Sequence-dependent cytotoxicity of combination chemotherapy using paclitaxel, carboplatin and bleomycin in human lung and ovarian cancer

Combination chemotherapy for non-small cell lung cancer (NSCLC) and ovarian cancer typically consists of a regimen of a taxane such as paclitaxel and a platinum-containing agent. Bleomycin, which halts cell cycle progression at G(2) phase, is an agent which might thereby increase taxane cytotoxicity . The goal of this study was to evaluate the effect of different paclitaxel -platinum or paclitaxel-bleomycin schedules on cytotoxicity in human NSCLC and ovarian cancer cells. The simultaneous combination of paclitaxel and ca rboplatin exhibited simple additivity in vitro, while sequential exposure s tudies indicated that carboplatin followed by paclitaxel produced greater t han additive cytotoxicity using the Isobologram analysis of combinatorial e ffects. In contrast, the simultaneous combination of paclitaxel and bleomyc in consistently exhibited greater than additive effects Indicating a potent ially synergistic combination. Sequential exposure studies of bleomycin fol lowed by paclitaxel produced similar synergistic findings. Experiments in S CID mice evaluating the combinations of paclitaxel and bleomycin supported the in vitro results, as significantly enhanced A549 lung tumor growth inhi bition was observed when paclitaxel was administered 1 h after bleomycin. T he synergistic activity shown by the combination of bleomycin and paclitaxe l indicates a potentially beneficial novel combination for treatment of NSC LC and ovarian cancer. [(C) 2001 Lippincott Williams & Wilkins.].