Functional analysis of P-glycoprotein and multidrug resistance associated protein related multidrug resistance in AML-blasts

Despite the high effectiveness of various P-glycoprotein (P-gp) modulating substances in vitro their clinical value e.g. for combination treatment of acute myelogenous leukemias (AML) remains still unclear. This might be expl ainable by recent findings that other factors than P-gp (e.g. the multidrug resistance associated protein (MRP)) may also be involved in clinical occu rring drug resistance. To study P-gp and MRP mediated MDR in AML blasts fro m patients with relapses at the functional level we measured rhodamine 123 (RHO) efflux in combination with a P-gp specific (SDZ PSC 833) or a MRP spe cific (MK571) modulator, respectively. Furthermore, direct antineoplastic d rug action was monitored by determination of damaged cell fraction of a bla st population using flow cytometry. We generally found strongly modulated R HO efflux by SDZ PSC 833 but slight RHO-efflux modulation by MK571 in blast s from relapsed states of AML expressing MDR1 or MRP mRNA at various levels . We could not demonstrate, though, significant PSC 833 or MK571 mediated m odulation of the cytotoxic effects of etoposide. The results point to the p ossibility that combination of etoposide and a modulator might not improve responses to chemotherapy by targeting P-gp or MRP exclusively. (C) 1999 El sevier Science Ltd. All rights reserved.