Mechanisms of altered sequestration and efflux of chemotherapeutic drugs by multidrug-resistant cells

This review considers the mechanisms associated with the pleiotropic resist ance of cancer cells to chemotherapeutic drugs, and more particularly those related to intracellular pH (pH(i)). The multidrug resistance (MDR) phenom enon responsible for the decreased accumulation and increased efflux of cyt otoxic drugs is generally associated with excess levels of P-glycoproteins (Pgps) encoded by MDR genes and/or the multidrug resistance-associated prot ein (MRP). MDR cell lines, derived from normal or tumor cells, frequently e xhibit abnormally elevated pH(i) and changes in the production of various p roteins. Recent studies have suggested that, in addition to the impact of t he ATP-dependent membrane transporters Pgp and MRP on drug transport, other mechanisms linked to pH(i) changes in MDR cells may play an important role in drug resistance. We have shown that alkalinization of the acidic compar tments (endosomes and lysosomes) by lysosomotropic agents could stimulate t he efflux of vinblastine from drug-resistant mouse renal proximal tubule ce lls. The fact that weak base chemotherapeutic drugs can be sequestered with in the acidic organelles of MDR cells sheds new light on the cellular mecha nisms of drug resistance.