P-glycoprotein-mediated multidrug resistance: experimental and clinical strategies for its reversal.

Abstract

The study of the cellular, biochemical, and molecular biology and pharmacology of MDR has provided one of the most active and exciting areas within cancer research and one that holds great promise for translation into clinical benefit. While convincing evidence for the functional role of P-gp in mediating clinical drug resistance in humans remains elusive, studies of the clinical expression of P-gp and trials of chemosensitizers with cancer chemotherapy suggest "resistance modification" strategies may be effective in some tumors with intrinsic or acquired drug resistance. However, even if P-gp-associated MDR proves to be a relevant and reversible cause of clinical drug resistance, numerous problems remain to be solved before effective clinical chemosensitization may be achieved. Such factors as absorption, distribution, and metabolism; the effect of chemosensitizers on chemotherapeutic drug clearance; toxicity to normal tissues expressing P-gp; and the most efficacious modulator regimens all remain to be defined in vivo. Clearly, the identification of more specific, potent, and less clinically toxic chemosensitizers for clinical use remains critical to the possible success of this approach. Nonetheless, the finding that a number of pharmacological agents can antagonize a well-characterized form of experimental drug resistance provides promise for potential clinical applications. Further study of chemosensitizers in humans and the rational design of novel chemosensitizers with improved activity should define the importance of MDR in clinically resistant cancer.