P-glycoprotein: Its role in drug resistance

Abstract

R esistance to multiple chemotherapeutic drugs is observed in many advanced human cancers. Studies with model cell lines have revealed that multidrug resistance (MDR) can develop rapidly in mammalian cells. This raises the possibility that similar MDR tumor cells can arise in human cancers, limiting a patient’s response to chemotherapy. Advances elucidating molecular and genetic bases of the MDR phenotype have indicated that the 170 kilodalton plasma membrane protein P-glycoprotein (PGP) is causative of the MDR phenotype (see references [l-3] for reviews). Other MDR mechanisms-such as drug detoxification involving glutathione-S-transferase,” altered drug accumulation and distribution involving multidrug resistanceassociated protein,” and altered drug targets involving topoisomerase II”-have been identified in cell lines and transplantable tumors. When PGP was used as a molecular marker for the detection of MDR tumor cells in clinical samples, it was observed in a broad range of human tumor cells.7-‘L’ In some instances of childhood malignancies, in multiple myeloma, and in some malignant leukemias, clinically relevant correlations between PGP expression and the results of chemotherapeutic treatment have been established.‘“-“’ Further, in recent years a number of lipophilic compounds able to reverse the PGP-mediated MDR have been identified.14*15 Although the mechanism by which these chemosensitizing agents modulate the MDR phenotype is poorly understood, the use of these agents with conventional chemotherapy has yielded encouraging results.“~‘“‘17 These results provide confirmation that the presence of PGP expressed in tumor cells plays some direct role in limiting response to conventional chemotherapy. These clinical findings are exciting, encouraging efforts to investigate mechanisms of drug resistance in cancer cells and their reversal.