DR. F. O.

WANGO

CANCER
Cancer is a disease characterized by a shift in the

control mechanism that governs cell proliferation and differentiation. Two important groups of genes involved in cancer physiology are oncogenes and Tumuor Suppressor Genes(p53).

CELL-CYCLE KINETICS.
Cell cycle has different phases and it is some of these

phases which are targeted by antineoplastic drugs. There are differences in the duration of cell cycles of different tissues. There are drugs which are cell cycle specific.

PHASES OF CELL CYCLE.

G1: Precedes the DNA synthesis. G0 : Resting phase.
S: DNA synthesis G2: An interval following the termination of DNA

synthesis-premitotic interval. MITOTIC PHASE.

CELL CYCLE-SPECIFIC AGENTS.

ANTIMETABOLITES.
BLEOMYCIN PEPTIDE ANTIBIOTICS. PODOPHYLIN ALKALOIDS PLANT ALKALOIDS.

CELL CYCLE-NONSPECIFIC AGENTS.

ALKYLATING AGENTS.
ANTIBIOTICS CISPLATIN NITROSOUREAS

CLASSES OF ANTINEOPLASTIC AGENTS

AKYLATING AGENTS.
ANTIMETABOLITES NATURAL PRODUCTS (1) Vinca Alkaloids (2) Taxanes

(3) Epipodophylotoxins (4) Antibiotics ENZYMES SUBSTITUTED UREA PROTEIN KINASE INHIBITORS HORMONE AND ANTAGONISTS

ALKYLATING AGENTS
Exert cytotoxic effects via transfer of their alkyl groups

to various cellular constituents. Alkylating DNA within the nucleus probably represents the major interaction that lead to cell death. They also react with sulphydryl , amino , hydroxyl, carboxyl and phosphate groups.

 The mechanism involves intramolecular cyclization to

form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent. The major site of alkylation within DNA is the N7 position of guanine and this reults in miscoding through abnormal base pairing.

 Cross-linking of DNA appears to be of major

importance to the cytotoxic action of alkylating agents. Though alkylating agents are not cell cycle-specific, cells are most susceptible in late G1 and S phases.

ADVERSE EFFECTS.
Vesicant effects.
Nausea and vomitting. Toxities on Bone marrow, GIT and Gonads. Cyclophosphamide does not have a direct vesicant

effects unless activated

ALKYLATING AGENTS.
Cyclophosphamide, Mechlorethemine, melphalan,

Chlorumbicil, thiotepa Busulphan. Carmustine, lomustine and semustine are nitrosoureas.

NITROSOUREAS
Require biotransformation to derivatives with both

alkylating and carbamoylating activities. They are highly lipid-soluble and can cross bloodbrain barrier. Initial halflife is 6hrs and second half life is 1-2 days. Urinary excretion appears to be the major route of elimanation from the body.

DRUG RESISTANCE
Capability to repair DNA lesions
Decreased permeability of the cell to the alkylating

drug. Increased production of glutathione which inactivates the alkylating agent.

RELATED DRUGS ACTING AS ALKYLATING AGENTS.

PROCARBAZINE: Inhibits the synthesis of DNA, RNA

and protein and produces chromosome breaks. Chemotherapeutic activity is most active in Hodgkins disease. It is also leukomonogenic, teratogenic and mutogenic.

 Dacarbazine: Used mostly in melanoma, hodgkins

disease and soft tissue sarcoma. Cisplatin and Carboplatin: Kills cells in all stages. Has relatively little effect on the bone marrow. Major antitumuor activity in genitourinary cancers.