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1.1. General introduction to cancer

Cancer is not just one disease, but a group of more than hundred diseases in which a

group of cells become abnormal, divide without control and invade other tissues. Cancer

cells can spread to other parts of the body through the blood circulation or lymph system.

The body is made up of many types of cells which are basic units of life and these cells

grow and divide in a controlled way to keep the body healthy. When cells become old or

damaged, they die and are replaced with new cells in a programmed way; this process is

called as apoptosis. However, sometimes this programmed process goes wrong. The

genetic material (DNA) of a cell regulates the normal cell growth and division. If DNA

become damaged or changed, producing mutations, cells do not die and cells keep

dividing when the body does not need them, these extra cells form a mass of tissue which

is called as tumor (Figure-1). Tumors are of two types; one is benign tumor, another one

is malignant tumor. Benign tumors are not cancerous, they do not spread to other parts of

the body but malignant tumors are cancerous, cells in these tumors can spread to other

parts of the body (metastasis).

1.1.1. Classification of cancers

Cancers are classified by the type of cells that constitutes the tumor and, therefore, the

tissue presumed to be the origin of the tumor.

• Carcinoma: cancer that affects the epithelial tissues that lines internal organs. The

most common cancers like breast, prostate, lung and colon cancer come under

this category.

• Sarcoma: cancer that begins in connective or supportive tissue (e.g., bone,

cartilage, fat, muscle, blood vessels).

• Leukemia: cancer related to blood-forming tissue.

• Lymphoma: cancers that affects the lymphatic tissue.

• Myeloma: cancer that begins in bone marrow.

• Blastoma: cancer that begins in embryonic tissue.

• Central nervous system cancers: cancers that begin in the tissues of the brain and

spinal cord.

1.1.2. Nomenclature of cancer

Malignant tumors are usually named using -carcinoma, -sarcoma or -blastoma as a suffix,

with the Latin or Greek word for the organ of origin as the root. For example, a cancer of

the liver is called hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For

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common cancers, the English organ name is used. For example, the most common type of

breast cancer is called ductal carcinoma. Here, the adjective ductal refers to the

appearance of the cancer under the microscope, resembling normal breast ducts. Benign

tumors are named using -oma as a suffix with the organ name as the root. For example, a

benign tumor of the smooth muscle of the uterus is called leiomyoma. Unfortunately,

some cancers also use the -oma suffix, examples being melanoma and seminoma.

1.1.3. Cause of cancer

Cancers are caused by abnormalities in the genetic material of the transformed cells.

These abnormalities may be due to the effects of carcinogens, such as tobacco smoke,

chemicals (carbon tetrachloride, benzene, vinyl chloride, asbestos, polychlorinated

biphenyls etc.), radiation, infectious agents (viruses/bacteria). Tobacco smoking and

chewing is associated with many forms of cancers such as lung, mouth, larynx, head,

neck, stomach, bladder, kidney, esophagus and pancreas, particularly 90% of lung cancer

is caused due to tobacco smoking. Tobacco smoke contains over fifty known carcinogens,

including nitrosamines and polycyclic aromatic hydrocarbons. Prolonged exposure to

asbestos fibres is associated with mesothelioma. Radiation such as gamma and X-ray can

cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to

melanoma and other skin cancers. It is estimated that 2% of future cancers will be due to

current CT scans. Radiation from mobile phones and towers has also been proposed as a

cause of cancer, but there is currently little established evidence of such a link. Viruses,

bacteria and parasites are responsible for up to 20% of human cancers worldwide. These

include HIV causing Kaposi's sarcoma and non-Hodgkin's lymphoma. Hepatitis B virus

(HBV) and hepatitis C virus (HCV) causes hepatocellular carcinoma (liver cancer).

Human papilloma virus (HPV-16 and 18) causes cervical, vaginal, vulvar, oropharyngeal

and penile cancers. Epstein-Barr virus causes burkitt lymphoma, non-Hodgkin

lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma. Kaposi's sarcoma herpes

virus (KSHV) causes Kaposi sarcoma. Human T-cell lymphotropic virus type-1 (HTLV1)

causes adult T-cell leukaemia. Helicobacter pylori cause stomach cancer. Schistosomes

(Schistosoma hematobium) parasite causes bladder cancer and liver flukes (Opisthorchis

viverrin) parasite cause liver cancer.

