Experimental modulation of MRP (multidrug resistanceassociated protein)-mediated resistance

Abstract

INTRODUCTION DURING THE years following the experimental description of the phenomenon of “multidrug resistance”, its association with decreased cellular accumulation of the involved drug, and the identification of P-glycoprotein as the underlying mechanism, many laboratories around the world began to isolate their own multidrug resistance (MDR) cell lines. For reasons which are still not entirely clear (to us at least), most investigators used doxorubicin (Adriamycin) as the selecting agent, although the cytotoxic action of this agent is complex and probably involves multiple mechanisms. Several laboratories working independently, but in parallel, succeeded in isolating MDR cell lines, which shared many features with lines having a “classical MDR” mechanism (that is, involving I’-glycoprotein), but in which overexpression of neither Pglycoprotein nor of mRNA from the encoding MDRl gene could be detected. A line isolated by Danks and colleagues by growth of cells in teniposide (VM26), whilst crossresistant to etoposide and the anthracyclines, showed no crossresistance to the vinca alkaloids and did not have a drug accumulation deficit [l]. The authors referred to this phenotype as “atypical MDR” and subsequently demonstrated that abnormalities in function of the nuclear enzyme, topoisomerase II, were responsible [2]. However, many of the other lines showed a clear deficit in drug accumulation and a full spectrum of crossresistance. In the absence of any clues to the mechanism, this phenotype became referred to as “non-P-glycoproteinmediated MDR”. It was not, of course, known whether all such lines (Table 1) [3-91 shared a common mechanism or whether a number of alternative routes to MDR existed.