ANTICANCER DRUGS

INTRODUCTION TO CANCER
Cancer is a disease characterized by uncontrolled multiplication and spread of abnormal forms of the body's own cells. It is the second most common cause of death in the developed nations and one in three people will be diagnosed with cancer during their lifetime.

ETIOLOGY

TYPES OF CANCERS
BENIGN TUMOUR Slow growing and noninvasive tumours. They are normally removed by surgical incisions. Ex: Fibroma (originates from fibrous tissue), Chondroma (originates from cartilage). MALIGNANT TUMOUR Rapidly growing cancerous tumours. They cannot be removed by surgery. Ex: Sarcomas, Carcinomas, Lymphomas, Leukaemia.

THE PATHOGENESIS OF CANCER

PROGRESSION OF CANCER

THE CELL CYCLE

A. DRUGS ACTING DIRECTLY ON CELLS (CYTOTOXIC DRUGS): 1. ALKYLATING AGENTS: Nitrogen mustards: Mechlorethamine Cyclophosphamide, Ethylenimine : Thio-TEPA Alkyl sulfonate : Busulfan, Nitrosoureas : Carmustine (BCNU), Lomustine (CCNU) Triazine : Dacarbazine (OTIC) 2. ANTIMETABOLITES Folate antagonist: Methotrexate (Mtx) Purine antagonist: 6-Mercaptopurine (6-MP) Pyrimidine antagonist: 5-Fluorouracil (5-FU),Cytarabine 3. VINCA ALKALOIDS: Vincristine (Oncovin), Vinblastine 4. TAXANES: Paclitaxel, Docetaxel 5. EPIPODOPHYLLO TOXIN: Etoposide

CLASSIFICATION OF ANTI-CANCER DRUGS

B. 1. 2. 3.
4.

5. 6. 7. 8. 9.

DRUGS ALTERING HORMONAL MILIEU GLUCOCORTICOIDS: Prednisolone and others ESTROGENS : Fosfestrol, Ethinylestradiol SELECTIVE ESTROGEN RECEPTOR MODULATORS: Tamoxifen. SELECTIVE ESTROGEN RECEPTOR DOWN REGULATORS: Fulvestrant. ANTIANDROGEN: Flutamide 5REDUCTASE INHIBITOR Finasteride GnRH ANALOGUES: Naferelin,Goserelin PROGESTINS: Hydroxyprogesterone AROMATASE INHIBITORS: Letrozole, Anastrozole, Exemestane.

ANTICANCER DRUGS & THEIR SITE OF ACTIONS

THE MECHANISMS AND SITES OF ACTION OF SOME CHEMOTHERAPEUTIC AGENTS USEFUL IN CANCER

ALKYLATING AGENTS: Cytotoxic agents- alkylation of DNA MECHANISM OF ACTION Cross-linkage Mispairing of bases Depurination USE: Hematologic and solid cancers and used in combination therapy. ADVERSE EFFECT: Direct vesicant effects, nausea and vomiting after 30-40 min. of injection, general side effects, Mutagenic

ANTIMETABOLITES These are structurally related to naturally occurring compounds , such as vitamins, amino acids, and nucleotides. These drugs can compete for binding sites on enzymes or can themselves become incorporated into DNA or RNA and thus interfere with cell growth and proliferation.
FOLATE ANTAGONISTS: METHOTREXATE MECHANISM OF ACTION: USES:

Curative combination chemotherapy for acute lymphoblastic leukemias, Burkitts lymphoma.

NATURAL ANTICANCER AGENTS

VINCA ALKALOID Biological source: Catharanthus roseus Family: Apocynaceae Part used: Dried whole plant Chemical constituent: Vincristine Vinblastine Ajmalicine Vindesine

MODE OF ACTION OF VINCA These drugs block the formation of mitotic Spindle by preventing the assembly of tubulin dimers into microtubules. They act primarily on the M phase of cancer cell cycle

VINBLASTINE
USES : Hodgkins disease Lymphomas Carcinoma Breast Testicular tumors

VINCRISTINE
USES: Childhood leukemias Childhood tumors-Wilms tumor, Neuroblastoma, Hodgkins disease

