DOES P-GLYCOPROTEIN PLAY A PIVOTAL ROLE IN THE DRUG-RESISTANCE OF AN MDR VARIANT, K562 DOX

A multidrug-resistant (MDR) variant, K562/Dox, was selected from repea ted exposure of human erythroleukemia cell line K562 to doxorubicin (D ox). K562/Dox displayed typical MDR features with respect to its cross -resistance to a variety of functionally and structurally unrelated co mpounds: vincristine (Vin), Dox, mitomycin C, reduced steady-state int racellular anthracycline accumulation, and elevated P-glycoprotein exp ression/mdrl mRNA transcription/mdrl gene amplification. Nevertheless, by incubation of cells with Dox/epirubicin (Epi)/daunorubicin (Dau) ( 5-80 mu g/ml), the initial drug uptake was similar (p > 0.05) in K562/ Dox and K562 cells, suggesting P-glycoprotein-mediated drug efflux wou ld not occur unless a relatively high cellular drug concentration was reached. After 8 h incubation of cells with 50 ng/ml Dox (5 times high er than its IC50 to K562 cells), there were only slight differences (p > 0.05) in intracellular drug levels between K562/Dox and K562 cells, clearly indicating that K562/Dox, circumventing drug toxicity in this case, was irrelevant to reduced drug accumulation caused by P-glycopr otein. Similar results were obtained when Epi or Dau was applied. Desp ite complete restoration of anthracycline accumulation in K562/Dox cel ls in the presence of 6 mu mol/l verapamil, the reversal of their drug resistance was incomplete. These results suggest that P-glycoprotein- mediated drug efflux possibly did not play a primary role in the drug resistance of K562/Dox cells.