective and less toxic drugs. All these chemo-preventive drugs have one or other kind of side effects on the patients like hair loss, development of burnt areas around the treated portion, development of heart diseases, mouth ulcer with pain, Gastric ulcer etc. Because of the serious side effects, many cancer patients seek alternative and complementary methods of treatment. The important preventive methods for most of the cancers include dietary changes, stopping the use of tobacco products, treating inflammatory diseases effectively, and taking nutritional supplements that aid immune functions. According to the estimates of the WHO, more than 80% of people in developing countries depend on traditional medicine for their primary health needs. A recent survey shows that more than 60% of cancer patients use vitamins or herbs as therapy [3].

Plants have been used for treating various diseases of human beings and animals since time immemorial. There are over a hundred chemical substances that have been derived from plants for use as drugs and medicines. They maintain the health & vitality of individuals, & also cure diseases, including cancer without causing toxicity
[3]

. Plants have a long history of use in the

treatment of cancer having more than 3000 plant species listed been used in the treatment. Natural Products, especially plants, have been used for the treatment of various diseases as medicines in China, India & Greece from ancient time and an impressive number of modern drugs have been developed from them. Documentations of the Ayurvedic system recorded in Susruta & Charaka dates from about 1000 BC. According to the estimates of the WHO, more than 80% of people in developing countries depend on traditional medicine for their primary health needs. Use of plants and phytomedicines for cancer treatment has increased dramatically in the last two decades. The United States National Cancer Institute (NCI) collected about 35,000 plant samples from 20 countries and has screened around 114,000 extracts for anticancer activity.

HISTORY:The search for anti-cancer agents from plant sources started in earnest in the 1950s with the

discovery and development of the vinca alkaloids, vinblastine and vincristine, and the isolation of the cytotoxic podophyllotoxin. These discoveries prompted the NCI to initiate an extensive plant collection program in 1960[5], focused mainly in temperate regions. This led to the discovery of many novel chemotypes showing a range of cytotoxic activities, including the taxanes and camptothecins, but their development into clinically active agents spanned a period of some 30 years, from the early 1960s to1990s. With the development of new screening technologies, the NCI revived the collections of plants and other organisms in 1986. This time the focus was on the tropical & sub-tropical
2

regions of the world. Plants have been collected from the African countries of Cameroon, the Central African Republic
[5]

, Gabon, Ghana, Madagascar & Tanzania. In Central and South

America, samples have been collected from Bolivia, Colombia, the Dominican Republic, Ecuador, Honduras, Paraguay, Peru & Puerto Rico
[5]

. The NCI collected about 35,000 plant

samples from 20 countries & screened around 114,000 extracts for anticancer activity. Of the 92 anticancer drugs commercially available prior to 1983 in the US and among world wide approved anticancer drugs between 1983 & 1994, 60% are of natural origin
[5]

. In this

instance, natural origin is defined as natural products, derivatives of natural products or synthetic pharmaceuticals based on natural product models. There are several medicinal plants all over the world. However, only few medicinal plants have attracted the interest of scientists to investigate the remedy for neoplasm (cancer). Hence, an attempt has been made to review some medicinal plants used for the prevention & treatment of cancer in foreign countries. The NCI has established collaborative programs in Brazil, Costa Rica, Mexico & Panama. Southeast Asian collections have been performed in Bangladesh, Nepal, Pakistan, Thailand & other countries. Collaborative programs have been established in Bangladesh, China, Korea & Pakistan. In each country, NCI contractors work in close collaboration with local botanical institutions.

Some of the collaborative programs are the following:The Kunming Institute of Botany in China studies Chinese medicinal plants. The H.E.J. Institute of Chemistry, University of Karachi, studies Pakistani plants. The University of Dhaka in Bangladesh studies plants and microbes.

The South African Council for Scientific and Industrial Research studies South African plants.

The Korean Research Institute of Chemical Technology examines Korean medicinal plants. The Zimbabwe National Traditional Healers Association and the University of Zimbabwe Study Zimbabwean medicinal plants.

DRUG DEVELOPMENT FROM PLANTS:The targets for chemotherapy that are currently recognized include anything that has to do

with cell growth and cell proliferation i.e. replication in all its details- transcription, translation, mitosis, the cell metastasis, the process by which the cells break off from the parenting malignant tumour and travel to distant sites through the circulation where they invade and setup a new foci for tumours (Suffness & Pezzuto 1991) [3]. It is possible to search for new drugs that interact with useful targets that are currently undefined since it really is not necessary to know the target if the effect of hitting the target can be predicted. Alternatively, a screen can be designed to monitor a desired response even if the target responsible for mediating the process is not known. The major problem is the harm to the normal cells along with the tumour cells. Furthermore, some tissues whose cells have rapid turnover rate will be extremely sensitive to agents, which affect the dividing cells
[4]

. Most

prominent of these are bone marrow and gastrointestinal epithelium which are the most frequent targets of these drugs used in chemotherapy of cancer that yield toxicological response. An ideal drug is one, which is highly selective for tumour tissues that it can kill or incapacitate tumour cells while not effecting normal tissues. The dose of chemotherapeutic drugs should be such that the rapidly dividing tumour cells incur maximum damage while normal cells remain unharmed so that system can recover. All the cell activities are controlled by the DNA. Genes receive information which modulates their activity. Various molecules are able to bind with the nucleic acids, modulating their activity and of various enzymes related. It is well
4

established that the effect of various molecules on DNA replication may dramatically affect biochemical processes, thus influencing cell life
[4]

. The aim of cancer therapy should be for

selecting molecules capable of specifically correcting or arresting cell disturbances at molecular level and enhancing beneficial gene expression. Thus challenge of cancer cells can be met at two different levels: (1) Cancer cell multiplication can be arrested without injury to normal cells. (2) Competence of the immune system must be protected and restored for an active response of the body. Several anticancer compounds, mostly from plants derived alkaloids, flavanones and flavonoids, which selectively destabilize cancer DNA, yet have no effect on normal DNA have being tested but do not effect normal DNA replication but they bind no replication- initiation sites or prevent chain elongation of cancer DNA[4].. They incapacitate highly malignant cells, but can revert to normal, cells in which malignant transformation has not gone to far. The present trend in the development of cancer medicine leads to isolation of active principles in the form of chemicals, which may be active or toxic. In the Ayurvedic system, several plant products mixed together and given as medicine.