1.1.4. Cancer-Global and Indian scenario

Cancer is a leading cause of death in India and other countries. Cancer can affect any part

of the human body and people at all ages, but risk for most types cancer increases with

age. An estimated 12.7 million new cancer cases and 7.6 million deaths occurred in 2008.

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Around 25 million persons are living with cancer around the world (Parkin et al., 2005).

Lung, stomach, liver, colon and breast cancer cause the most cancer deaths each year. The

most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total),

breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most

common causes of cancer death are lung (1.38 million, 18.2% of the total), stomach (0.74

million, 9.7%) and liver cancers (0.69 million, 9.2%). Cancer is a major public health

burden in both developed and developing countries. About 72% of all cancer deaths in

2007 occurred in low and middle-income countries. Every year about 8,50,000 new

cancer cases being diagnosed and about 5,80,000 cancer related death occurs every year

in India (Dhanamani et al., 2011).� India had the highest number of the oral and throat

cancer cases in the world. Deaths from cancer worldwide are projected to continue rising,

with an estimated 12 million deaths in 2030.

1.1.5. Cancer treatment

Cancer can be treated by surgery, chemotherapy, radiation therapy and immunotherapy.

The choice of therapy depends upon the location/grade of the tumor, stage of the disease

and health status. Worldwide people spend several billions of dollars for cancer treatment

each year. The economic burden, losses of human life and suffering due to cancer have

triggered a concerted effort to fight against this dangerous disease. Although, significant

advances have been made in early detection, preventive measures and medical treatment

of this disease, much more effort is needed to develop more efficient and safer drugs.

1.1.5.1. Surgery

Surgery is generally used to obtain small samples of tissue for examination and also for

the removal of tumors. It is highly effective treatment in eliminating most types of cancer

before it has spread to lymph nodes or other sites of the body. If the cancer has not

metastasized, surgery may cure the person. Surgery is not the main treatment once a

cancer has metastasized and for early-stage cancers surgery is not preferred treatment.

The cure through surgical treatment will depend on the size, location and stage of the

disease. Because some cancers occur in inaccessible sites and in some cases, necessary

organs are required to be removed along with the tumors. In such cases, other treatment

methods like radiation and chemotherapy may be preferable.

1.1.5.2. Radiation therapy

Radiation therapy is the treatment of cancer with external beam of radiation. Generally

gamma radiation is used for this purpose and in few cases electron or proton beam

radiation is also used. These external beams of radiations are focused on the particular

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area or organ of the body that contains the cancer. Proton/electron beam radiation, which

can be focused on a very specific area, effectively treats certain cancers in areas in which

damage to normal tissue is a particular concern, such as the eyes, brain, or spinal cord.

External beam radiation therapy is given as a series of equally divided doses over a

prolonged period of time. In other radiation therapy strategies, a radioactive substance

may be injected into a vein to travel to the cancer (for example, radioactive iodine, which

is used in treatment of thyroid cancer). Another technique uses small pellets (seeds) of

radioactive material placed directly into the cancer (for example, radioactive palladium

used for prostate cancer). These implants provide intense radiation to the cancer, but little

radiation reaches surrounding tissues. Implants contain short-lived radioactive substances

that stop producing radiation after a period of time.

Radiation therapy plays a key role in curing many cancers, including Hodgkin lymphoma,

early-stage non-Hodgkin lymphoma, squamous cell cancer of the head and neck,

seminoma (a testicular cancer), prostate cancer, early-stage breast cancer, some forms of

non small-cell lung cancer, brain and spinal cord tumor. Even though several precautions

have been taken to avoid overexposing the radiation on normal tissue, it can damage

normal tissues near the tumor. Particularly radiation greatly damages the skin, bone

marrow, hair follicles, and the lining of the mouth, esophagus, intestine and

ovaries/testes.

