Genetic aspects of multidrug resistance

Abstract

Mammalian cells exposed to a single cytotoxic natural product drug, such as vincristine or dactinomycin, can develop resistance to the selective agent and cross-resistance to a broad spectrum of structurally and functionally distinct antibiotics and alkaloids. This phenomenon, termed multidrug resistance (MDR), has been widely studied experimentally. The most consistent feature of cells with high-level MDR is amplification and overexpression of genes encoding an integral plasma membrane protein known as P-glycoprotein. The MDR genes belong to a small family (two members in humans and three members in mouse and Chinese hamster). Based on several lines of evidence, P-glycoprotein is thought to act as an adenosine triphosphate-dependent efflux pump that decreases accumulation of drugs and increases resistance to their effects. The normal function of P-glycoprotein, apart from its role in MDR, is not known. Proposed roles in detoxification and steroid transport systems are speculative but suggest that the membrane protein may have distinct functions in normal tissues and in tumor cells with acquired MDR. Although possible endogenous substrates for P-glycoprotein have not been identified, insight into normal function may be gained from tissue distribution studies. For example, studies using molecular probes to P-glycoprotein messenger RNA and monoclonal antibodies to different epitopes of the molecule have shown that P-glycoprotein is expressed at high levels in the more differentiated or specialized cells of the colon or kidney. Amplification of MDR genes in vivo has not been observed. Whether intrinsic or acquired MDR plays a causal and potentially modifiable role in clinical nonresponsiveness to cancer chemotherapeutic agents is a topic of current interest. Prospective studies and serial determinations during the course of disease are needed to clarify the importance of this membrane protein in clinical drug resistance.