CIRCUMVENTION OF P-GLYCOPROTEIN-MEDIATED DRUG-RESISTANCE IN HUMAN LEUKEMIC-CELLS BY NONIMMUNOSUPPRESSIVE CYCLOSPORINE-D ANALOG, SDZ-PSC-833

Cyclosporin A (CSA) exhibits greater multidrug resistance (MDR) modula ting activity in vitro than other MDR modulators such as verapamil and quinidine, However, the immunosuppressive and nephrotoxic effects of CSA may limit its clinical use, PSC 833, a new cyclosporin D derivativ e, exerts a higher MDR reversal activity but lacks toxic or immunosupp ressive effects. The drug-resistant sublines K/DAU(100), K/DAU(200), K /DAU(300), K/DAU(400), K/ DAU(500) and K/DAU(600) have been derived fr om the drug-sensitive parental cell line, K562 cl.6 and CEM/VLB(100) i s a drug-resistant derivative of CCRF-CEM. We report a comparison of t he effects of PSC 833 and CSA on daunorubicin (DAU) transport kinetics and chemosensitivity in these cell lines, Both CEM/VBL(100) and K562 cl.6 DAU-resistant cells displayed high levels of P-glycoprotein (PGP) , decreased DAU accumulation and increased DAU efflux when compared to their parental cells. PSC 833 was 1.6-, 3.4-, 4.9- and 4.6-fold more effective than CSA in reversing DAU resistance in higher resistance CE M/VLB(100), K/DAU(400), K/DAU(500) and K/DAU(600) cells respectively, DAU transport kinetics showed that PSC 833 was more effective than CSA in increasing cellular DAU accumulation and decreasing DAU efflux in higher resistant leukaemia subclones, PSC 833 could restore DAU retent ion at lower doses and was more active than CSA in all the resistant c ells. A 89-100% restoration of intracellular DAU retention were gained by PSC 833 at 1.0 mu M in K562 cl.6 DAU-resistant sublines, whereas a 73-100% restoration of DAU retention was obtained by CSA only at 30.O mu M in the same resistant sublines. PSC 833 at 3.0 mu M is sufficien t to restore full DAU retention in all resistant cells. CSA, however, even at 30.0 mu M, cannot confer full restoration of DAU retention in higher resistance K562 cl.6/DAU sublines. By measuring MDR modulator-m ediated short-term inhibition of PGP function, PSC 833 was found to be at least 10-30 times more active than CSA. As no effect on DAU retent ion and sensitivity has been found in sensitive parental cells with PS C 833, it is suggested that PSC 833 may act by blocking the effluxing function of PGP in the resistant leukaemia cells.