anil project

8/7/2019 anil project

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Chapter 1

INTRODUCTION


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Herbal treatment of cancer

Cancer is insidious and non-communicable disease affecting mankind in every

country of the world1.

Chronic diseases such as cancer and other non-communicable diseases are fast

replacing communicable diseases in India and other developing countries, We deal

here with the epidemiology of cancer, its control and prevention measures and

applicable to Indian situation.

The main objective of epidemiological study of cancer is to collect, collate,

analyze and interpret data on cancer incidence, mortality and survival worldwide.

These data provide the background for studies of cancer epidemiology andprevention. The study supports and coordinates cancer registration throughout the

world. Collaboration is most active with registries in developing countries, where the

problems caused by cancer are poorly defined, and includes field studies to elucidate

the causes of cancers that are important locally. Cancer Prevention activities in

particularly, early detection and screening programmes and chemoprevention are also

evaluated.

The main forms of treatment for cancer in humans are surgery, radiation and

drugs (cancer chemotherapeutic agents). Cancer chemotherapeutic agents can often

provide temporary relief of symptoms, the prolongation of life, and occasionally

cures. In recent years, a lot of effort has been applied to the synthesis of potential

anticancer drugs. Many hundreds of chemical variants of known classes of cancer

chemotherapeutic agents have been synthesized. A large proportion of these has

arisen from the discovery in 1940s of the antileukaemic properties of the chemical

warfare agents, the nitrogen mustards. The activity of these compounds is ascribed to

their capacity for biological alkylation. However, the effective dose of such alkylating

agents was almost the same as the toxic dose, a fact attributed to the lack of selectivity

of the agent. These simple alkylating agents are highly reactive and this leads to

indiscriminate reactions with a wide range of cell constituents. A successful

anticancer drug should kill or incapacitate cancer cells without causing excessive

damage to normal cells. This is difficult, or perhaps impossible, to attain, and is why

cancer patients frequently suffer unpleasant side-effects when undergoing treatment.

Maharshi arvind institute of pharmacy , Jaipur 2


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Synthesis of modifications of known drugs continues as an important aspect of

research. However, a vast amount of synthetic work has given relatively small

improvements over the prototype drugs. There is a continued need for new prototypes,

new templates to use in the design of potential chemotherapeutic agents; natural

products are providing such templates. Recent studies of tumour-inhibiting

compounds of plant origin have yielded an impressive array of novel structures. Many

of these structures are extremely complex, and it is most unlikely that such

compounds would have been synthesized in empirical approaches to new drugs.



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Chapter 2

CANCER : Causes & Mechanisms



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Cancer is a general term of a series of neoplastic disease (New plasma formation)

which are characterized by changes in cell leading to their abnormal self

proliferation.

2.1 Cancer & its types

Cancer is a tissue illness that consists of an excessive and disorderly cellular division.

Cancers cells are not under cell-cycle controls and they do not grow as normal cell.

They tend to invade other tissues (metastasis). Cancer cells destroy the invaded

healthy tissues, mainly when they provoke an increased need for nutrients in the tissue

where they are growing. As the abnormal cells have not control on their metabolic

functions, they can divide quickly and get the nutrients from the media before the

normal cells. In the competence, cancers cells always are the winners. When normal

cells die, the cancers cells feed with the wastes of the dead cell.

Broadly neoplastic diseases can be divided into two categories.

Benign Tumor: - Tumors, which do not metastasize.

Malignant Tumors:- Tumors which metastasize (Metastasis:- It is a secondary

growth originating from the primary tumor and growing else where in the body).

The medical term for Cancer or tumor is neoplasm, which means a relatively

autonomous growth of tissue.

A Cancerous tumor is a malignant neoplasm with potential danger.

Some tumors are named after the individual who first described the condition,

such as Ewings tumor of bone, Pagels disease and Hodgkins disease.

Some are named after the tissue of origin, such as papillary, cystic, or

follicular tumors. The suffix-oma literally means tumor, and word with this suffix

refer to neoplasm Exceptions are, granuloma is growth of inflammatory tissue &

hematoma is a mass of blood within a tissue but outside the blood vessels.

Benign Tumors are named with a prefix that refers to the tissue from which

they arose and the suffix-oma. A benign tumor of fibrous tissue is called a fibroma of



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cartilage, a chondroma and of glandular tissue, an adenoma. Exception is lymphoma,

i.e., a tumor of lymph tissue that may be malignant and dangerous.

According to embryologic origin cancers are divided into two general

categories.

1) Sarcoma

2) Carcinoma

In the early embryo of a multicellular organisms there are three layers,

Ectoderm, Mesoderm, Endoderm.

Mesodermal cells form bone, muscle, cartilage and related tissues. A cancer

that arises from Mesodermal tissue is called a sarcoma. Ectodermal cells form skin, its

appendages and nerve tissue. Endodermal cells form the intestinal system and its

associated organs. A cancer that arises from Ecto/Endodermal cells is called

a.carcinoma.

A highly malignant tumor with the appearance of both a carcinoma and a

sarcoma is termed a carcinosarcoma to indicate derivation from two embryonic layers.

