Anil Project

Chapter – 1
INTRODUCTION
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 and
prevention. 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

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.

Chapter 2
CANCER : Causes & Mechanisms

“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 & it’s types
Cancer is a tissue illness that consists of an excessive and disorderly cellular division.
Cancer’s 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, cancer’s cells always are the winners. When normal
cells die, the cancer’s 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 Ewing’s tumor of bone, Pagel’s disease and Hodgkin’s 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

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 of

leukocytes 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

• 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.

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.

Chapter – 3
Herbal treatment of Cancer

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.

Mechanism of action -
Vincristine, vinblastine & their semi synthetic derivatives work by inhibiting mitosis
(cell division) in metaphase. 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-
Vinblastine or 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,

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.

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 side
effect 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.

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

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

alkaloids, which block mitosis by keeping the spindle from being formed in the first
place).
Chemical constituents: -
1. Paclitaxel
2. Docetaxel

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

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:-

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
Kaposi’s sarcoma, lymphomas and malignant melanomas.
2. Teniposide is used less often than etoposide mainly, it is used to treat

lymphomas.

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 2–3 mm in diameter. The fresh corn is
conical in shape, 4cm wide, side of the corn is convex and opposite is flat. Dried corn
consists 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

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 cancer cells 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 abnormally
high 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.

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 cm
in 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.

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.

Camptothecin and topotecan, ß-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

Habitat -
It is mostly found in India and Pakistan and some where in the Asian region’s. It is a
spice commonly used in curries and other South Asian cooking. Its active ingredient
is curcumin. It is a significant ingredient in most commercial curry powders. Turmeric
is also used to give a yellow color to some prepared mustards, canned chicken broth,
and other foods (often as a much cheaper replacement for saffron).
Characteristics:-
The primary rhizomes are ovate or pear shaped oblong or pyriform or cylindrical and
often short branched. The rhizomes are known as ‘Bulb’ or round turmeric. The
secondary more cylindrical lateral branched tapering on both ends, rhizomes are 4-7
cm long 1-1.5 cm wide and called as fingers. Taste is aromatic, pungent, bitter and
odour is distinct.
Curcumin kills cancer cells
Curcumin can stop cancer in its earliest stages, long before it's detectable. It works at
the level of the cell. One of the things it does is to tell damaged cells to self-destruct
so they won't keep multiplying. The process is called "apoptosis" and it's the body's
way of destroying abnormal cells that can become cancerous. Cancer cells can

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 that
stop 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 potent
inhibitors 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

ingestion. Curcumin has displayed antitumor activity and may be protective against
some cancers, such as colon cancer. In laboratory tests, curcumin’s 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 acid
seems 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.

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 to
solamargine-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.

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.


Chapter 4
New natural products with

antitumour activity

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 antidysenterica is used in Ethiopia in the treatment of cancer, and systematic
fractionation of this plant has led to the isolation of bruceantin, which shows high
antileukaemic 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

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 of C.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 of
the 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.


Chapter 5
Future Developments

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 future
policy.
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

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 animal
studies 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

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.

Chapter 6
Summary

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.

Chapter 7
References

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 curcumin’s 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.

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 Boik’s 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

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Chapter – 1

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

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

Maharshi arvind institute of pharmacy , Jaipur 2

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

Maharshi arvind institute of pharmacy , Jaipur 3

CANCER : Causes & Mechanisms

Maharshi arvind institute of pharmacy , Jaipur 4

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

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

A “Cancerous tumor” is a malignant neoplasm with potential danger.

Maharshi arvind institute of pharmacy , Jaipur 5

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

According to embryologic origin cancers are divided into two general

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

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

e.g. Neuroblastoma, Myloblastoma.

Cancers of blood: - A cancer of the blood involving abnormal increase of

Normal count :- 7500/ mm3

Abnormal count ;- 105-106/ mm3

2.2 Causes of Cancer

• Exposure to the carcinogenic hydrocarbons or to excessive radiation

Maharshi arvind institute of pharmacy , Jaipur 6

• The hereditary factors involved in the caution of cancer include

• Occupational factors like, ionsing radiation, chemicals and other

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

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

2.3 Cell – Cycle Kinetics

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

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

Maharshi arvind institute of pharmacy , Jaipur 7

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.

Maharshi arvind institute of pharmacy , Jaipur 8

Herbal treatment of Cancer

Maharshi arvind institute of pharmacy , Jaipur 9

Maharshi arvind institute of pharmacy , Jaipur 10

Vinblastine or vincristine or vindensine are the most important chemical constitute of

Maharshi arvind institute of pharmacy , Jaipur 11

Maharshi arvind institute of pharmacy , Jaipur 12

Vindesine has a serum half-

Maharshi arvind institute of pharmacy , Jaipur 13

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

3.2 Taxus brevifolia and Texol

Botanical name: - Taxus brevifolia

Maharshi arvind institute of pharmacy , Jaipur 14

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

Maharshi arvind institute of pharmacy , Jaipur 15

Maharshi arvind institute of pharmacy , Jaipur 16

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

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

3.3 Podophyllum and Podophyllum Resin

Botanical name: - Podophyllum peltatum

Maharshi arvind institute of pharmacy , Jaipur 17

Chemical constitute: Etoposide and teniposide are semi synthetic derivatives of

Maharshi arvind institute of pharmacy , Jaipur 18

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