pH and multidrug resistance

Most chemotherapeutic drugs in use today are hydrophobic small molecules that are also typically either weakly basic, weakly acidic or charged. Thus, changes in the electrochemical parameters of tumour cell membranes have important effects on their transmembranous diffusion and cellular retention. Changes in these parameters can also modulate the function of immunological agents, and affect the signal transduction associated with induction of apoptosis. For these reasons, it is logical to propose that many (if not most) of the characteristics of multidrug-resistant (MDR) tumour cells could be due to perturbations in cellular ion transport. Indeed, many reports of altered ion transport in MDR cells can be found in the literature. Moreover, many studies suggest that P glycoprotein (Pgp) overexpression confers this altered ion transport, however, detailed physical-chemical analysis of this phenomenon has been confused by the complexity of the model systems devised to study Pgp. To help resolve this confusion, our laboratory has focused on a detailed characterization of 'pure' and stable Pgp transfectants unadulterated by the complications of chemotherapeutic drug exposure, various yeast strains and yeast vesicle preparations, and purified, reconstituted Pgp preparations. Recent data obtained with these model systems are summarized in this paper.