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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 expandingcontinuously. 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].
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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
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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.
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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
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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
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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.
Following stages are to be followed in anticancer drug development from plants:-
1. 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.
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Collection and identification of various
plants
Preparation of various plant extracts
Primary screening for anti-tumour activities Large scale collection of active plants and their various partsBioassay directed fractionation to isolate pure active compounds Structural elucidation of the active compound(s) Tumour panel testing Preclinical study (Formulation, Pharmacology and Toxicology) Large scale production for drug development
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FLOW CHART SHOWING STAGES OF DRUG
DEVELOPMENT
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Clinical trails
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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 anti-
tumour 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.
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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 ofin 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.
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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. Immuno-
stimulation 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
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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 chemo-
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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-the-
counter (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
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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 Shakarkandtubers have
potential cancer chemoprotective effect. 4-Ipomeanol (a furanoterpenoid) isolated
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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 ofcancer[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 teahas 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
vitrohuman breast cancer tumours and in vivoanimal 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 didnot.[9]
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http://en.wikipedia.org/wiki/Camellia_sinensishttp://en.wikipedia.org/wiki/Green_teahttp://en.wikipedia.org/wiki/Green_teahttp://en.wikipedia.org/wiki/Antioxidanthttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Kaempferolhttp://en.wikipedia.org/wiki/Catechinshttp://en.wikipedia.org/wiki/Catechinhttp://en.wikipedia.org/wiki/Epicatechin_gallatehttp://en.wikipedia.org/wiki/Epigallocatechin_gallatehttp://en.wikipedia.org/wiki/Oolong_teahttp://en.wikipedia.org/wiki/Black_teahttp://en.wikipedia.org/wiki/Oxidationhttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/White_teahttp://en.wikipedia.org/wiki/White_teahttp://en.wikipedia.org/wiki/Camellia_sinensishttp://en.wikipedia.org/wiki/White_teahttp://en.wikipedia.org/wiki/White_teahttp://en.wikipedia.org/wiki/Tamoxifenhttp://en.wikipedia.org/wiki/In_vitrohttp://en.wikipedia.org/wiki/In_vitrohttp://en.wikipedia.org/wiki/In_vitrohttp://en.wikipedia.org/wiki/In_vivohttp://en.wikipedia.org/wiki/In_vivohttp://en.wikipedia.org/wiki/Health_effects_of_tea#cite_note-5http://en.wikipedia.org/wiki/Taiwanhttp://en.wikipedia.org/wiki/Chung_Shan_Medical_Universityhttp://en.wikipedia.org/wiki/Health_effects_of_tea#cite_note-6http://en.wikipedia.org/wiki/Camellia_sinensishttp://en.wikipedia.org/wiki/Green_teahttp://en.wikipedia.org/wiki/Antioxidanthttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Kaempferolhttp://en.wikipedia.org/wiki/Catechinshttp://en.wikipedia.org/wiki/Catechinhttp://en.wikipedia.org/wiki/Epicatechin_gallatehttp://en.wikipedia.org/wiki/Epigallocatechin_gallatehttp://en.wikipedia.org/wiki/Oolong_teahttp://en.wikipedia.org/wiki/Black_teahttp://en.wikipedia.org/wiki/Oxidationhttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/White_teahttp://en.wikipedia.org/wiki/White_teahttp://en.wikipedia.org/wiki/Camellia_sinensishttp://en.wikipedia.org/wiki/White_teahttp://en.wikipedia.org/wiki/Tamoxifenhttp://en.wikipedia.org/wiki/In_vitrohttp://en.wikipedia.org/wiki/In_vitrohttp://en.wikipedia.org/wiki/In_vivohttp://en.wikipedia.org/wiki/Health_effects_of_tea#cite_note-5http://en.wikipedia.org/wiki/Taiwanhttp://en.wikipedia.org/wiki/Chung_Shan_Medical_Universityhttp://en.wikipedia.org/wiki/Health_effects_of_tea#cite_note-68/2/2019 Sarita Project 27-01-11
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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 :-
Plant Bioactive Principle Action
Alstonia scholaris Alakaloid Tumour regression[3,24]
Azadirachta
indica (Neem)
Alakaloids, Flavonoids Inhibit carcinogenesis, DNA
fragmentation, Decrease in cell
viability[7]
Aspergillus species Jawaharene Antitumour[3]
Asparagus Aspargine,
Asparagoside
Effective in Reducing breast,
pancreatic, & Cervical cancer on mice.
[24]
Brucea javanica Quassinoid
Glycosides
Antitumor to EAC,Walker-256
carcinoma, P-388 [22]
Plant Bioactive Principle Action
Beta vulgaris carotene Antitumour to DLA[3]
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Camellia thea Flavonols Antitumour to EAC
Camellia sinensis. Flavonoids such as
kaempferol & catechins
potential to reduce incidence ofcancerby
Deactivating Enzymes.[8,9]
Citrus limon
(Nibu)
flavonoid, tangeretin,
nobiletin &Limonoids
Inhibitors of tumour cell growth,
activate the detoxifying P450 enzyme
system. Inhibit tumour formation [24]
Ipomoea batatas
(Shakarkand)
caffeoylquinic acid chemo-protective effect[23]
Indigofera
tinctoria
Indirubicin Anticancer activity, Inhibition on
Lewis Lung carcinoma & Walker
carcinoma. [23]
Utrica dioica
(Stinging nettle)
steroids 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
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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 & leukaemia-
16; 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;Pterismultifida
in sarcoma-180, sarcoma-37 and Yoshidas sarcoma;Pygeum africanum
in prostate cancer; Solanum lyratiin 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]:-
Botanical name
of plant with
Parts used and their main
active components
Origin/
native
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their family name place Agave americana
Agavaceae
Leaf contains steroidal saponin, alkaloid,
coumarin, isoflavonoid, hecogenin and
vitamins (A, B, C).