Tumor derived from three all these layers, is called teratoma, and may be

benign or malignant.

Blastoma :- The suffix, blastoma is used to certain types of tumors that have a

primitive appearance resembling embryonic structures.

e.g. Neuroblastoma, Myloblastoma.

Cancers of blood: - A cancer of the blood involving abnormal increase ofleukocytes is called leukemia.

Normal count :- 7500/ mm3

Abnormal count ;- 105-106/ mm3

2.2 Causes of Cancer

Many factors are implicated in the induction of cancer. These factors may include:

Exposure to the carcinogenic hydrocarbons or to excessive radiation



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The hereditary factors involved in the caution of cancer include

chromosomal abnormality, enzymes, immune defense system and

hormonal imbalances, e.g. the susceptibility to the lung cancer is

associated with high inducible levels of the enzymes, aryl hydrocarboxy

hydroxylase.

Occupational factors like, ionsing radiation, chemicals and other

carcinogenic substances play an important role. For example coal tar,

mustard gas, chromium, Nickel and asbestos can trigger lung cancer in

employees working in chemical, insulation and gas factories.

Viruses also cause cancer:- e.g. Human T-lymphotropic virus type-I

(HTLV-1) has been proven to cause a form of leukemia.

Culture factors:- These factors play a dominant role by causing about

70% of all cancers. Such important cultural factors include diet,

smoking, drinking and sexual habits.

2.3 Cell Cycle Kinetics

During cell-cycle, each cell divides into two daughter cells having identical genetic

material. Each of these cell may immediately reenter a new cell-cycle or pass into a

non-proliferative resting state. The growth and division of cells can be defined into

four prominent phases of cell-cycle.

These include:-

1) S Phase: - This phase is a phase of DNA Synthesis. In human tumors,

it is approximately of 10-20 hours.

2) G2 phase: - This period last for 1 to 3 hours during which the cell is

made ready for mitosis. In this phase the cells contain a tetraploid number of

chromosomes. This phase is followed by mitosis.

3) M-phase: - It is a phase of mitosis that involves chromo-somal

condensation, spindle formation and cell division. It lasts for approximately one hour.



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The resulting two daughter cells may either immediately enter into G1-phase (Post

mitotic rest) or pass into a non-proliferative resting phase (G0-phase).

Since proliferating cells are usually more sensitive to chemotherapy, the cells

in G0- phase are least affected by chemotherapeutic agent.

The cells readily pass into G0-phase if they are far away from the blood

vessels through which nutrients as supplied. The growth of a tumor usually follows

exponential pattern, that is growth occurs initially at much higher rate which is then

followed by plateau region. The decrease in the growth rate with increasing tumor

size may be correlated with an increase in the rate of cell loss due to hypoxic necrosis,immunological defense mechanism and poor nutrient supply. Since proliferating cells

are generally more sensitive to chemotherapy, smaller tumors (i.e. tumors with high

growth rate) will be more sensitive to chemotherapy than the large solid tumors (i.e.

tumors with slow growth rate).

S phase phase of DNA synthesis

M phase phase of Mitosis

G1 phase phase of Post-mitotic rest

G2 phase phase of post-synthetic rest

G0 phase Non- proliferating phase.



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Chapter 3

Herbal treatment of Cancer



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3.1 Vinca

Botanical name: Catharanthus roseus

Family - Apocynaceae

Catharanthus roseus

Habitat-

Vinblastine and vincristine are alkaloids found in the Madagascar periwinkle, it is

commonly available at the northern region as well as South African region and

Cultivated as an ornamental plant in southern Florida, Africa, India, Thailand

Eastern Europe and Australia.

Characteristics-

Catharanthus is an erect everblooming, pubescent Herb or sunshrub, 40-80 cm high

woody at the base. The flowers are axillary, violet, rose or white or white with red

Eyes 4-5 cm in diameter. The fruit is a divergent follicle, it has Slight odour and taste

is bitter.



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Mechanism of action -

Vincristine, vinblastine & their semi synthetic derivatives work by inhibiting mitosis

(cell division) inmetaphase. These alkaloids bind to tubulin, thus preventing the cell

from making the spindles which are needed to be able to move its chromosomes

around as it divides. These alkaloids also seem to interfere with cells' ability to

synthesize DNA and RNA. They are all administered intravenously in their sulfate

form once a week. These solutions are fatal if they're administered any other way, and

can cause a lot of tissue irritation if they leak out of the vein. Although these three

compounds are very similar in structure and have the same basic action, they have

distinctly different effects on the body.

Chemical constituents-

Vinblastineor vincristine or vindensine are the most important chemical constitute of

vinca alkaloids.