1.1.5.3. Immunotherapy

The immune system enables our body to recognize and attack foreign materials allowing

it to fight off infection and disease. It also enables our bodies to recognize abnormal cells

and to respond quickly by destroying them. Cancer immunotherapy is used to stimulate

the body's immune system against cancer. For example, vaccines composed of antigens

derived from tumor cells can boost the production of antibodies or immune cells (T

lymphocytes). Cancer vaccines are of two types, one is preventive vaccine and another

one is therapeutic vaccine. The U.S. Food and Drug Administration (FDA) has approved

two preventive vaccines (Gardasil and Cervarix), that protect against infection by HPV-

16 and HPV-18 that cause approximately 70 % of all cases of cervical cancer worldwide.

HPV-16 and HPV-18 also cause some vaginal, vulvar, anal, penile, and oropharyngeal

cancers (Doorbar, 2006; Parkin, 2006). In April 2010, the U.S. FDA has approved the

first cancer vaccine (Sipuleucel-T) for the treatment of metastatic prostate cancer in men.

Presently several cancer vaccines are under clinical trials for the treatment or prevention

of various cancers.�

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1.1.5.4. Chemotherapy

Chemotherapy is the treatment of cancer with drugs and chemotherapy is the widely used

method for the treatment of cancer. An ideal drug should destroy cancer cells without

harming normal cells; however most drugs are nonselective. Instead, drugs are designed

to inflict greater damage on cancer cells than on normal cells, typically by using drugs

that affect a cell's ability to grow. However, because normal cells also need to grow, and

some grow quite rapidly (such as those in the bone marrow and those lining the mouth

and intestine), all chemotherapy drugs affect normal cells and cause side effects.

One new approach to limit the side effects and increase the effectiveness of anticancer

drugs uses a variety of "molecularly targeted" drugs. These drugs kill cancer cells by

attacking specific pathways and processes vital to the cancer cells survival and growth.

For example, cancer cells need blood vessels to provide extra oxygen and nutrients. Some

drugs can block blood vessel formation to cancer cells or the master signalling pathways

that control cell growth. Common side effects associated with cancer chemotherapy are

nausea, vomiting, loss of appetite, hair loss, weight loss, fatigue, and low blood cell

counts that lead to anaemia and increased risk of infections.

There are many different chemotherapy drugs, some derived from natural, and some from

synthetic sources, however natural product derived drugs are predominate. In view of the

several side effects associated with the existing anticancer drugs there is an urgent need

for new drugs which are less toxic and more specific towards cancer cells.

1.2. Natural products in folk medicine

Natural products, derived from plant sources have been used to treat various human

disease since the dawn of medicine. Plant and animal based medicines have been used in

India, China, Japan, Egypt, and Greece since ancient times and several modern drugs

have been developed from them. The first written records on the medicinal uses of plants

appeared in about 2600 BC from the Sumerians and Akkaidians (Samuelsson, 1999). The

Egyptian “Ebers Papyrus” from about 1552 B.C. is one of the oldest preserved medical

documents. It contains 700 formulas and folk remedies. The Chinese Materia Medica,

which describes more than 600 medicinal plants, has been well documented with the first

record dating from about 1100 BC (Cragg et al., 1997). The Greek De Materia Medica,

which describes more than 600 medicinal plants, has been well documented with the first

record dating from about 100 AD (Samuelsson, 1999). Indian Ayurveda is one of the

oldest traditional medical practices and it is well documented with Susruta and Charaka

Samhita dating from about 1000 BC (Kappor, 1990). These two well-known ayurvedic

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classics contain description of 1120 illnesses, 700 medicinal plants, and a detailed study

on anatomy. Charaka and Sushruta Samhitas, describe cancer as inflammatory or non-

inflammatory swelling and mention them as either granthi (minor neoplasm) or arbuda

(major neoplasm). During the 7th century BC, Atreya and Dhanwantari used herbal

medicines for treating the early stages of cancer and surgery in advanced cases. In the 8th

century AD, Vagbhata, a Buddhist physician composed two texts: Astanga Hridaya and

