The effects of Bay 11-7085, an inhibitor of I-kappa-B-alpha kinase, were compared in the wild-type and deoxyadenosine-resistant mouse leukemia cell lines. At higher concentrations, Bay 11-7085 caused apoptosis and necrosis in the two cell lines. However, at much lower concentrations of Bay 11-7085, the deoxyadenosine-resistant cells became much more apoptotic than the parental wild-type L1210 cells. Under these conditions (low drug concentrations), the level of apoptotic cells far exceeded the fraction of necrotic cells. The apoptotic effects of Bay 11-7085 on the deoxyadenosine-resistant cells was both time- and concentration-dependent. Caspase-3 activity was activated in the Bay 11-7085-treated cells. The molecular basis for the difference in the apoptotic response between the wild-type and deoxyadenosine-resistant L1210 cells is not defined at this time, but these cell lines may provide a comparative model system in which differences in the cells that lead to apoptotic or necrotic responses to drugs can be defined and used in development of appropriate drugs for clinical use.