STAGES OF DRUG DEVELOPMENT:The orthodox chemotherapeutic approach to cancer is based upon drugs that inhibit the

characteristically uncontrolled development of abnormal cells. This is done by either inhibiting cell division or by killing the cells. A recent survey shows that more than 60% of cancer patients use vitamins or herbs as therapy. More than 50% of all modern drugs in clinical use are of natural products, many of which have the ability to control cancer cells. Different compounds have being isolated from plants which are used in drugs i.e. podophyllotoxin from the roots of Podophyllum peltatum, terpenoid, taxol, mytomycin, etc. The search for anticancer compounds

from plants still continues. [4] According to Hartwell (1971), it has been estimated that more than 3000 species of plants have been used through out the world to treat cancer.
1.

Following stages are to be followed in anticancer drug development from plants:Collection and identification of various plants: Plants are collected & identified on the

basis of information available from collected data & various source like folklore, ancient Documentations of the Ayurvedic system, Greek scriptures, etc.
2.

Preparation of various plant extracts: Plant extracts are prepared using various

extraction techniques like crushing, grinding, etc from plant parts like roots, leaves, bark, etc. These extracts contain various chemical compounds like podophyllotoxin, terpenoid, alkaloids, vinblastine and vincristine.
3.

Primary screening for anti-tumor activities: Plant extracts prepared, then screened using

various techniques to obtain various chemical Compound Having anti-tumour activities. Routine testing of extract fractions is usually done via an in-vitro cytotoxicity test.
4.

Large scale collection of active plants and their parts: Plants & their parts showing

antitumour activities are then separated & actively collected from their natural sources in large scale to obtain anti-tumour chemical compounds.
5.

Bioassay directed fractionation to isolate pure active compounds:

Any information

about anticancer activity of plants can be obtained only using suitable assay procedure on the plant products which include various steps of fractionation & isolation, etc. A range of chromatography Techniques are then applied for more refined separation of constituents. This is a highly skilled process, needing to avoid chemical changes & separate very similar molecules.

Collection and identification of various plants

Preparation of various plant extracts

Preclinical study (Formulation, isolate development BioassayLarge scale productionto Pharmacology and compounds Largedirected screening fortesting scale collection of of for drug and their various parts Structural fractionation anti-tumour activities Toxicology) Tumour panel the active compound(s) Primary elucidationactive plantspure active

Clinical trails

FLOW CHART SHOWING STAGES OF DRUG

DEVELOPMENT

6.

Structural elucidation of the active compound(s): After screening & assay processes,

structures of isolated compounds are elucidated so that their anti-tumour activities. The chemical structure of the compounds is determined by reviewing spectrophotographic findings together with phytochemical & biosynthetic reasoning. X-ray crystallography is often employed to establish a definitive structure.
7.

Tumor panel testing: Usually only those fractions showing biological activities are

studied further. Compounds are isolated & after structural elucidation are tested for their antitumour activities like inhibition of cell multiplication, depletion of glutathione from cells, arrest of carcinogens, etc & extent of effectiveness. Promising chemicals are then tested on cancer tissues which have been developed to standardize experimental findings.
8.

Preclinical study (Formulation, Pharmacology and Toxicology): If these results are

encouraging, the next stage is pre-clinical toxicological studies along with formulation of different concentrations of these compounds in drugs at various mixture levels. The total therapeutic activity is greater than, or different from the therapeutic activities of the Individual chemicals. Synergism or antagonism due to the complex nature of the extract has been postulated as an explanation.
9.

Clinical trails: Few compounds reach clinical trials. A low therapeutic index (the ratio of

maximum tolerated dose to minimum effective dose), undesirable side-effects or high toxicity may outweigh beneficial tumour-inhibitory activity. Of 25,000 screens conducted annually by the NCI (including both synthetic and natural materials), only 8-12 compounds are likely to be selected for pre-clinical testing, & only 6-8 may go on to clinical trials.
10.

