DRUG-RESISTANCE MECHANISMS AND MRP EXPRESSION IN RESPONSE TO EPIRUBICIN TREATMENT IN A HUMAN LEUKEMIA-CELL LINE

A drug resistant series of sublines were developed by treating the hum an leukaemia CCRF-CEM cell line with 16-1000 ng/ml of the anthracyclin e, epirubicin. The sublines developed resistance in two stages, neithe r involving detectable levels of P-glycoprotein. Treatment with up to 50 ng/ml epirubicin produced sublines with cross resistance limited to the anthracyclines and etoposide. Treatment with 100-1000 ng/ml epiru bicin produced sublines with increased expression of the mrp gene, inc reased resistance to the anthracyclines and etoposide, additional cros s resistance to vincristine and colchicine, decreased drug accumulatio n and reversal of resistance by verapamil and by buthionine sulphoximi ne (BSO; an inhibitor of glutathione synthesis). Our results indicate an interaction between MRP and glutathione metabolism as a mechanism f or multidrug resistance.