3.1.1 Vinblastine

Vinblastine is typically

administered at a dose of 6

milligrams per square meter

of body surface. It's marketed as

Velban by Eli Lilly and has a half-

life in the bloodstream of 24 hours. Vinblastine is mainly useful for treating

Hodgkin's disease, lymphocytic lymphoma, histiocytic lymphoma, advanced

testicular cancer, advanced breast cancer, Kaposi's sarcoma and Letterer-Siwe

disease. It also seems to fight cancer by interfering with glutamic acid metabolism

(specifically, the pathways leading from glutamic acid to the Krebs cycle and to urea

formation). People with bacterial infections should not be given this drug, nor should

pregnant women, since it caused severe birth defects in animal studies. Side effects

include hair loss, nausea, lowered blood cell counts, headache, stomach pain,

http://biotech.icmb.utexas.edu/search/dict-search.phtml?title=mitosishttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=metaphasehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=metaphasehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=metaphasehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=tubulinhttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=spindlehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=dnahttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=rnahttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=rnahttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=metaphasehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=tubulinhttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=spindlehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=dnahttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=rnahttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=mitosis


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numbness, constipation and mouth sores. Bone marrow damage is the typical dose-

limiting factor.

3.1.2 Vincristine

Vincristine, which is marketed as Oncovin by Eli Lilly, has a serum half-life of about

85 hours. It's used mainly to treat acute leukemia, rhabdomyosarcoma,

neuroblastoma, Hodgkin's disease and other lymphomas. The typical dose in 1.4

milligrams per square meter of body surface once a week, and neurotoxicity is the

dose limiting factor (it can cause damage to the peripheral nervous system). Because

of this, people with neuromuscular disorders should steer clear of this drug if possible.

Likewise, people with some forms of Charcot-Marie-Tooth syndrome should avoid

vincristine. Pregnant women should definitely not take it, because it causes severe

birth defects in animal tests. Side effects include those found with vinblastine, plus

nervous system problems such as sensory impairment. Some people may also develop

breathing problems or lung spasms shortly after the drug is administered. People

occasionally develop secondary cancers if they receive the drug along with other

anticancer drugs that are known to be carcinogens.



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3.1.3 Vindesine

Vindesine has a serum half-

life of about 24 hours and is

administered at a dose of 3

milligrams per square meter

of body surface. Its

toxicity and side effects are

similar to those of

vinblastine. Vindesine, which is marketed under the names Eldisine and Fildesin, is

used mainly to treat melanoma and lung cancers (carcinomas) and, with other drugs,

to treat uterine cancers.

3.1.4 Other

Vinorelbine is currently in Phase II clinical trials as a treatment for ovarian cancer. It

will be marketed as Navelbine by Glaxo, Welcome, Inc., if the trials are successful

and the FDA approves the drug. Thus far, vinorelbine seems to have a wider range of

antitumor activity than the other vinca alkaloids. In preclinical trials, it showed

promise in treating patients with epithelial ovarian cancers and, in combination with

the chemotherapy drug cisplatin, in treating patients with non-small-cell lung cancers.

The side effects of this drug include diarrhea, nausea and hair loss. It has less sideeffect on nerve cells than vindesine.

Uses:-

1. Vinblastine is mainly useful for treating Hodgkin's disease, lymphocytic

lymphoma, histiocytic lymphoma, advanced testicular cancer, advanced breast

cancer, Kaposi's sarcoma, and Letterer-Siwe disease.



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2. It is used mainly to treat acute leukemia, rhabdomyosarcoma, neuroblastoma,

Hodgkin's disease and other lymphomas.

3 Vindesine, which is marketed under the names Eldisine and Fildesin, is used

mainly to treat melanoma and lung cancers (carcinomas) and, with other drugs

to treat uterine cancers.

3.2 Taxus brevifolia and Texol

Botanical name: - Taxus brevifolia

Family : - Taxaceae



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Habitat:-

It is commonly available at the northern region as well South Africa and India

Europe, Australia.

Characteristics:-Taxus brevifolia is an erect driedbark and seeds of 20-40 cm in height & woody at the

base. The leaf of pacific yew is axillary violet and white. It has slight odour and taste

is bitter.

Mechanism of action: -

Paclitaxel and docetaxel are taxoid drugs extracted from the bark of the Pacific yew

and the needles of the English yew, respectively. Both work against cancer by

interfering with mitosis, but they each do it a little differently.

Paclitaxel, which is sold as Taxol by Bristol-Myers Squibb, binds to

microtubules and inhibits their depolymerization (molecular disassembly) into

tubulin. This means that paclitaxel blocks a cell's ability to break down the mitotic

spindle during mitosis (cell division). With the spindle still in place the cell can't

divide into daughter cells (this is in contrast to drugs like colchicine and the Vinca



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alkaloids, which block mitosis by keeping the spindle from being formed in the first

place).

Chemical constituents: -

1. Paclitaxel

2. Docetaxel



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Uses:-

1. Paclitaxel is given intravenously (it irritates skin and mucous membranes on

contact), and is most effective against ovarian carcinomas and advanced breast

carcinomas. Slightly less than half of the patients receiving paclitaxel during clinical

trials developed an allergic reaction.

2. Docetaxel, which is also given intravenously, is being tested on carcinomas of the

bladder, cervix, lung, and ovaries, on malignant melanoma, and on non-Hodgkin's

lymphoma.

3.3 Podophyllum and Podophyllum Resin

Botanical name: -Podophyllum peltatum

Family - Podophyllaceae



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Habitat:-

Normally it is not available in the as usual way yet it is found in the African region &

also in eastern parts of Canada and the U.S.A.