Large scale production for drug development: For large scale production, it requires

relatively large amounts of material, larger-scale extractions & fractionation facilities. Selected plants are collected in large scale for different natural sources & places.
8

BIOASSAYS OF PLANT PRODUCTS:Any information about anticancer activities of plants can be obtained only by using suitable

assay procedures on the plant products. This can be carried out by several methods using cancer cell-lines; the effect of this drug on the growth of this cell-line rather the preventive effect of the growth can be determined. Without an effective assay system, it is not possible to evaluate the effect of drug either for treatment in experimental animals or estimating at various stages of purification process. Each step of fractionation and isolation of bioactive compounds from the plant extract is guided by both in-vitro techniques using human epidermoid carcinoma (KB) & murine lymphocytic leukemia cells in culture & in-vivo techniques using mice bearing transplantable leukemic (p-388) and solid tumour derived murine as well as human sources [4]. The random-selection screening program for natural products having anticancer activities was terminated by the NCI in 1983. Nevertheless, the number of cytotoxic & anti-tumour agents identified was enormous. The NCI has certainly not lost confidence in the potential of natural products as leads for new anti-cancer agents. Instead of the random-selection screening program, a new screening system was begun in 1986, reducing the scale of the operation, & concentrating on the less thoroughly investigated groups of organisms, including plants to discover agents with high selectivity for the major forms of human solid tumours. Agents showing differential or selective activity of in vitro growth inhibition will be subsequently evaluated by in vivo tests in mice bearing the same human tumour cell lines found sensitive in vitro. This new in vitro-in vivo screening is closer to the real human turnover situation than those used previously & therefore the drugs discovered by this screening may be expected to be more predictive of clinical activity than drugs discovered by older methods.

The Central Drug Research Institute, Lucknow, has carried out investigations of various plants of Indian origin and foreign origin for their bioactivity including anticancer properties in collaboration with the National Cancer Institute (NCI), USA [5].

PLANTS USED CANCER TREATMENT:The classic anticancer drugs do not distinguish between normal cells and tumour cells.

Using a sensitive biochemical test (oncotest), some plant alkaloids and flavonones capable of distinguishing in vivo and in vitro human & animal cancer cells from normal ones are isolated. This prevents in vitro proliferative capacity of cancer cells only. They bind to cancer DNA and ignore normal DNA. They inhibit tumour development in mice. They exhibit a strong synergistic effect with classic anticancer compounds such as cyalophosphamide [4]. As the age of modern medicine and single pure drugs emerged, plant-derived active principles and their semi-synthetic and synthetic analogs have served as a major route to new pharmaceuticals. They show efficient cytotoxic and anti-tumour activities. Most of the present day drugs, used in chemotherapy, are leading to serious side effects. Therefore it is important to search for new compounds, which can reduce the harmful effects of anticancer drugs. Immunostimulation is a therapeutic concept, which aims at the stimulation of our nonspecific immune system. This type of unspecific immuno-stimulation constitutes an alternative or adjuvant for conventional chemotherapy of tumours. A graphic summary of plant exploration for the NCI is depicted on a world map showing 58 floristic regions. It is estimated that less than one-half of the world flora is economically feasible for collection. Random screening of approximately 35,000 species has led to guidelines that precluded further screening of all species in 333 genera and another 2,905 species in 1,773

10

genera

[6]

. These taxa are reported to represent one-half to two-thirds of the species that

characterize vegetation in geographic areas most frequently explored for the NCI. Nine plant-derived compounds have been approved for use as anticancer drugs vinblastine, vincristine, etoposide, teniposide, taxol, navelbine, taxotere, topotecan, and irinotecan [6]. Another eleven agents [10-hydroxycamptothecin, (-)-sophocarpine, monocrotaline, d-tetrandrine, lycobetaine, indirubin, colchicinamide, curcumol, curdione, gossypol, and homoharringtonine] are used currently in China. Various types of plants are used to extract compounds having anticancer and anti-tumour activities.

Medicinal Plants:Medicinal plants grow naturally around us. Over centuries, cultures around the world have

learned how to use plants to fight illness and maintain health. These readily available & culturally important traditional medicines form basis of an accessible & affordable health-care regime and are an important source of livelihood for indigenous & rural populations. Increasingly, medicinal species that reside in natural areas have received scientific & commercial attention. Medicinal plants possess immunomodulatory and antioxidant properties, leading to anticancer activities. They are known to have versatile immunomodulatory activity by stimulating both non-specific and specific immunity. Plants contain several phytochemicals, which possess strong antioxidant activities. The antioxidants may prevent and cure cancer and other diseases by protecting the cells from damage caused by free radicals the highly reactive oxygen compounds. Thus consuming a diet rich in antioxidant plant foods will provide a milieu of phytochemicals, nonnutritive substances in plants that possess health protective effects. Many naturally occurring substances present in the human diet have been identified as potential chemo11

preventive agents; & consuming relatively large amounts of vegetables & fruits can prevent the development of cancer. Some of them are here:-

PLANTS OF INDIAN ORIGIN :India has a very long, safe & continuous usage of many herbal drugs in the officially

recognized alternative systems of health viz. Ayurveda, Unani, Siddha, Homeopathy & Naturopathy. These systems have rightfully existed side-by-side with Allopathy. Millions of Indians use herbal drugs regularly, as spices, home-remedies, health foods as well as over-thecounter (OTC) as self-medication or also as drugs prescribed in the non-allopathic systems. There is vast literature on Ayurveda in Sanskrit, Hindi & regional languages that is often not accessible to the other language groups. A large number of academic, industrial & government institutes are conducting research on the medicinal plants of India. More than 70% of Indias 1.1 billion populations still use these non-allopathic systems of medicine. Currently, there is no separate category of herbal drugs or dietary supplements, as per the Indian Drugs Act. There are various plants of Indian origin and some of them are listed:

Neem (Azadirachta indica): Neem has been used in buccal carcinogenesis, skin

carcinogenesis, mammary carcinogenesis, gastric carcinogenesis, Ehrlich carcinoma & B16 melanoma. Dietary neem flowers caused a marked increase in glutathione S-transferase (GST) activity in the liver, while resulting in a significant reduction in the activities of some hepatic P450-dependent monooxygenases
[7]

