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 gr owth by acting with opposed mechanisms of action and binding to differ ent sites. The purpose of this study was to evaluate in vitro the cyto toxicity of these two drugs as single agents, in combination and in se quence, against a human carcinoma ovarian cell line A2780S and its dox orubicin-resistant subline A2780R. The cell growth inhibitions were de termined by the MTT assay. The cytotoxic effect of drug combinations a t the IC50 level were analysed by the isobologram method of Steel and Peckham. On simultaneous exposure to paclitaxel and vinorelbine, syner gistic effects were observed in A2780S and A2780R cell lines. On seque ntial exposure to paclitaxel first followed by vinorelbine or vice ver sa, a strong antagonistic interaction was observed. These data demonst rate that the interactions of vinorelbine and paclitaxel are highly sc hedule-dependent. These findings could have implications for the desig n of further clinical protocols and suggest that the simultaneous admi nistration of the two agents may be the most suitable sequence while s equential administration may be avoided. Further preclinical and clini cal studies are required to elucidate the relationship between vinorel bine and paclitaxel with regard to both anti-tumor activity and toxici ty.