Characteristics:-

Podophyllum occurs in subcylindrical reddish brown Piece, length 5-20 cm breadth 5-

6 mm. The nodes are elongated stem scars are present on the upper surface while on

the lower side of each node 5-12 root scars or root portions exists.

Mechanism of action:-

Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin and are

increasingly used in cancer medicine. Teniposide is more highly protein-bound than

etoposide, and its uptake and binding to cells is also greater. Etoposide and teniposide

are phase-specific cytotoxic drugs acting in the late S and early G2 phases of the cell

cycle. They appear to act by causing breaks in DNA via an interaction with DNA

topoisomerase II or by the formation of free radicals. Teniposide is more potent as

regards the production of DNA damage and cytotoxicity.

Etoposide and teniposide both block the cell cycle in two specific places. They

block the phase between the last division and the start of DNA replication (the G1

phase) and they block the replication of DNA (the S phase). However, researchers

don't have a very good understanding of how the compounds do this.

Chemical constitute: Etoposide and teniposide are semi synthetic derivatives of

podophyllotoxin.

Uses:-



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1. Etoposide (which is sold by Bristol-Myers Squibb as VePesid, aka VP-16) is

administered intravenously or orally as liquid capsules. It is used mainly to treat

testicular cancer which hasn't responded to other treatment and as first-line

treatment for small-cell lung cancers. It is also used to treat chorionic carcinomas

Kaposis sarcoma, lymphomas and malignant melanomas.

2. Teniposide is used less often than etoposide mainly, it is used to treat

lymphomas.



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3.4 Colchicines:-

Botanical name:- Colchicum antumnale

Family : - Liliaceae

Habitat -

The plant is an annul herb found in England, Poland, U.S.A.

Characteristics:-

Seeds are ovoid or globular in shape and 23 mm in diameter. The fresh corn is

conical in shape, 4cm wide, side of the corn is convex and opposite is flat. Dried cornconsists of transverse or longitudinal slices which are 3 cm Long and 2-5 mm thick.


Blocks or suppresses cell division by inhibiting mitosis, the division of a cell's

nucleus.

Specifically, it inhibits the development of spindles as the nuclei are dividing.

Normally, the cell would use its spindle fibers to line up its chromosomes, make a

http://biotech.icmb.utexas.edu/search/dict-search.phtml?title=mitosishttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=nucleushttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=spindlehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=chromosomehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=mitosishttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=nucleushttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=spindlehttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=chromosome


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copy of them, and divide into two new cells with each daughter cell having a single

set of chromosomes. With colchicine present, the spindle fibers don't form, and so the

cell can't move its chromosomes around. The cell may end up copying some or all of

the chromosomes anyway, but can't parcel them out into new cells, and so it never

divides.

Because cancercells divide much more rapidly than normal cells, cancers are

more susceptible to being poisoned by mitotic inhibitors such as colchicine,

paclitaxel, and the Vinca alkaloids.

Chemical constituent:

USES:-

Colchicine can cause a temporary reduction in the number of leukocytes (white blood

cells) in the bloodstream. Afterward, the leukocyte count can rebound to abnormallyhigh levels. Colchicine also causes teratogenic birth defects in lab animals, and so

pregnant women with gout should not use colchicine-containing drugs.

New thiocolchicine derivatives were designated as toxic anticancer agent

possessing the power full anticancer activity of colchicines.

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2.5 Bitter apple (Colocynth)

Botanical name: - Citrulius colocynthis

Family : - Cucurbitaceae

Habitat:-

The plant occurs in Syria, Cypris, Sudan, north Africa, Turkey, Spain and widely

throughout India.

Characteristics:-

The fruit is almost a globular berry, 4-10 cm in diameter. The peeled fruits are 4-8 cmin diameter, the pulp is light pithy and spongy, easily broken white or light yellow In

color, fruit is odorless and taste is very bitter.

Chemical constituents:-

Ether, chloroform soluble resin cucurbitin and alpha elatrin and glycoside compound

colocynthine.



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Uses:-

It is used in antitumor activity, necrotic activity and powerful cathrotic.

3.6 Lapacho Tree

Botanical name - Tabebuia avellanedae

Family - Bignoniaceae

Habitat: -

Southern Asia, West India, China, Africa, India & cultivated countries.

Characteristics:-

The plant is a glabrous, succulent, perennial herb bearing 2-8 cm and 1-2 cm thick.

The odour is very marked in the fresh drug and become faint alter words

taste is slightly bitter.



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Camptothecin and topotecan, -lapachone inhibits DNA topoisomerase. Researchers

have found that this compound has promising anticancer and antiviral properties.

Topoisomerase inhibitors, including beta-lapachone, seem to be effective

against several types of cancer, including lung, breast, colon and prostate cancers and

malignant melanoma. The use of beta-lapachone in humans has been limited due to its

toxicity. Beta-lapachone works by disrupting DNA replication. Topoisomerase I is an

enzyme that unwinds the DNA that makes up the chromosomes. The chromosomes

must be unwound in order for the cell to use the genetic information to synthesize

proteins, beta-lapachone keeps the chromosomes wound tight, and so the cell can't

make proteins. As a result, the cell stops growing. Because cancer cells grow and

reproduce at a much faster rate than normal cells, they are more vulnerable to

topoisomerase inhibition than are normal cells. Beta-lapachone also interferes with

the replication of HIV-1, a virus that causes AIDS, thereby slowing the advancement

of the disease.

