pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The primary mechanism leading to a multidrug-resi stant phenotype is assumed to be plasma-membrane localized overexpression o f drug efflux transporters, such as P-glycoprotein (P-gp). However, acidic intracellular organelles can also participate in resistance to chemotherape utic drugs. In this study, we investigated, both experimentally and theoret ically, the effect of acidic vesicle turnover on drug resistance. We have d eveloped a general model to account for multiple mechanisms of resistance t o weakly basic organic cations, e.g. anthracyclines and Vinca alkaloids. Th e model predicts that lower cytosolic concentrations of drugs can be achiev ed through a combination of high endosomal. turnover rates, a low endosomal pH, and an alkaline-inside pH gradient between cytosol and the extracellul ar fluid. Measured values for these parameters have been inserted into the model. Computations using conservative values of all parameters indicate th at turnover of acidic vesicles can be an important contributor to the drug- resistant phenotype, especially if vesicles contain an active uptake system , such as H+/cation exchange. Even conservative estimates of organic cation -proton antiport activity would be sufficient to make endosomal drug extrus ion a potent mechanism of resistance to weakly basic drugs. The effectivene ss of such a drug export mechanism would be comparable to drug extrusion vi a drug pumps such as P-gp. Thus, turnover of acidic vesicles can be an impo rtant factor in chemoresistance, especially in cells that do not overexpres s plasma membrane-bound drug pumps like P-glycoprotein. (C) 1999 Elsevier S cience Inc.