In vitro synergy of paclitaxel (Taxol) and vinorelbine (navelbine) against human melanoma cell lines

Abstract

Paclitaxel (PTXL) (Taxol), a taxane, and vinorelbine (VRB), a semisynthetic vinca alkaloid drug, have tubulin as their common intracellular target, but inhibit growth by binding to different sites. We evaluated in vitro the antiproliferative activity of these two drugs as single agents and in combination, against two human melanoma cell lines, G361 and StM111a. The SRB (sulphorhodamine B) assay was used to determine growth inhibition. Possible drug-drug interaction at the cellular level was assessed by constructing Isoboles (Isobologram analysis) and applying the concept of an 'envelope of additivity'. Both agents were active in the nanomolar range at clinically achievable concentrations. The mean IC50 for G361 was 46.6 nM (PTXL) and 19.9 nM (VRB) after a 1 h drug exposure. Mean IC50 (1 h) for StM111a was 9.7 nM (PTXL) and 26.9 nM (VRB). Isobole analysis at the isoeffect levels of 25%, 50% and 75% indicated that drug interaction was predominantly synergistic (supra-additive) when paclitaxel and VRB were added concurrently for 1 h to cultures of StM11 1a or G361. In some experiments, this synergy was observed with particularly low concentrations of paclitaxel (3 nM) and VRB (0.01 nM). A new points were located within the envelope of additivity or in the subadditive (antagonism) region of the isobole. An overall synergy was also found if the data were analysed by the median effect analysis. The effect of these agents on the cytoskeleton and ultrastructure were studied with immunofluorescence and electron microscopy, respectively. These results confirm the in vitro inhibitory activity of paclitaxel and VRB against malignant melanoma, but more importantly the two drugs appear to act synergistically at relatively low concentrations.