Uses:-

It is used as anticancer and antiviral.

3.7 Turmeric

Botanical name -Curcuma longa

Family - Zingiberaceae

http://biotech.icmb.utexas.edu/search/dict-search.phtml?title=enzyme&search_type=beghttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=protein&search_type=beghttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=enzyme&search_type=beghttp://biotech.icmb.utexas.edu/search/dict-search.phtml?title=protein&search_type=beg


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circumvent the process, but curcumin can override them and send "self-destruct"

signals to many different types of cancer cells. Curcumin does not induce apoptosis of

healthy cells, only cancerous ones. It identifies cancer cells by their abnormal

chemistry.

Before apoptosis is induced, curcumin stops cancer cells from multiplying. In

cancer research, this is known as "interrupting the cell cycle." The cell cycle can be

interrupted at several different points. This is the rationale behind using various

chemotherapy treatments in one person. One drug stops the cells when they are in one

stage of growth, another stops them at another stage. Using a variety of drugs thatstop growth at different stages increases the chances of killing all the cancer cells.

Curcumin arrests the growth of cancer cells in the G2 stage.

Other phytochemicals stop the cell cycle at other stages. Genistein, a soy

phytochemical, arrests growth at G2, like curcumin. But epigallocatechin-3-gallate

(EGCG) from green tea, arrests cancer cell growth at the G1 phase. Combining

EGCG with curcumin increases the odds of killing more cells. Researchers at Sloan-

Kettering Cancer Center have suggested that EGCG and curcumin be used together

for cancer prevention

MECHANISM OF ACTION

The mechanism of action is not fully understood. Turmeric has anti-inflammatory and

choleretic action. Anti-inflammatory action may be due to leukotriene inhibition. Its

curcuminoids (curcumin) and volatile oil are both partly responsible for the anti-

inflammatory activity. Curcuminoids induce glutathione S-transferase and are potentinhibitors of cytochrome P450. Turmeric acts as a free radical scavenger and

antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. In vitro and

animal models of breast cancer show turmeric may inhibit chemotherapy-induced

apoptosis via inhibition of the JNK pathway and reactive oxygen species generation.

The isolated constituent alpha r-turmerone has been shown to arrest the reproduction

and slaughterer activity of human lymphocytes, which may contribute to its anti-

inflammatory action. Curcumin is more effective by parenteral injection than by oral



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ingestion. Curcumin has displayed antitumor activity and may be protective against

some cancers, such as colon cancer. In laboratory tests, curcumins antitumor actions

appear to be due to interactions with arachidonate metabolism and its in vivo

antiangiogenic properties.

Uses :-

It is used as anticancer.

3.8 Betula alba

Betulinic acid is a pentacyclic triterpene. It has several botanical sources, but can also

be chemically derived from betulin, a substance found in abundance in the outer bark

of white birch trees (Betula alba). Betulinic acid has been found to selectively kill

human melanoma cells while leaving healthy cells alive. For the past four decades,

the incidence of melanoma has been increasing at a higher rate than any other type of

cancer.

The cytotoxic potential of betulinic acid was tested using three human

melanoma cell lines, MEL-1, -2, -3, and -4. The growth of all of the cell lines was

inhibited significantly by treatment with betulinic acid. The effectiveness of betulinic

acid against melanoma cancer cells was also tested using athymic (nude) mice. The

mice were injected with human melanoma cells, and tumor size was observed for 40

days following injections of betulinic acid. The betulinic acid seemed to effectively

inhibit the growth of tumors in the mice, and the mice did not suffer from drug

toxicity side effects, such as weight loss.

Betulinic acid seems to work by inducing apoptosis (programmed cell death)

in cancer cells. Due to its apparent specificity for melanoma cells, betulinic acidseems to be a more promising anti-cancer substance than drugs like Taxol because

Taxol seems to be a more general cell poison and is not specific to cancer cells. In

fact, the specificity of betulinic acid for melanoma cells is unique in comparison to

the specificity of a number of chemotherapy drugs, including camptothecin,

ellipticine, mithramycin A, etoposide, vinblastine, and vincristine.



