In vitro schedule-dependent interaction between irinotecan and vinorelbine in NCI H460 non-small cell lung cancer...

Despite recent developments, treatment outcome in advanced non-small cell lung cancer (NSCLC) remains far from satisfactory. Vinorelbine and irinotecan have shown good single-agent activity against NSCLC. These two anticancer agents target different phases of the cell cycle: the cytotoxicity of camptothecin occurs mainly in the S-phase while the cytotoxicity of vinca alkaloids occurs mainly in the M-phase. Thus, it seemed interesting to study the combined activity of these two drugs against human NSCLC cell lines in vitro. In this study, the cytotoxic interaction between vinorelbine and SN 38 (the active metabolite of irinotecan), administered at various schedules, was assessed against a human NSCLC cell line, NCI H460. Cell growth inhibition was determined by the MTT assay. The effects of drug combinations were analysed by the isobologram method. The mean IC50 was 2.06 x 10(-6) mg/ml or vinorelbine, 2.72 x x 10(-3) mg/ml for irinotecan and 2.76 x 10(-6) for SN 38. On simultaneous exposure to these two drugs, additive effects were observed, while antagonistic effects were observed on sequential exposure to vinorelbine followed by SN 38. On sequential exposure to SN 38 first followed by vinorelbine, a slight antagonistic effect was observed at the isoeffect 50%; at the isoeffect 70%, additive effects were observed. These findings suggested that simultaneous exposure to vinorelbine and SN 38 may be the optimum schedule for this combination, while sequential administrations may be less cytotoxic and inadequate. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and SN 38 with regard to both anti-tumor activity and toxicity.