. These results strongly indicate that neem flowers may

have chemopreventive potential. Young animals were fed with AIN-76 purified diets containing either 10-12.5% ground freeze-dried neem flowers for 1 week prior to, during, & for 1 week after the administration of each carcinogen. Interestingly, it was found that neem flowers
12

resulted in a marked reduction of the incidence of mammary gland (~ 35.2%) & liver tumours (61.7% & 80.1% for benign & malignant tumours)[7].Furthermore, the multiplicity of tumours per rat was also lower in the neem flower groups, i.e. those for mammary gland tumours and benign and malignant liver tumours were reduced to 44.0%, 87.9% and 88.9%, respectively. These results clearly demonstrated that neem flowers contain some chemo-preventive agents capable of inhibiting liver & mammary gland carcinogenesis in rats. Administration of ethanolic neem leaf extract (ENLE) inhibited DMBA induced hamster buccal pouch carcinogenesis, as revealed by the absence of neoplasm. These results suggest that the chemo-preventive effect of ENLE may be mediated by induction of apoptosis
[7]

. The

modulatory effect of neem leaf with garlic on hepatic and blood oxidant-antioxidant status may play a key role in preventing cancer development at extra-hepatic sites. The ethanolic extract of neem has been shown to cause cell death of prostate cancer cells (PC 3) by inducing apoptosis, as evidenced by a dose-dependent increase in DNA fragmentation & decrease in cell viability.

Nibu (Citrus limon):

Nibu fruit contains flavonoid, flavone, limonoid, limonene,

nobiletin & tangeretin. The flavonoid, tangeretin and nobiletin are potent inhibitors of tumour cell growth & can activate the detoxifying P450 enzyme system. Limonoids inhibit tumour formation by stimulating the GST enzyme. The limonene (a terpenoid) also possesses anticancer activity. Nibu fruit is used for inhibition of human breast cancer cell proliferation &delaying of mammary tumourigenesis. It is also used in metastasis and leukemia.

Shakarkand (Ipomoea batatas): The derivatives (viz. chlorogenic, dicaffeoylquinic

and tricaffeoylquinic acids) of caffeoylquinic acid contained in Shakarkand tubers have potential cancer chemoprotective effect. 4-Ipomeanol (a furanoterpenoid) isolated
13

from Shakarkand has been found to exhibit anticancer activity against non-small cell lung cancer lines.

Partheinium hysterophorus: The plant extracts of this plant shows anti-tumour properties.

They have the capacity to modulate bio-transforming enzymes in transplantable murine leukaemias.
Tea(Camellia sinensis): Green tea flavonoids are potent antioxidant compounds in vitro,

with potential to reduce incidence of cancer [8] .The major flavonoids in green tea are kaempferol & catechins (catechin, epicatechin, epicatechin gallate (ECG),

and epigallocatechin gallate (EGCG)). In producing teas such as oolong & black teas, the leaves are allowed to oxidize, during which enzymes present in the tea convert some or all of the catechins to larger molecules. However, green tea is produced by steaming the fresh-cut tea leaves, which deactivates these enzymes, & oxidation does not significantly occur.[9] White tea is the least processed of teas & is shown to present the highest amount of catechins known to occur in Camellia sinensis. White tea has been claimed to be more effective, based upon preliminary work by Santana-Rios et al. Another study from the Life Science journal Carcinogenesis showed that green tea, in combination with tamoxifen, is effective in suppressing breast cancer growth in vitro human breast cancer tumours and in vivo animal experiments in mice.[6] A study at Taiwan's Chung Shan Medical University found that people drinking at least one cup of green tea per day were 5 times less likely to develop lung cancer than those who did not.[9]

14

Fig (1): Green tea contains flavonoids[9] Indigofera tinctoria: The plant yielding a compound, namely, Indirubicin, have anticancer activity. It yielded a marked inhibition on Lewis Lung carcinoma and Walker carcinoma.

TABLE (1):- Anticancer Plants of Indian Origin :Bioactive Principle

Alakaloid Alakaloids, Flavonoids

Plant
Alstonia scholaris Azadirachta indica ( Neem)

Action
Tumour regression[3,24] Inhibit viability[7] carcinogenesis, DNA

fragmentation, Decrease in cell

Aspergillus species Jawaharene Asparagus Aspargine, Asparagoside Brucea javanica Quassinoid Glycosides

Antitumour [3]

Effective in Reducing breast, pancreatic, & Cervical cancer on mice.

[24]

Antitumor to EAC,Walker-256 carcinoma, P-388 [22]

Plant
Beta vulgaris

Bioactive Principle
carotene

Action
Antitumour to DLA[3]
15

Camellia thea Camellia sinensis.

Flavonols Flavonoids such as kaempferol & catechins

Antitumour to EAC potential to reduce incidence of cancer by Deactivating Enzymes.[8,9] Inhibitors of tumour cell growth, activate the detoxifying P450 enzyme system. Inhibit tumour formation [24]

Citrus limon (Nibu) Ipomoea batatas (Shakarkand) Indigofera tinctoria Utrica dioica (Stinging nettle)

flavonoid, tangeretin, nobiletin &Limonoids

caffeoylquinic acid

chemo-protective effect[23]

Indirubicin

Anticancer activity, Inhibition on

Lewis Lung carcinoma & Walker steroids carcinoma. [23] Inhibit membrane Na+, K+, ATPase activity, suppressing Prostate
Cell metabolism and Growth.[22,23]

PLANTS OF FOREIGN ORIGIN:Data on 62 medicinal plants of foreign origin have been collected from the literatures.