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3.9 Solanum Indicum

Solamargine, an herbal and molluscicidal medicine derived from Solanum incanum, is

a steroidal alkaloid glycoside. To characterize the anticancer mechanism of

solamargine on human hepatoma cells (Hep3B), changes of cell morphology, DNA

content, and gene, expression of cells after solamargine treatment were studied. The

appearance in solamargine-treated cells of chromatin condensation, DNA

fragmentation, and a sub-G peak in a DNA histogram suggests that solamargine

induces cell death by apoptosis. The maximum number of dead Hep3B cells was

detected within 2 hr of incubation with constant concentrations of solamargine, and

no further cell death was observed after an extended incubation with solamargine,

indicating that the action of solamargine was irreversible. To determine the

susceptibility of cell phases to solamargine-mediated apoptosis, Hep3B cells were

synchronized at defined cell cycles by cyclosporin A, colchicine, and genistein,

followed by solamargine treatment. The IC(50) values of solamargine for control,

G(0)/G(1)-, M-, and G(2)/M-synchronized Hep3B cells were 5.0, > 10, 3.7, and 3.1

microg/mL, implying that cells in the G(2)/M phases are relatively susceptible tosolamargine-mediated apoptosis. In addition, a parallel up-regulation of tumor

necrosis factor receptor (TNFR)-I and -II on Hep3B cells was detected after

solamargine treatment, and the solamargine-mediated cytotoxicity could be

neutralized with either TNFR-I or -II specific antibody. Therefore, these results reveal

that the actions of TNFR-I and -II on Hep3B cells may be independent, and both are

involved in the mechanism of solamargine-mediated apoptosis.



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3.10 Opium alkaloid

An alkaloid from opium noscapine is used as an antitussive drug and has low toxicity

in human and mice. But noscapine binds stochiometrically to tubulin alter its

conformation affects microtubules assembly, and arrest mammalian cells in mitosis.

Furthermore noscapine causes apoptosis in many cell types and has potent antitumor

activity against solid marine lymphoid tumer and against human breast cancer and

bladder tumor implemented in nude mice. Because noscapine is water soluble and

absorbed after oral administration,

3.11 Green tea

Moderate consumption of green tea appears safe. There is a some evidences that green

tea may prevent the occurrence of some form of cancer, but the mechanism of action

of its specific constituents are poorly understood.

Green tea is obtained from buds of shrubs camellia sinensis. Drinking one cup

of green tea per weak appear to reduces the risk of stomach cancer green tea contain

many polyphenol known as catechins including epigallocathecin-3gallate(EGCG),

epigallocathecin(ECG) and epicathechin-3 gallate(ECG) advocate claims used in

cancer treatment. Invitro studies of green tea poly phenol induced programmed cell

death in cancer cell.

Human cancer cells need proteolytics engymes to invades cell and for

metastates. one of these engyme is urokinase(uPA) inhibition of uPA can decease

tumour size or even cause complete remission of cancer in mice. We postulated that

the well known anticancer activity of green tea is driven by inhibition of uPA, one of

the most frequently over expressed enzyme in human cancer.

Recent studies suggested that theanine (a peculiar amino acid) enhances the

anti tumour activity of doxorubicin and adriamycin in mice.



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Chapter 4

New natural products with

antitumour activity



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The systematic studies have also resulted in the isolation of many new natural

products exhibiting antitumour activity, and a number of these have been considered

sufficiently active for clinical studies to be commenced. Tylocrebine, a

phenanthroindolizidine alkaloid from Tylophora crebiflora was sufficiently active for

further development, but in a clinical trial unmanageable CNS effects precluded

continuation of the studies. Two bis-benzylisoquinoline alkaloids, thalicarpine from

Thalictrum dasycarpum and tetrandrine from Cyclea peltata appeared particularly

promising and were selected for development. Clinical trials showed no antitumour

activity, and these compounds have been dropped from further study. Once again,

these are examples of compounds isolated because the screens employed at that time

were too sensitive. On the other hand, tetrandrine is currently of interest for its ability

to block calcium channels, and may yet have applications in the treatment of

cardiovascular disorders. Camptothecin and derivatives, alkaloids from the Chinese

tree Camptotheca acuminata, showed broad-spectrum activity and produced a fair

response in limited clinical trials, but toxicity and poor solubility were problems. The

natural 10-hydroxycamptothecin is more active than camptothecin, and is used in

China against cancers of the neck and head. Synthetic analogues 9-

aminocamptothecin and particularly the water-soluble derivatives. topotecan and

irinotecan showed good responses in a number of cancers. Topotecan and irinotecan

are now available for the treatment of ovarian cancer and colorectal cancer,

respectively. irinotecan is a carbamate por-drug of 10-hydroxy 7-ethylcamptothecin

and is converted into the active drug by liver enzymes.

Brucea antidysentericais used in Ethiopia in the treatment of cancer, and systematic

fractionation of this plant has led to the isolation of bruceantin, which shows highantileukaemic activity at low dosages, and over a wide dose

range. Bruceantin acts through inhibition of protein synthesis, and has undergone

clinical trials in man.

Maytenus serrata (Celastraceae) and other species of Maytenus contain maytansine,

an ansa macrolide, which was regarded as an antitumour agent of exceptional



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promise. It is active against several of the experimental neoplasms at very low dosage

(micrograms per kilograms of animal body weight) over a 50- to 100-fold dosage

range, and shows a favorable therapeutic index. It acts through inhibition of mitosis.

In clinical trials, maytansine was a big disappointment, and showed few beneficial

effects. Synthetic or semi-synthetic derivatives may offer more hope. Other

maytansine was chosen for study simply because of its relatively higher concentration

in the plants.

Several other natural products have also proved sufficiently interesting to

justify clinical trails, or toxicological testing prior to further study. The diterpenes

triptolide and tripdiolide isolated from Tripterygium wilfordii are potent

antileukaemic agents that contain a reactive triepoxide system. The plant is not readily

accessible and contains only small amounts of these compounds.

