In vitro schedule-dependent interaction between paclitaxel and vinorelbine in A2780 parental and multidrug-resistant human ovarian cancer cell lines

Paclitaxel, a taxane, and vinorelbine, a semisynthetic vinca alkaloid drug, have tubulin as their common intracellular target but inhibit growth by acting with opposed mechanisms of action and binding to different sites. The purpose of this study was to evaluate in vitro the cytotoxicity of these two drugs as single agents, in combination and in sequence, against a human carcinoma ovarian cell line A2780S and its doxorubicin-resistant subline A2780R. The cell growth inhibitions were determined by the MTT assay. The cytotoxic effect of drug combinations at the IC50 level were analysed by the isobologram method of Steel and Peckham. On simultaneous exposure to paclitaxel and vinorelbine, synergistic effects were observed in A2780S and A2780R cell lines. On sequential exposure to paclitaxel first followed by vinorelbine or vice versa, a strong antagonistic interaction was observed. These data demonstrate that the interactions of vinorelbine and paclitaxel are highly schedule-dependent. These findings could have implications for the design of further clinical protocols and suggest that the simultaneous administration of the two agents may be the most suitable sequence while sequential administration may be avoided. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and paclitaxel with regard to both anti-tumor activity and toxicity.