ENHANCEMENT OF DAUNOMYCIN TOXICITY BY THE DIFFERENTIATION INDUCER HEXAMETHYLENE BISACETAMIDE IN ERYTHROLEUKEMIA-CELLS

Cytotoxic effects of daunomycin were investigated upon differentiation of Friend erythroleukemia cells induced with hexamethylene bisacetami de, a process during which a 20-fold increase in the hemoglobin conten t occurred. Daunomycin proved to be more toxic to differentiated Frien d cells than to their undifferentiated counterparts. No changes in the daunomycin uptake rates of the two cell types were detectable. Extern ally added catalase and desferrioxamine mesylate protected against the additional cytotoxicity of daunomycin in differentiated cells, pointi ng to hydrogen peroxide and iron ions as mediators of the toxic effect . Daunomycin-dependent, cyanide-insensitive oxygen consumption of cont rol and induced cells did not differ significantly, and the rate of fo rmation of the daunomycin semiquinone radical electron paramagnetic re sonance signal was similar in both cell types, indicating that the dif ference in toxicity was not due to increased drug activation by plasma membrane enzymes. Differentiated cells had a lowered catalase content ; the cellular iron content was shown to increase by 2.8-fold upon cel l differentiation, with hemoglobin-bound iron being about 50% of the t otal. Altogether, the results suggest increased intracellular hydrogen peroxide generation mediated by hemoglobin, combined with a decrease in catalase activity and an increase in accessible iron, as responsibl e for the higher sensitivity to daunomycin shown by differentiated Fri end cells. This represents the first experimental system where the inc rease in anthracycline cytotoxicity upon cell differentiation can be a ttributed to redox activation and the formation of reactive oxygen spe cies.