These plants are used against various types of tumours/cancers such as sarcoma, lymphoma, carcinoma & leukemia.
[22, 23]

Many of these medicinal plants have been found effective in

experimental & clinical cases of cancers. In USA, use of plants & phytomedicines has increased dramatically in the last two decades. A National Centre for Complementary and Alternative Medicine has been established in USA. Use of plants as a medicinal remedy is an integral part of the South African cultural life. It is estimated that 27 million South Africans use herbal medicines from more than 1020 plant species. In fact, there are several medicinal plants all over the world, which are being used traditionally for the prevention & treatment of cancer. According to the NCI, at least 70 % of new drugs introduced in the USA in the last 25 years are
16

derived from natural sources. Plant-derived anti-cancer drugs such as taxol, first isolated from the Pacific yew, save at least 30,000 lives per year in the USA. Some medicinal plants (Table 2) have been found effective in various types of malignant (cancer) & benign tumours of humans & experimental animals. These include: Agrimonia pilosa[24]in sarcoma-180; Ailanthus altissima [24] in intestinal cancer, sarcoma-180 & leukaemia16; Akebia quinata in sarcoma-180 & sarcoma-37; Fritillaria thunbergii in tumours of throat, chest & breast Lonicera japonica in ascites carcinoma & sarcoma-180; Oldenlandia diffusa in leukaemia, sarcoma-180 & Ehrlichs ascites sarcoma; Phaleria macrocarpa in oesophageal cancer; Pteris multifida in sarcoma-180, sarcoma-37 and Yoshidas sarcoma; Pygeum africanum in prostate cancer; Solanum lyrati in sarcoma-180, Ehrlich ascites carcinoma & stomach cancer.

Fig (2):- Plants, such as the Pacific yew (Taxus brevifolia) & the Mayapple (Podophyllum peltatum), have been used to develop powerful anti-cancer drugs

Table

{2}:- Anticancer Plants of Foreign Origin[7]:name Parts used and their main with active components Origin/ native
17

Botanical of plant

their family name

Agave americana Agavaceae Broyonia dioica Cannabis sativa Cannabinaceae Eupatorium cannabinum Asteraceae Galium aparine Rubiaceae Junchus effuses Juncaceae Lantana camara Verbenaceae Pygeum africanum

place
Leaf contains steroidal saponin, alkaloid, Central coumarin, isoflavonoid, hecogenin and America vitamins (A, B, C). Root contains glycoside & cucurbitacin Europe Leaf contains stereo isomers of cannabitrion South Africa Whole plant contains Lactone, Sesquiterpene, pyrrolizidine Alkaloid and Flavonoid. Cleaver contains iridoid, Tannin, Polyphenolic acid, anthraquinone Whole plant contains effusol, juncanol, phenylpropanoid, -tocopherol and Europe, Asia North America Europe, Africa Australia China, Japan, Korea

tridecanone. Whole plant contains various alkaloids Tropical America (camerine, isocamerine, micranine lantanine, lantadene) Bark contains phytosterol, Africa triterpene and tannin Whole plant contains volatile oil, flavonoid and tannin Fruit contains gallic acid Whole plant Flower trifolitin, contains glucosides (trifolin, and South Europe Indonesia China, Japan,

Boraginaceae Thymus vulgaris Lamiaceae Phaleria macrocarpa Patrinia scabiosaefolia Vlerianaceae Trifolium pratense Fabaceae

Korea Asia, Europe, Africa, Australia

trifolianol),

flavonoid

phenolic acid

Herbal Plants:In the written record, the study of herbs dates back over 5,000 years to the Sumerians, who

described well-established medicinal uses for such plants as laurel, caraway & thyme. Ancient Egyptian medicine of 1000 B.C. are known to have used garlic, opium, castor oil, coriander,

18

mint, indigo, & other herbs for medicine & the Old Testament also mentions herb use & cultivation, including mandrake, vetch, wheat, barley, and rye. In Indian Ayurveda medicine has used many herbs such as turmeric possibly as early as 1900 B.C. Many other herbs & minerals used in Ayurveda were later described by ancient Indian herbalists such as Charaka & Sushruta during the 1st millennium BC. The Sushruta Samhita attributed to Sushruta in the 6th century BC describes 700 medicinal plants, 64 preparations from mineral sources, & 57 preparations based on animal sources. In Tamil Nadu, Tamils have their own medicinal system now popularly called the Siddha medicinal system. It contains roughly 300,000 verses covering diverse aspects of medicine to cure many diseases that are relevant even today.[22] The herbal products have been classified under dietary supplements & are included with vitamins, minerals, amino acids &other products intended to supplement the diet. Plants contain several phyto-chemicals, which possess strong antioxidant activities. The antioxidants may prevent & cure cancer & other diseases by protecting the cells from damage caused by free radicals.

Ashwagandha (Withania somnifera): An extract from the roots & leaves of the plant

Withania somnifera, is just such an adaptogen, with proven effects in the prevention & treatment of cancer. Shohat and colleagues (1970)[23] found that 2 isolated components from it, Withaferin A & Withanolide E, "inhibit tumour growth" in Swiss-albino & BDF1 mice, exhibiting a strong immunosuppressive effect by stopping cancerous cell division in its tracks[22]. P. Uma Devi and coworkers (1992)
[23]

attempted to ascertain "the antitumour activity of

Ashwagandha root & to determine an effective drug dose which can be used without serious side
19

effects." They found that administration of an alcohol extract of the plant resulted in complete remission of tumour growth in 25 % of treated animals & more than 50 % regression of tumour growth in 63 % of the animals, & without mortality, & any side effects. Selective tumourinhibitory activity of the leaf extract (i-Extract) Known as withanone was identified by in vivo tumour formation assays in nude mice and by in vitro growth assays of normal and human transformed cells. To investigate the cellular targets of i-Extract, a gene silencing approach using a selected small hairpin RNA library and found that p53 is required for the killing activity of iExtract. By molecular analysis of p53 function in normal and a variety of tumour cells, we found that it is selectively activated in tumour cells, causing either their growth arrest or apoptosis.