Astanga Sangraha in which he described new methods for cancer treatment. Other

ayurvedic texts of internal medicine, viz., Chakradatta composed by Chakrapani (10th

century AD), the Sarangadhara Samhita by Sarangadhara (14th century AD), the

Bhavaprakasha Samhita by Bhavamisra (15th century AD), the Satmya Darpan Samhita

by Viswanath (16th century AD), the Vaisajya Ratnabali by Binoda Lala Sen Gupta (18th

Century AD), the Rasatarangini by Sadananda Sharma (19th century AD), etc. explain

numerous remedies to treat internal and external neoplasm’s. In Indian ayurveda several

herbs have been used in the treatment of cancer. For example Amorphopallus

campanulatus, Baliospermum montanum, Barleria prionitis, Basella rubra, Curcuma

domestica, Ficus bengalensis, Flacourtia romantchi, Madhuca indica, Moringa oleifera,

Oxoxylum indicum, Pandanus odoratissimum, Pterospermum acerifolium, Raphanus

sativus, Prosopis cineraria, Vitis vinifera (Patwardhan et al., 2004; Premalatha and

Rajgopal, 2005; Rao et al., 1999). Even today most of the Indians and Chinese rely on

traditional medicine for their primary health care and consider it as cheapest & safest.

Plants have long been used in the treatment of cancer (Hartwell, 1982). Of the 79 FDA

approved anticancer drugs from 1983-2002, 60% are either natural products or natural

product derived.

1.3. Natural product derived anticancer agents in clinical use

Vinblastine and vincristine (Figure-2) are vinca alkaloids found in the Madagascar

periwinkle, Catharanthus roseus (formerly known as Vinca rosea). These two natural

products are approved by United States Food and Drug Administration (US FDA) for the

treatment of cancers like leukemia, lymphomas, Hodgkin’s lymphoma, breast cancer,

acute lymphoma, soft tissue sarcomas, multiple myeloma and neuroblastoma (Cragg and

Newman, 2005). Vinblastine and vincristine are antimicrotubule agents which led to a

new era of the use of plant material as anticancer agents. These discoveries prompted the

United States National Cancer Institute (NCI) to initiate an extensive plant collection

program. Approximately 35,000 plant samples from 20 countries were collected that

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provided 1,14,000 different extracts, which were screened for anticancer activity (Shoeb,

2006).

Taxol commonly known as paclitaxel is a diterpenoid. It was first isolated in 1966 from

the pacific yew, Taxus brevifolia in Washington State as part of a random collection

program by the U.S. Department of Agriculture for the National Cancer Institute (Wani et

al., 1971; Rowinsky et al., 1992). Later on, it was isolated from several other species of

Taxus including Taxus wallichiana, the Himalayan yew. Paclitaxel is a blockbuster

anticancer drug which is in clinical use for the treatment of refractory ovarian cancer,

metastatic breast and lung cancer and Kaposis sarcoma. It acts as microtubulin stabilizing

agent. The use of various parts of T. brevifolia and other Taxus species (e.g. T. canadensis

Marshall, T. baccata L.) by several Native American tribes for the treatment of some non-

cancerous conditions has been reported, while the leaves of T. baccata are used in the

Indian ayurveda for the treatment of cancer. The discovery of paclitaxel is another

example of the success of natural product drug discovery. The main problem is, the

availability of the taxol (the bark of T. brevifolia contains only trace amounts of taxol,

0.01–0.03 %; in addition, the collection of the bark from the tree is associated with death

of the plant source), which was overcome by the development of a semi-synthetic

production process, that is based on the natural product 10-deacetyl baccatin III (10-

DAB) as a readily available precursor. 10-DAB is available in sufficient quantities from

the regenerating needles of the fast growing European yew tree (T. baccata); elaboration

of this precursor into taxol involves reaction with a synthetic �-lactam (comprising the

C13 side chain) and can be achieved in seven chemical steps. Production of taxol through

plant cell culture has been attempted with some success and research is in progress to

optimize the yields to evolve the process as possible alternative to isolation form Yew

tree needles.

Systematic chemical modifications of natural products is used to produce analogues with

greater pharmacological activity, improved bio-availability and with fewer side effects.