Of many sesquiterpene lactones tested, few show useful in vivo antitumour

activity, but several of the best in vivo active compounds, e.g. the germanacrolide

elephantopin from Elephantopus elatus, have been evaluated.

Chinese researchers have reported favourable results in clinical studies using

alkaloidal fractions ofC.harringtonia, and homoharringtonine in particular is active in

patients with leukaemia resistant to existing chemotherapies. Homoharringtonine is

only a minor constituent in Cephalotaxus, but can be obtained by semi-synthesis from

the more abundant cephalotaxine. Tissue cultures of Cephalotaxus also synthesize

cephalotaxine and the active esters and may offer potential access to these alkaloids in

useful quantities. The Central American tree Phyllanthus cuminatus contains in its

roots a complex mixture of glycosides, two of which, phyllanthostatin 1 and

phyllanthoside is in early clinical trials. The cis-stilbene combretsatatin A-4 is one ofthe most potent antimitotic agents from about 20 active substances isolated from the

African tree Combretum caffrum. A water-soluble phosphate pro-drug is now in

clinical development.

A series of novel alkaloidal esters fro Cephalotaxus species are currently being

isolated on a large scale for toxicological studies preliminary to clinical trails. The

parent alkaloid cephalotaxine is inactive, but the esters harringtonine and

homoharringtonine from C. harringtonia show good activity in a number of systems.



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Chapter 5

Future Developments



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The search for new antitumour compounds in nature is by no means confined to

plants. Microorganisms, widely employed as sources of antibiotics produce a

considerable number of metabolites having antitumour activity. Many of these also

have antibiotic properties. Amongst materials in general use against cancers are

dactinomycin (actinomycinD), bleomycin, doxorubicin (adriamycin), daunorubicin,

mithramycin and mitomycin C. Microorganisms have particular advantages over

plants as far as ease of culture and the opportunity for genetic manipulation are

concerned. The recent identification of epothilones from the bacterium Sorangium

cellulosum has thus generated considerable interest, since these agents mimic the

effects of taxol, and some analogues are much more potent than taxol, especially

towards multidrug-resistant cell lines. marine animals, e.g. corals and starfish, may

also be a fruitful source of potentially useful anticancer agents and this area of

research is also producing a number of natural products with antitumour activity.

Compounds of particular note are the depsipeptide didemnin B, isolated from the

Caribbean sea-squirt Trididemnum solidum, the bryostatins, a group of macrocyclic

lactones from the marine bryozoan Bugula neritina, and dolastation 10, a linear

peptide from the sea hare, Dolabella auricularia. Didemnin B shows activity against

several human cancers (including prostate, lung and brain cancers and lymkinase C

which mediates growth of cancer cells. Dolastation 10 is a very potent inhibitor of

microtubule assembly, and synthetic material is now available for testing. All three

compounds are in clinical trails.

However, despite the success of the screening programmes in identifying

cytotoxic and antitumour agents, there is some measure of disappointment at the small

number of clinical agents produced. This has caused the NCI to rethink its futurepolicy.

The major success area for anticancer drugs in general is against rapidly

proliferating tumours and there are now effective treatments for cancers such as

childhood leukaemias, testicular tumours and non-Hodgkin's lymphoma that formerly

were soon fatal. Adult solid tumours such as lung, breast and colon tumours still

respond poorly to chemotherapy. There are large differences amongst tumour types in

heterogeneity, accessibility, size and diffuseness, as well as growth rate, and these



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lead to significant differences in sensitivity to drugs. It is highly unlikely that broad-

spectrum anticancer drugs will actually be found. Of necessity, the assay methods

used in the NCI screens had to be fairly rapid to cope with the large throughput of

samples, and consequently rapidly-dividing tumour lines were employed. Thus, the

antitumour agents detected were those effective against fast-growing tumours and it is

not surprising then that they have little activity against slow-growing tumours in

human studies. In addition, these slow-growing tumours grow and divide more slowly

than rapidly proliferating normal human tissues such as bone marrow and

gastrointestinal epithelium. These tissues thus suffer toxic effects from the

administered drug, and the major side-effects of cancer chemotherapy, bone marrow

repression plus nausea and vomiting, tend to limit the dosage tolerated by the patient.

There is obviously a need for more specificity, and ideally the drug should

selectively and specifically affect tumour tissue without damaging any normal tissue.

If drugs can be targeted to specific organs, or alternatively, if they are specifically

bioactivated only in the target organ, then more effective and better tolerated

treatments will result. A natural product of high interest the the NCI is 4-ipomeanol, a

toxin isolated from mould-infected sweet potatoes (Ipomoea batatas) which, when

ingested, affects the lungs and kidneys of mammals. 4-Ipomeanol is selectively

oxidized by enzymes in certain lung cells to give a reactive dialdehyde, and this

provides a powerful alkylating agent only in those cells containing the enzyme

system. 4-Ipomeanol is undergoing clinical trails against lung cancers. There is a high

possibility of discovering other selective agents amongst natural toxins. Targeting of

cytotoxic agents or toxins to cancer cells or tumours using monoclonal antibodies is

also receiving considerable attention, and some success has been achieved in animalstudies using the castor seed toxin ricin bound to monoclonal antibodies. Knowledge

of the basic biological mechanisms by which antitumour agents act is also aiding the

screening programmes. Assays have now been developed to observe the effects to

compounds on specific enzyme systems, whether they bind to nucleic or other cell

components, and so on.