Asparagus: Asparagus Extract well known for its function as a cancer preventative

agent, Asparagus contains high levels of selenium, which enhances the activity of glutathione peroxidase, one of the three most important enzymes associated in the removal of the body's dangerous free radicals. Stirpe discovered that Asparagoside is able to restrict DNA synthesis and the translation of proteins and inhibit adenocarcinoma. Gorgann
[24]

revealed that Asparagoside is effective in

reducing breast, pancreatic, & cervical cancer on mice. Sati [24] used Asparagoside to reduce JTC26 (human cervical cancer cell) and P-388 (leukaemia cell) in mice. Asparagus Extract doubles the activity of IL-2 for healthy humans and, more importantly, cancer patients. Asparaginase

is an enzyme used to treat some forms of cancer in the blood. The USP Drug information book
[24]

lists asparaginase as treatment for acute lymphocytic, leukaemia, acute myelocytic leukaemia

(AML), Hodgkin's lymphoma & non-Hodgkin's lymphoma. In order for cells to grow, they need

20

a chemical called aspargine, synthesised from aspartic acid. Cancer cells cannot produce their own asparagines relying on the normal cells to live.

Garlic: Scientists have uncovered fresh evidence that garlic can protect against some forms

of cancer. The research, by a team from the University of North Carolina at Chapel Hill, shows that people who eat raw or cooked garlic regularly cut their risk of stomach cancer by about a half compared with those who eat none. They also cut their risk of colorectal cancer by as much as 2/3.

Black cumin (Nigella sativa): Black cumin has demonstrated analgesic properties in mice.

The mechanism for this effect is unclear. In vitro studies support antimicrobial, anticancer, antiinflammatory & immune modulating effects. have been published.

[24]

However few randomized double blind studies

Stinging nettle (Urtica dioica): In some clinical studies effective for benign prostatic

hyperplasia & the pain associated with osteoarthritis.[22] In-vitro tests show anti-inflammatory action. In a rodent model, stinging nettle reduced LDL cholesterol and total cholesterol. another rodent study it reduced platelet aggregation.[23]
[23]

In

PLANTS parts used for treatment:

Use of plants for cancer treatment includes the Plant extract preparations before

administration orally or by any other methods. Plant extracts are prepared from various plant parts like roots, leaves, flowers, Rhizome, etc. In ancient methods, it tends to use extracts from parts of plants but not isolate particular phytochemicals. Pharmaceutical medicine prefers single

21

ingredients on the grounds that dosage can be more easily quantified. Herbalists often reject the notion of a single active ingredient, arguing that the different phytochemicals present in many herbs will interact to enhance the therapeutic effects of the herb and dilute toxicity. Various parts of plants (Table 3) have been used to prepare extracts which can be used. These include: Acrorus calamus (bach) rhizome; Agrimonia Pilosa (Hairy agrimony) Whole plant; Azadiracbta indica (Neem) Bark, leaf and Flower; Citrus limon (Nibu) fruit; Ipomoea batatas (Sarkkarnkand) Whole plant; Camellia sinesis (GreenTea, black tea) Leaf
[8, 9]

; Eugenia

caryopbyllata (Laung, clove) Whole plant, Flower bud; Glycerrbiza glabra (Mulathi) Stem (tuber); etc.

Table {3}:- Plants parts used for Cancer treatment:Main components active PlantPart s Used
Rhizome Whole plant Bark, leaf and Flower Leaf

Botanical name Family (with common Name)

Acrorus calamus (bach) Agrimonia Pilosa (Hairy agrimony) Azadiracbta indica (Neem) Camellia sinesis Araceae Rosaceae Meliaceae Theaceae

Asarone, eugenol, methyl eugenol, palmitic acid & champhene Argimonolide, flavonoid, Tannin, Triterpene and Coumarin. Alkaloid and insolitol[7] Chrysophanol, isochrysophanol,

Botanical (with

name Family

Main components

active PlantPart s Used

common Name)
(GreenTea, black tea) Cassia absus (Chaksu) Citrus limon (Nibu) Caesaliniaceae Rutaceae rhein & - sitosterol[8,9] Hydrocyanic acid, delphinidin & Cyaniding Resin plant contains essential oil, coumarins (ellagic acid derivatives)
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Leaf Fruit

Eugenia caryopbyllata (Laung, clove) Ipomoea batatas (Skarkand) Glycerrbiza (Mulathi) glabra

Myrtaceae

Dimethlsulfone, kaempferol- diglucoside and caffeic acid Essential oils (menthol, Menthone, limonene) Monophenolase, catalase, Anthocyanins Cytochrome c-oxidase, & Caffeic Acid. Lauric, Conjugated dienoic, oleic & stearic acids.

