Human monocytic leukemia U937 cells underwent apoptosis when the cells were treated with a variety of antitumor drugs. We isolated and characterized a mutant, UK711, that was resistant to apoptosis induced by antitumor agents. When U937 cells were treated with etoposide (VP-16), an inhibitor of DNA topoisomerase II, apoptosis occurred in a large number of cells, and flow-cytometric analysis revealed that the majority of cells in S phase underwent apoptosis within 2 h of the end of treatment. Such treatment, however, induced apoptosis in only a few UK711 cells. The levels of protein-DNA covalent links and DNA double-strand breaks caused by VP-16 were similar in both cell lines, indicating that the initial DNA damage caused by VP-16 were comparable, whereas the following cellular responses that resulted in apoptosis differed between these cell lines. UK711 cells also showed resistance to apoptosis induced by such antitumor agents as 1-(beta-D-arabinofuranosyl) cytosine (Ara-C), adriamycin, mitomycin C, camptothecin, and by cytotoxic stimuli such as staurosporine, cycloheximide, and uv irradiation. UK711 cells, however, were sensitive to apoptosis induced by tumor necrosis factor (TNF), as were U937 cells. In accordance with resistance to apoptosis induced by antitumor agents, UK711 cells showed significant actual drug resistance to these antitumor agents. The present results indicate that UK711 cells acquired resistance to apoptosis induced by a variety of cytotoxic stimuli resulting in actual anticancer drug resistance. This cell line may be useful in studying the mechanism of apoptosis induced by cytotoxic agents.