Multi-drug resistance genes in the management of neoplastic disease

P-gp can function as an ATP-dependent cytotoxic drug-efflux pump. In normal tissues, protein expression is localized to cell surfaces that face excretory lumina; hence, P-gp may function as a toxic-waste disposal system. Tumors that are derived from these tissues can be high expressors of P-gp, and these tumors tend to display intrinsic chemoresistance. Other non-expressing tumors can become P-gp positive after treatment or at relapse, suggesting that mdr may be involved in acquired resistance. The use of MDR-modifying agents has had some clinical success, and further trials of chemosensitizers are proceeding. P-gp overexpression does not explain how clinical resistance to anthracyclines, alkylating agents, and cis-platinum can arise simultaneously. In these cases, multiple genetic mechanisms of resistance may coexist. Eventually, mdr status can be used to select the most effective chemotherapy protocol for the individual. Currently, conversion of a previously mdr negative tumor to mdr expression, in the face of clinical resistance, justifies changing to a non-MDR drug protocol, or if not feasible, the use of MDR sensitizers.