For example, docetaxel commonly known as taxotere is semi synthetic derivative of

taxol, which is in clinical use for the treatment of locally advanced or metastatic breast

and lung cancer. It also has better pharmacological properties such as improved water

solubility, and acts on the microtubules. It enhances polymerization of tubulin into stable

microtubule bundles leading to cell death. Taxotere is now known as a better anticancer

drug than taxol. Cabazitaxel is a semisynthetic derivative of taxol approved by the U.S.

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Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate

cancer.

Based on the SAR of taxol, several analogues have been generated (Figure-4). According

to the Adis R&D insight database, eight taxol derivatives are under clinical trials stage

(BMS-184476, 188797, 275183, taxoprexin, TL-00139, DJ-927, RPR-109881A and

ortataxel) (Choy et al., 1998; Nicoletti et al., 2000; Polizzi et al., 2000; Ali et al., 2001;

Altstadt et al., 2001; Rose et al., 2001; Vredenburg et al., 2001; Cisternino et al., 2003;

Mastalerz et al., 2003; Sampath et al., 2003; Shionoya et al., 2003).

Homoharringtonine isolated from the Chinese tree Cephalotaxus harringtonia var

drupacea (Cephalotaxaceae), is another plant-derived agent in clinical use (Itokawa et al.,

2005; Powell et al, 1970). A racemic mixture of harringtonine and homoharringtonine has

been used successfully in China for the treatment of acute myelogenous and chronic

leukemia (Cragg and Newman, 2005; Kantarjian et al., 1996). Anthracyclines

(daunorubicin, doxorubicin, epirubicin, idarubicin and valrubicin) are well known

anticancer drugs which are derived from Streptomyces bacteria (Figure-4). These

anthracyclines are useful in the treatment of leukaemia, lymphoma, breast-, uterine-,

ovarian- and lung-cancers.

Camptothecin (Figure-3) is an alkaloid, which was first isolated from the Chinese

ornamental tree Camptotheca acuminata, also known as the tree of joy and tree of love. It

has also been isolated from Ophiorrhiza pumila and Mapia foetida.

Camptothecin is a potent cytotoxic agent (Cragg and Newman, 2005). It shows anticancer

activity mainly for solid tumors. It inhibits DNA topoisomerase-I and exhibits anticancer

activity mainly against colon and pancreatic cancer cells. Camptothecin was advanced to

clinical trials by the NCI in the 1970s, but was dropped because of severe bladder toxicity.

However, extensive research was performed by pharmaceutical companies in a search for

more effective camptothecin derivatives and topotecan, developed by Glaxo SmithKline,

and irinotecan, originally developed by the Japanese company, Yakult Honsha, are now in

clinical use. Topotecan is used for the treatment of ovarian and small-cell lung cancers,

while irinotecan is used for the treatment of colorectal cancers. Similarly cyclo lignan

podophyllotoxin which is isolated from Podophyllum peltatum and Podophyllum

hexandrum is a highly toxic molecule and it is not being used in the treatment of cancer,

but its semi synthetic derivatives such as etoposide and teniposide are in clinical use

(developed by Sandoz Laboratories in the 1960s and 1970s) for the treatment of various

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cancers like testicular, small-cell lung cancer, lymphoma, leukemia and Kaposi’s sarcoma.

Elliptinium is a derivative of ellipticine, isolated from a Fijian medicinal plant Bleekeria

vitensis is marketed in France for the treatment of breast cancer (Cragg and Newman,

2005).

1.4. Natural product derived anticancer agents in clinical development

The combretastatins were isolated from the South African “bush willow”, Combretum

caffrum (Combretaceae), collected in Southern Africa in the 1970s for the NCI by the

USDA, working in collaboration with the Botanical Research Institute of South Africa.

These collections were part of a random collection program aimed at the discovery of

novel anticancer agents. Species of the Combretum and Terminalia genera, both of which

belong to the Combretaceae family, are used in African and Indian traditional medicine

for the treatment of a variety of diseases, including hepatitis and malaria. Several

Terminalia species have reportedly been used in the treatment of cancer. Combretastatin

A-4 is the most potent naturally occurring combretastatin known, its phosphate prodrug

(CA-4-P) in combination with paclitaxel/carboplatin is under phase III clinical trial for

the treatment of anaplastic thyroid cancer (Ohsumi et al., 1998; Pettit et al., 1995). There

is currently no fully FDA approved treatment for this form of cancer. Combretastatin A-4

is known as an antimicrotubule agent acting at the colchicine-binding site on tubulin.

