Establishment of three bleomycin-resistant human carcinoma cell lines and their cross-resistance to other antitumor agents.

Three bleomycin-resistant (BLMr) human carcinoma cell lines (HeLa-BLMr, KB-BLMr, and Hepd-uvBLMr) were established in culture by progressively increasing the concentration of bleomycin (BLM). HeLa-BLMr and KB-BLMr were obtained after 5 and 2 months of incubation with BLM, whereas the establishment of Hepd-uvBLMr required 3 months of incubation with BLM after ultraviolet treatment. These cells have been successfully subcultured for more than 150 passages during more than 2 years in the presence of 1 microgram/ml of BLM. The degrees of BLM resistance were 20-fold, 11.6-fold, and 186-fold for HeLa-BLMr, KB-BLMr, and Hepd-uvBLMr, respectively, and the resistant phenotype of both HeLa-BLMr and Hepd-uvBLMr was stable when they were cultured for 30 passages in BLM-free medium, but unstable in KB-BLMr. Although each cell line exhibited cross-resistance to 3 to 5 other antitumor agents including peplomycin, combined use of BLM with a polyene antibiotic, a calcium channel blocker, or a poly(ADP-ribose) polymerase inhibitor overcame the BLM resistance in vitro to various degrees.