Central
America
Broyonia dioica Root contains glycoside & cucurbitacin Europe
Cannabis sativa
Cannabinaceae
Leaf contains stereo isomers of cannabitrion South Africa
Eupatorium cannabinum
Asteraceae
Whole plant contains Lactone,
Sesquiterpene, pyrrolizidine
Alkaloid and Flavonoid.
Europe, Asia
North America
Galium aparine
Rubiaceae
Cleaver contains iridoid, Tannin,
Polyphenolic acid, anthraquinone
Europe, Africa
Australia
Junchus effuses
Juncaceae
Whole plant contains effusol, juncanol,
phenylpropanoid, -tocopherol and
tridecanone.
China,
Japan, Korea
Lantana camara
Verbenaceae
Whole plant contains various alkaloids
(camerine, isocamerine, micranine lantanine,
lantadene)
Tropical America
Pygeum africanum
Boraginaceae
Bark contains phytosterol,
triterpene and tannin
Africa
Thymus vulgaris
Lamiaceae
Whole plant contains volatile
oil, flavonoid and tannin
South Europe
Phaleria macrocarpa Fruit contains gallic acid Indonesia
Patrinia scabiosaefolia
Vlerianaceae
Whole plant China, Japan,
Korea
Trifolium pratense
FabaceaeFlower contains glucosides (trifolin,
trifolitin, trifolianol), flavonoid and
phenolic acid
Asia, Europe,
Africa, Australia
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,
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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 otherherbs & 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
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http://en.wikipedia.org/wiki/Menthahttp://en.wikipedia.org/wiki/Old_Testamenthttp://en.wikipedia.org/wiki/Mandrakehttp://en.wikipedia.org/wiki/Vetchhttp://en.wikipedia.org/wiki/Wheathttp://en.wikipedia.org/wiki/Barleyhttp://en.wikipedia.org/wiki/Ryehttp://en.wikipedia.org/wiki/Ayurvedahttp://en.wikipedia.org/wiki/Turmerichttp://en.wikipedia.org/wiki/List_of_herbs_and_minerals_in_Ayurvedahttp://en.wikipedia.org/wiki/Charakahttp://en.wikipedia.org/wiki/Sushrutahttp://en.wikipedia.org/wiki/1st_millennium_BChttp://en.wikipedia.org/wiki/Sushruta_Samhitahttp://en.wikipedia.org/wiki/Tamil_Naduhttp://en.wikipedia.org/wiki/#cite_note-68http://en.wikipedia.org/wiki/Menthahttp://en.wikipedia.org/wiki/Old_Testamenthttp://en.wikipedia.org/wiki/Mandrakehttp://en.wikipedia.org/wiki/Vetchhttp://en.wikipedia.org/wiki/Wheathttp://en.wikipedia.org/wiki/Barleyhttp://en.wikipedia.org/wiki/Ryehttp://en.wikipedia.org/wiki/Ayurvedahttp://en.wikipedia.org/wiki/Turmerichttp://en.wikipedia.org/wiki/List_of_herbs_and_minerals_in_Ayurvedahttp://en.wikipedia.org/wiki/Charakahttp://en.wikipedia.org/wiki/Sushrutahttp://en.wikipedia.org/wiki/1st_millennium_BChttp://en.wikipedia.org/wiki/Sushruta_Samhitahttp://en.wikipedia.org/wiki/Tamil_Naduhttp://en.wikipedia.org/wiki/#cite_note-688/2/2019 Sarita Project 27-01-11
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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 tumour-
inhibitory 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 i-
Extract. 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 JTC-
26 (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
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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 Carolinaat 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 cuminhas demonstrated analgesic properties in mice.
The mechanism for this effect is unclear. In vitro studies support antimicrobial, anticancer, anti-
inflammatory & immune modulating effects. [24]However few randomized double blind studies
have been published.
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. [23]In
another rodent study it reduced platelet aggregation.[23]
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
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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:-
Botanical name
(with
common Name)
Family Main active
components
PlantPart
s Used
Acrorus calamus
(bach)
Araceae Asarone, eugenol, methyl eugenol,
palmitic acid & champhene
Rhizome
Agrimonia Pilosa
(Hairy agrimony)
Rosaceae Argimonolide, flavonoid,
Tannin, Triterpene and Coumarin.
Whole plant
Azadiracbta indica
(Neem)
Meliaceae Alkaloid and insolitol[7] Bark, leaf
and Flower
Camellia sinesis Theaceae Chrysophanol, isochrysophanol, Leaf
Botanical name
(with
common Name)
Family Main active
components
PlantPart
s Used
(GreenTea, black tea) rhein & - sitosterol[8,9]
Cassia absus
(Chaksu)
Caesaliniaceae Hydrocyanic acid, delphinidin
& Cyaniding
Leaf
Citrus limon
(Nibu)
Rutaceae Resin plant contains
essential oil, coumarins
(ellagic acid derivatives)
Fruit
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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 clinically-
active 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 ofC. 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 antioxidantplant 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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