MDR gene acts by aEUR'
Causes efflux of drug A major problem in cancer chemotherapy is development of cellular drug resistance. These are of two types:- (i) Primary resistance When there is absence of response to drug on first exposure e.g. Malignant melanoma, Renal cell cancer and brain cancer. The presence of inherent drug resistance is thought to be associated with genomic instability that gave rise io the cancer. (ii) Acquired resistance In these cases the cancers were initially drug sensitive and became drug resistant, later on in the course of therapy. It can be :- Single drug resistance Cancer is resistant to a single drug and is based on change in genetic apparatus of a given tumour cell. Multi drug resistance Resistance develops to a variety of anticancer drugs. It is associated with increased expression of a normal gene --)MDR1 gene. MDRI gene encodes for P-glycoprotein Pcgp). P glycoprotein is a protective mechanism possessed by normal cells. Pgp is an ATP dependent membrane efflux pump. Its function is to expel a variety of foreign molecules including antitumour drugs from the cell. Long lived cells such as the haemopoietic stern cells, cells on excretory surfaces such as biliarr hepatocytes, proximal renal tubules and intestinal cells and the cells of the blood- brain barrier, all have high expression of Pgp. The MDR phenomenon illustrates how tumour cells adapt and enhance normal cell mechanism to deal with the effects of chemotherapy and how repeated cycles of chemotherapy select out a population of cells which have developed adaptive survival mechanism e.g. in myeloma where MDR proteins are rare at diagnosis but common at progression.
Block drug activation
Block intracellular DNA synthesis
Cause efflux of drug
DNA repair inhibition