Combretastatin A-4 is active against colon, lung and leukemia cancers and it is expected

that this molecule is the most cytotoxic phyto-molecule isolated so far (Ohsumi et al.,

1998; Pettit et al., 1995).

Betulinic acid, a pentacyclic triterpene, is a common secondary metabolite of plants,

primarily from Betula species (Betulaceae) (Cichewitz et al., 2004).�Betulinic acid was

also isolated from Zizyphus species, e.g. mauritiana, rugosa and oenoplia (Pisha et al.,

1995; Nahar et al., 1997) and displays selective cytotoxicity against human melanoma

cell lines (Balunas et al., 2005).

Epothilones (A-F) (Figure-5) are isolated from common soil bacteria Sporangium

cellulosum in 1980’s by Hofle and Reichenbach. Epothilones inhibits microtubules

function. All the epothilones (A-F) are in clinical trials stage against various cancers and

epothilone-B (ixabepilone) is in clinical use for aggressive metastatic and advanced breast

cancer treatments. Pervilleine A is isolated from the roots of Erythroxylum pervillei Baill.

(Erythroxylaceae) (Silva et al., 2001). Pervilleine-A was selectively cytotoxic against a

multidrug resistant (MDR) oral epidermoid cancer cell line (KB-V1) in the presence of

the anticancer agent vinblastine (Mi et al., 2001). Pervilleine A is currently in preclinical

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development (Mi et al., 2003). Silvestrol was first isolated from the fruits of Aglaia

silvestris (Hwang et al., 2004). Silvestrol exhibits cytotoxicity against lung and breast

cancer cell lines (Cragg and Newman, 2005). Biological studies are ongoing to determine

the mechanism(s) of action for silvestrol. Flavopiridol is a synthetic flavone, derived from

the plant alkaloid rohitukine, which was isolated from Dysoxylum binectariferum

(Meliaceae) (Kellard et al., 2000). It is currently in phase I and II clinical trials against a

broad range of tumors, including leukemia, lymphomas and solid tumors (Christian et al.,

1997). The synthetic agent roscovitine which is derived from natural product olomucine,

originally isolated from Raphanus sativus L. (Brassicaceae), is in Phase II clinical trials in

Europe (Cragg and Newman, 2005; Meijer et al., 2003).

Even though nature provides innumerable primary leads in their diverse structural types,

stereochemistry, a limited number of natural products have been modified so far by

chemical methods. Thus, most original compounds still await full exploitation of their

structures. Moreover, the majority of the isolated compounds were never investigated

systematically with regard to their mode of action and their specific target interaction.

We may add here that every natural molecule is an "untreated diamond" waiting for

cutting and refining. Undoubtedly, chemical modification of a given structure of a natural

product is often more rewarding than the tedious and time-consuming synthesis of

recurrent skeletons and homologues. There are several reports available on

podophyllotoxin and camptothecin derivatives in literature, in which these derivatives

have showed better anticancer activity than etoposide, teniposide, topotecan etc., this

clearly shows there are still possibilities in the development of drug candidates from these

molecules. There are thousands of unexploited plants waiting for the screening of

anticancer activity. Screening and refining the structures will yield possible drug

candidates.

1.5. Drug delivery vehicles in cancer chemotherapy

Even though several aforementioned natural products and their derivatives have been

used as life saving drugs in cancer chemotherapy, most of these molecules are associated

with severe mammalian toxicity owing to their nonspecific mode of action. An ideal

anticancer drug would only destroy the cancer cells without harming the normal cells or

their functions. The discovery and development of new drugs is a time-consuming and

expensive process.

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Figure-1: Cell division in normal cells and cancer cells

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���Figure-2: Natural product derived molecules which are in clinical use as anticancer drugs.