PODOPHYLLUM
Biological Source: Podophyllum hexandrum Family: Berberidaceae Part used: dried rhizomes & roots Uses: Used in treatment of small cell carcinoma of lung, prostrate and testicular carcinomas Chemical constitutent: Podophyllotoxin Etoposide Teniposide Podophyllotoxin

MECHANISM OF ACTION OF PODOPHYLLUM

Acts by inhibiting topoisomerase II These drugs are most active in late S and early G2 phase

TAXANES
Biological source: Taxus brevifolia Family: Taxaceae Part used: Stem bark Uses: Ovarian cancer Lung carcinoma Gastric & Cervical cancers Prostate & colon cancer Chemical constituent: Taxol Paclitaxel Docetaxal

MECHANISM OF ACTION OF TAXANES

These drugs act by interfering with mitotic spindle They prevent micotubule disassembly into tubulin monomers

ANTICANCER DRUG SCREENING

The aim of screening efforts is to identify products that will produce antitumor effects matching the activity criteria used to define which compounds can progress to the next stage in the preclinical development program. Anticancer drug screening can be performed using various types of in vitro and in vivo tumor models. The ideal screening system, however, should combine speed, simplicity, and low costs with optimal predictability of pharmacodynamic activity.

HISTORY OF ANTICANCER DRUG SCREENS

National Cancer Institute (NCI), inaugurated a screening programfor testing and isolation of bacterial polysaccharides employing mice bearing sarcoma 37 as test systems for necrosis and hemorrhage. The program was quickly extended to plant extracts and synthetic compounds. In the early 1950s the program had evaluated more than 300 chemicals and several hundreds of plant extracts. Two of these materials were tested clinically. As a result, the program of Shear at the NCI was extended to incorporate the evaluation of synthetic agents and natural products for antitumor activity

THE NCI SCREEN

ANTICANCER MODELS
INVITRO INVIVO

IN VITRO METHODS
MICROCULTURE TETRAZOLIUM TEST(MTT ASSAY)

PROCEDURE Cells from particular cell lines in log phase of growth are trypsinised , Check the cell viability through haemocytometer . Adjust to appropriate density in suitable medium and inoculated in multiwell plates. Cells were treated with various Conc. of test compounds and Incubated the plate at 37 C in 5% CO 2 /95% humidified air (1-4 d) Cultures were taken out and 10 l of MTT dye was added (5 mg/ml) into each well and incubated for 4hrs.

 Centrifuge the plate, discard the supernatant and precipitated formazan salt was dissolved in 100 l of isopropanol/DMSO . The plate samples were read at 570 nm microtiter plate reader. EVALUATION: IC 50 of drugs can be determined by counting the viable cells

SRB (SULPHORHADAMINE B) ASSAY

PROCEDURE: Cell lines are counted, cultured and innoculated in 96 well plates. After incubation with different concentrations of test compounds, the cell cultures are stained with SRB dye. Washing with CH 3 COOH removes the unbound dye and the protein bounded dye is extracted using Triss base and optical density is determined by 96-well plate reader.

INVIVO METHODS
CHEMICAL CARCINOGEN MODEL NCI in vivo screening program DMBA induced mouse skin papillomas Two stage experimental carcinogenesis Initiator DMBA, promotor TPA. PROCEDURE: Mice Single dose 2.5 g of DMBA followed by 5 to 10 g of TPA in 0.2 ml of acetone twice weekly. Papilloma begins to appear after 6 to 7 wks - 100% Percent tumor incidence & multiplicity of treatment group is compared with DMBA control group

MNU INDUCED RAT MAMMARY GLAND CARCINOGENESIS Induces hormone dependent tumors. Single i.v of 50 mg/kg of MNU 50 days old sprague dawley rats. A denocarcinoma will be produced within 180 days of post carcinogen 75 to 95% Reduction in tumor size is compared Drawback cannot detect inhibition of carcinogen activation.

REFERENCES
1. KD Tripathi, Essentials Of Medical Pharmacology, 6th

edition.
2. Rang & Dale's, Pharmacology 7th edition. 3. Gupta SK, Drug screening methods, 2009, Ed:2,Anticancer agents:166-82;. 4. Steele VE, Lubet RA, Moon RC, Preclinical animal models for the development of cancer chemoprevention drugs; springer.com; 2005:vol:2;568-71.