The current NCI screens are being designed to overcome the shortcoming of

the random mass screening approach and to direct more effort towards discovery of



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agents of value in treating human cancers spanning a wider range of types. It currently

screens against about 60 different cell lines representing a variety of human tumour

types spanning leukaemias, melanomas, and tumours of the lung, colon, kidney,

ovary, breast, prostate and brain. It is also gradually introducing screens developed

from knowledge of the basic biological mechanism of action of known clinically

effective anticancer agents.

These include tubulin binding (vincristine, vinblastine), tubulin stabilization

(taxol), topoisomerase I (camptothecin), and topoisomerase II (etoposide). In this

way, it is hoped to discover agents that are tissue-specific or highly tissue-selective

and so produce more useful and effective drugs. Natural product extracts for the

testing programme are to be selected from plants, microorganism and marine animals

with emphasis on plants used locally us medicinals and on species and groups which

have not been extensively studied in the past. The continued effort to isolate and

identify tumour-inhibitory compounds from natural sources may well result in the

introduction of new anti-cancer drugs in the future.



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Chapter 6

Summary



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The present work in the form of project is a compilation about various tumour

inhibitor drugs obtained from plants which are used to control the tumour cells or in

other way say it control cancer which is nothing but uncontrolled cell division.

We have studied about drugs from natural sources which are used to control tumour

but have less side effects.

The commonly used drugs from plants are:

1. vincristine and vinblastine

2. paclitaxel

3. colchicines

4. curcumin

5. ricin

6. solmargine

7. betulinic acids

8. camptothecin

9. etoposides

The latest research indicates that the development of tumour inhibitor was a major

advance in the treatment of cancer.



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Foye, W.O., Principles of medicinal chemistry, 4th Edition, B.I. Waverly Pvt. Ltd.,

New Delhi, 1995, Page No. 822-824.

1. Murthy, N.S., and Methew Aleyamma, Cancer Epidemiology, Prevention and

control, current science, vol. 86, No. 4, 25th Feb. 2004, Page No. 518-520.

2. Kadam S.S., et.al, principles of medicinal chemistry, vol. 1, Nirali prakashan,

Pune, 6th Edition, 1999, Page No. 141-144.

3. GANN, Monograph on cancer research, cancer in Asia, opportunity for

prevention, detection and treatment, Japanese, cancer association, university, park

press, monograph, No. 18, 1997, Page No.153, 265.

4. Indian Council of Medical Research, New Delhi, 1982.

5. www.google.com\herbal medicine for cancer.asp

6. Bull, WHO, control of oral cancer in developing countries, 1984, Page No. 62,

817-830.

7. National cancer registry program biennial report, 1988-1989.

8. Clark PI, slevin, ML., clinpharmacokinet,1987, April, 12(4). Page No. 223-

252.

9. www.pubmed.com

10. Plant based drug and medicine by leslie taylor, ND, October 13, 2000.

11. Life extension magazine, July 2002, A report on curcumins anti cancer effect

by Terri Mitchell.

12. www.en.wikipedia.com

13. Somasundram, Edmund NA, Moore DT, cancer res, 2003 15 August, Page

No. 5165-5166.

14. Health and science by Hwaa Irfan, 21 / 9 / 2002.

15. Natural product radiance Volu - 3 (6) Nov. Dec. 2004 page No. 208, 516, 522,

520.

http://www.pubmed.com/http://www.en.wikipedia.com/http://www.pubmed.com/http://www.en.wikipedia.com/


43/43


16. Natural product radiance Volume 4 (4) July, August - 2005, Page No. 260,

299.

17. Natural product Radiance Vol. 3 (3) May - June 2004; Page No. 105, 183.

18. Natural product radiance Vol. 4 (2) March - April 2005 Page No. 137.

19. Trease and evans , Pharmacognosy 15th edition page no 394-406.

20. Indian herbal pharmacopoeia revise edition published by Indian manufacturer

association mumbai page no. 169.

21. Dr. S. H. Ansari, Essential of pharmacognosy, 1st edition 2005-2006. Birla

Publication Pvt. Ltd. Page no 700.

22. Tripathi K. D.pharmacology, 5th edition Jaypee publication page no 774-775.

23. Clin pharmacokinet 1987 april 12(4) page no 223-252.

24. Pisha et al 1995 nature medicine 1(10) page no 1046-1051.

25. www.elsvier.com\pharmacy

26. B.C cancer agency

27. John Boiks Oregon medical press online.

28. www.kosmixhealth.com

29. Indian meteria medica ,vol.1&2 ;Dr.K.M. Nadkarni.

30. Medicinal plants;Robert Bentley&Henry Trimen
http://www.kosmixhealth.com/http://www.kosmixhealth.com/

anil project

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