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Figure-4: Few taxol derived molecules which are in clinical development as anticancer

drugs.

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O

O

OO

O33. Combretastatin A4

34. Combretastatin A4 phosphate

H

HHO

O

OH

H

37. Betulinic acid

O

N

OH O

HO

36. Flavopiridol

ClHO

H

H

P OH

OH

O

NH

HON

N

N

N

HN

35. Roscovitine

Figure-5: Few natural product derived molecules which are in clinical development as anticancer drugs.

Chapter-I�

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Each new candidate is estimated to take around 10-15 years to bring it from conception to

market, with a cost of more than $500 million. Some problems associated with currently

available anticancer drugs is toxicity (no selectivity), low water solubility, poor

bioavailability, poor absorption etc. All these problems can be solved using suitable drug

delivery vehicles attached to anticancer compounds.

Several nanoparticles (polymer and liposome) and peptide based drug delivery vehicles

have been found to be effective for such a combination therapy.

1.5.1. Nanoparticles as drug delivery vehicles

The fate of a drug after administration in vivo is determined by a combination of several

processes, such as distribution, metabolism and elimination when given intravenously or

absorption, distribution, metabolism and elimination when an extra vascular route is used.

The result depends mainly on the physicochemical properties of the drug and therefore on

its chemical structure. Nanoparticles play a very important role in cancer research. Due to

extremely small size of nanoparticles they are easily and more readily taken up by the

human body. Biological membranes and access cells, tissues and organs are eligible for

entrance of nanoparticles. These cells are not able for cross by the larger-sized particles.

Nanoparticles are stable, solid colloidal particles consists of biodegradable polymer or

lipids and size range 10-1000 nm. Nanoparticles loaded with anticancer agents can

successfully increase drug concentration in cancer tissues and also act at cellular levels,

enhancing antitumor efficacy.

1.5.1.1. Polymeric nanoparticles

Naturally occurring polymers such as albumin, chitosan, and heparin are becoming

increasingly important in the field of drug delivery (Felix, 2008). In 2005, a nanoparticle

formulation of albumin bound paclitaxel (abraxane), was approved by U.S. FDA for

breast cancer treatment, in which serum albumin is included as a carrier (Gradishar et al.,

2005). Besides breast cancer, abraxane has also been evaluated in clinical trials involving

many other cancers including non-small cell lung cancer and recently positive results

were published from phase-III clinical trials for the treatment of non-small cell lung

cancer (Nyman et al., 2005; Green et al., 2006). Several synthetic polymers such as N-(2-

hydroxypropyl)-methacrylamide copolymer (HPMA), polystyrene-maleic anhydride

copolymer, polyethylene glycol (PEG), and poly-L-glutamic acid (PGA) have been

developed for drug delivery. Among all these synthetic polymers PGA was the first

biodegradable polymer to be used for conjugate synthesis (Li, 2002). Several

Chapter-I�

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representative chemotherapeutics that are used widely in the clinic have been tested as

conjugates with PGA in vitro and in vivo and showed encouraging results (Li, 2002).

Among them, Xyotax (PGA-paclitaxel) and CT-2106 (PGA-camptothecin) are now in

clinical trials (Bhatt et al., 2003; Sabbatini et al., 2004). HPMA and PEG are the most

widely used non biodegradable synthetic polymers (Duncan, 2003). PK1, which is a

conjugate of HPMA with doxorubicin, was the synthetic polymer-drug conjugate that

completed Phase-I clinical trials (Vasey et al., 1999).

1.5.1.2. Polymeric micelles

The functional properties of micelles are based on amphiphilic block copolymers, which

assemble to form a nano-sized core/shell structure in aqueous media. The hydrophobic

core region serves as a reservoir for hydrophobic drugs, whereas the hydrophilic shell

region stabilizes the hydrophobic core and renders the polymers water-soluble, making

the particle an appropriate candidate for i.v. administration (Adams et al., 2003). The

drug can be loaded into a polymeric micelle in two ways: physical encapsulation

(Batrakova et al., 1996) or direct attachment (Nakanishi et al., 2001). The first polymeric

micelle formulation of paclitaxel, Genexol-PM (PEG-poly(D,L-lactide)-paclitaxel), is a

cremophor-free polymeric micelle-formulated paclitaxel, a phase I and pharmacokinetic

study has been conducted in patients with advanced refractory malignancies (Kim et al.,

2004). Multifunctional polymeric micelles containing targeting ligands and imaging and

therapeutic agents are being actively developed (Nasongkla et al., 2006) and will become

the mainstream among several models of the micellar formulation in the near future.