Whole plant, flower bud Whole plant Stem (tuber)

Convolvulaceae Fabaceae

Plant-Derived Anti-Cancer Agents in CLINICAL USE:The first agents to advance into clinical use were so-called vinca alkaloids, vinblastsine

(VLB) & vincristine (VCR), isolated from Madagascar periwinkle, Catharanthus roseus G. Don. (Apocynaceae), which was used for the treatment of diabetes by various cultures [23]. These drugs were first discovered during an investigation of plant as a source of potential oral hypoglycemic agents. It was noted that extracts reduced white blood cell counts & caused bone marrow depression in rats, & subsequently it was found that the treatment of mice bearing a transplantable lymphocytic leukemia caused significant life extension. This led to the isolation of VLB and VCR as the active agents, so their discovery may be indirectly attributed to the observation of an unrelated medicinal use of the source plant. More recent semi-synthetic analogues of these agents are vinorelbine (VRLB) & vindesine (VDS). These agents are primarily used in combination with other cancer chemotherapeutic drugs for the treatment of a variety of cancers. VLB is used for treatment of leukemias, lymphomas, advanced testicular & breast cancers & Kaposis sarcoma, & VCR, in addition to the treatment of lymphomas, also shows efficacy against leukemias, particularly acute lymphocytic leukemia in childhood. VRLB
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has shown activity against non-small-cell lung cancer & advanced breast cancer. Of over 2069 anti-cancer clinical trials recorded by NCI as being in progress as of July 2004, over 160 are drug combinations including these agents against a range of cancers. Another important addition to the anti-cancer drug armamentarium is the class of clinicallyactive agents derived from camptothecin, which is isolated from the Chinese ornamental tree, Camptotheca acuminata Decne (Nyssaceae), & known in China as Tree of joy. Camptothecin was discovered from extracts of plants originally collected by the U.S.D.A as a possible source of steroidal precursors for production of cortisone [23]. Extract of C. acuminata was the only one of 1000 of these plant extracts tested for anti-tumour activity which showed efficacy & camptothecin was isolated as the active constituent. However, extensive research was performed by several pharmaceutical companies in a search for more effective camptothecin derivatives, & Topotecan (Hycamtin), developed by SmithKline Beecham (now Glaxo SmithKline), and Irinotecan (CPT-11; Camptosar), originally developed by the Japanese company, Yakult Honsha, are now in clinical use. Topotecan is used for the treatment of ovarian & small-cell lung cancers while Irinotecan is used for the treatment of colorectal cancers. Of the 2069 cancer clinical trials recorded by the NCI as being in progress, as of July2004, 94 or ~ 4.5% are listed as involving camptothecin-derived drugs, including 64 with irinotecan (CPT-11), 26 with topotecan, & 4 with other miscellaneous analogues, either as single agents or in combination. In addition, 15 other camptothecin derivatives are in isolated from the Chinese tree, Cephalotaxus harringtonia var. drupacea (Sieb & Zucc.) (Cephalotaxaceae), & elliptinium, a derivative of ellipticine, isolated from species of several genera of the Apocynaceae family, including Bleekeria vitensis A. C. Sm.

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The flavone, flavopiridol is totally synthetic, but the basis for its novel structure is a natural product, rohitukine, isolated by chemists at Hoechst India Ltd. in early 1990s from Dysoxylum binectariferum Hook. f. (Meliaceae), which is phylogenetically related to the Ayurvedic plant, D. malabaricum Bedd., used for rheumatoid arthritis. Rohitukine was isolated as the constituent responsible for anti-inflammatory &immunomodulatory activity. A total synthesis was undertaken, & one of the over 100 analogues synthesized during structure-activity studies was flavopiridol, which was found to possess tyrosine kinase activity & potent growth inhibitory activity against a series of breast & lung carcinoma cell lines. It also showed broad spectrum in vivo activity against human tumour xenografts in mice, & this led to its selection for preclinical and clinical studies by the NCI in collaboration with Hoechst. It is currently in 18 Phase I & Phase II clinical trials, either alone or in combination with other anti-cancer agents. While flavopiridol alone is probably not a viable treatment, use of compound in Conjunction with other agents such as paclitaxel & cisplatin has led to partial & complete remissions in a number of Phase I patients, leading to Phase II studies in patients with a variety of paclitaxel-resistant tumours. As mentioned above, a number of naturally-derived agents were entered into clinical trials and were terminated due to lack of efficacy or unacceptable toxicity. The case of maytansine illustrates how the emergence of novel technologies can revive interest in these older agents. It is also worth remembering that the development of effective drugs, such as paclitaxel (taxol) and the camptothecin derivatives, topotecan and irinotecan, required 20 to 30 years of dedicated research and patience, and considerable resources, to ultimately prove their efficacy as clinical agents.

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Another example of an old drug of the same vintage as taxol and camptothecin, and having a possibility of revival, is bruceantin which was first isolated from a tree, Brucea antidysenterica J. F. Mill. (Simaroubaceae), has been used in Ethiopia for the treatment of cancer [23]. Activity was observed in animal models bearing a range of tumors, but no objective responses were observed in clinical trials, and further development was terminated. Interest has been revived by the observation of significant activity against panels of leukemia, lymphoma and myeloma cell lines, as well as in animal models bearing early and advanced stages of the same cancers. This activity has been associated with the down-regulation of a key oncoprotein (c-myc), and these data are being presented as strong evidence supporting the development of bruceantin as an agent for the treatment of hematological malignancies. Betulinic acid is a lupane-type triterpene which has been isolated from many taxonomically diverse plant genera. A major source is the birch tree, Betula spp. (Betulaceae), which is also a primary source of its C28 alcohol precursor, betulin. It is interesting to note that the isolation of betulin was first reported in 1788. Betulinic acid has been associated with a variety of biological activities, including antibacterial, anti-inflammatory and anti-malarial, but the most important activities have been associated with inhibition of the replication of strains of the human immunodeficiency virus (HIV), and cytotoxicity against a range of cancer cell lines. Significant in vivo activity has been observed in animal models bearing human melanoma xenografts, and the NCI is assisting in the development of systemic and topical formulations of the agent for potential clinical trials.