1.5.1.3. Dendrimers

Dendrimers are a family of nanosized, three-dimensional polymers characterized by a

unique tree-like branching architecture and compact spherical geometry in solution. Their

name is derived from the Greek word “dendron”, which means “tree”. Dendrimers are

first discovered in the early 1980’s by Tomalia et al (1985). The inherent stability of

dendritic micelles, as well as their ability to encapsulate guest molecules, makes them

good candidates for the design of novel drug delivery agents.

A dendrimer is a synthetic polymeric macromolecule of nanometer dimensions,

composed of multiple highly branched monomers that emerge radially from the central

core. Properties associated with these dendrimers such as their monodisperse size,

modifiable surface functionality, multivalency, water solubility, and available internal

cavity make them attractive for drug delivery (Svenson and Tomalia, 2005).

Polyamidoamine dendrimer, most widely used as a scaffold, was conjugated with cis-

Chapter-I�

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platin (Malik et al., 1999). The easily modifiable surface characteristic of dendrimers

enables them to be simultaneously conjugated with several molecules such as imaging

contrast agents, targeting ligands, or therapeutic drugs, yielding a dendrimer-based

multifunctional drug delivery system (Svenson and Tomalia, 2005).

1.5.1.4. Liposomes

Liposomes are hollow structures, composed of a lipid bilayers and an internal aqueous

pool. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other

diseases also. Liposomes improve the solubility of lipophilic drugs that would otherwise

be difficult to administer intravenously. Liposomes can also prolong the duration of drug

exposure by controlled release of the drug. Liposomes can even protect a drug against

degradation and also reduces the side effects of the encapsulated drug. For example, the

dose limitation of the cytotoxic drug doxorubicin is its (irreversible) damage to heart

muscles. Liposome encapsulation greatly reduces exposure of the heart to doxorubicin

and thereby its cardiotoxicity. Several liposomal chemotherapeutics are in clinical use

viz., doxorubicin (doxil, myocet) and daunorubicin (daunoxome) are approved for the

treatment of metastatic breast cancer and AIDS-related Kaposi’s sarcoma (Rosenthal et

al., 2002; Rivera, 2003; Markman, 2006). Several liposomal chemotherapeutics are

currently being evaluated in clinical trials (Hofheinz et al., 2005).

1.5.2. Tumor specific peptides as drug delivery vehicles

Tumor specific peptides are considered as an important class of drug delivery vehicles in

cancer chemotherapy. Tumor blood vessels express molecular markers that distinguish

them from normal blood vessels (Laakkonen et al. 2002). Many of these tumor vessel

markers are related to angiogenesis, but some are selective for certain tumors (Rouslahti,

2002). Tumor specific peptides selectively recognize these markers and therefore

accumulate at the tumor site. Tumor specific peptides also exhibit anticancer property and

these peptides also useful to improve the water solubility of the drug. We can use these

tumor homing peptides as carriers for tumor specific drug delivery. Anchoring anticancer

drug to tumor homing peptides with a suitable linker will improve the selectivity,

efficiency, water solubility and decrease the dosage of the drug. Several anticancer drugs

like chlorambucil (Myrberg et al., 2008), doxorubicin (Arap et al., 1998), cisplatin

(Sumitra et al. 2008; Cohen and Lippard, 2001) etc. have been successfully conjugated

with tumor specific peptides.

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1.6. Conclusion

A majority (> 60%) of all the FDA approved anticancer drugs are either natural products

or their analogues, demonstrating the important role in the development of new anticancer

drugs. Drug delivery vehicles play an important role in the cancer chemotherapy for the

reduction of dosage of anticancer drugs and consequently, reduction of toxicity of these

drugs towards normal cells.

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