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Fig (3): Plant-derived anti-tumor agents in preclinical development

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CONCLUSION:Plants have been a prime source of highly effective conventional drugs for the treatment of

many forms of cancer. In many instances, the actual compound isolated from the plant may not serve as the drug, but leads to the development of potential novel agents. With the development of new technologies, some of the agents which failed earlier clinical studies are now stimulating renewed interest [23]. The ability to attach agents to carrier molecules directed to specific tumours holds promise for the effective targeting of highly cytotoxic natural products to tumours while avoiding toxic side effects. With rapid identification of new proteins having significant regulatory effects on tumour cell cycle progression, & their conversion into targets for high throughput screening, molecules isolated from plants are proving to be an important source of novel inhibitors of action of these key proteins & have potential for development into selective anti-cancer agents. Medicinal plants maintain health & vitality of individuals, & also cure various diseases, including cancer without toxicity. The medicinal plants possess good immunomodulatory & antioxidant properties, leading to anticancer activities. Thus, consuming a diet rich in antioxidant plant foods will provide health-protective effects [24]. Natural products discovered from medicinal plants have played an important role in the treatment of cancer. Natural products or natural product derivatives comprised 14 of top 35 drugs in 2000 based on worldwide sales (Butlet, 2004). Two plant derived natural products, paclitaxel & camptothecin were estimated to account for nearly one-third of the global anticancer market or about $3 billion of $9 billion in total annually in 2002 (Oberlines & Kroll, 2004). There are more than 270,000 higher plants existing on this planet. But only a small portion has been explored phytochemically. It is anticipated that plants can provide potential bioactive compounds for the development of new leads to combat cancer diseases.

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REFERENCES:and cancer website, 2006; www.womenshealth.com,www.amazon.com

1. Estrogen

2. American Cancer Society, A biotechnology company dedicated to Cancer

treatment, 3. Anticancer Department

viewed agents of from

on medicinal University

25 plants; of

January Mohammad Dhaka

2006; Shoeb; 1000,

www.cancervax.com/info/index.htm Chemistry, Dhaka,

Bangladesh. [29 November 2006] 4. Anticancer Drug Design Based on Plant-Derived Natural Products; KuoHsiung Lee; Natural Products Laboratory; School of Pharmacy; University of North Carolina; Chapel Hill; N.C; U.S.A. 5. The National Cancer Institute (NCI); Facts and figures, 1999. 6. World Resources Institute; Article: Plant Based Medicinal Drugs 7. Pandey, Govind and Madhuri,S., Medicinal Plants: Better remedy for Neoplasm.; Indian origin Drugs;2006. 8. M. Zhang, C.W. Binns and A.H. Lee; Tea consumption And Ovarian Epidemol.

Cancer Risk. A case Control Study in China. Cancer Biomarkers Rev.11 (2002).

9. S.D. Hsu; B.B. Singh; J B Lewis; J.L. Broke; D .P. Dickinson; et al; Gen. Dent. 50 Chemoprevention of Oral Cancer by Green Tea.2002 10. Kim IH, Takashima S, Hitotsuyanagi Y, et al. New quassinoids, javanicolides C and D and javanicosides B--F, from seeds of brucea javanica. J Nat Prod May 2004;67(5):863-8. 11. Current Status of Herbal Drugs in India: An Overview; Ashok D.B. Vaidya and Thomas P.A. Devasagayam.

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12. USDA, ARS, National Genetic Resources Program. Germplasm Resources Information Network (GRIN) Online Database. National Germplasm Resources Laboratory, Beltsville, Maryland; source url: http://www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?2688

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13. Prajapati, N .D; Purohit. S. S; Sharma, A.K. and Kumar, T., A; Hand book of Medical Plants, Agrobioas (India), 2003, 1st Edition. 14. Boik, J., Cancer and Natural Medicine, Oregon Medical Press, Princeton, MN, 1995. 15. Minyi, Chang, Anticancer Medicinal Herbs; Human Sciences and Technology Publishing House, Changsha, 1992. 16. Archana R, Namasivayam A. Antistressor effect of Withania somnifera. J Ethnopharmacol 1999; 64:913. 17. Ashwagandha: an anti-cancer, anti-arthritis, anti-ulcer 'adaptogen.' by James J. Gormley; Feb, 1996 18. The USP Drug information book; 1998 ed., p.3213 & 3215. 19. "Randomized controlled trial of nettle sting for treatment of base-of-thumb pain". J R Soc Med. 93 (6): 3059. June 2000. PMID 10911825: 10911825. 20."Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB". FEBS Lett. ;(): 442 (1): 8994. 1999-0108. PMID 9923611: 9923611. 21. Salem (2005). "Immunomodulatory and therapeutic properties of the Nigella sativa L. seed". International Immunopharmacology 5 (13-14): 1749 1770.doi:10.1016/j.intimp.2005.06.008. PMID 16275613. 22. Theivaththin Kural, Chandrasekarendra saraswathi sankaracharya,Vol.3,pp737 23. PLANTS AS A SOURCE OF ANTI-CANCER AGENTS;G. M. Cragg and D. J. Newman; Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, , Maryland, U S A. S. Madhuri (1) and Govind Pandey (2); (1) Department of Zoology and Biotechnology, Model Science College, Jabalpur 482 001, India;(2) Rinder Pest (A.H./Veterinary Department, Government of Madhya Pradesh), Jabalpur Division, Jabalpur 482 001, India.
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