A. Photiou et al., IN-VITRO SYNERGY OF PACLITAXEL (TAXOL) AND VINORELBINE (NAVELBINE) AGAINST HUMAN-MELANOMA CELL-LINES, European journal of cancer, 33(3), 1997, pp. 463-470
Paclitaxel (PTXL) (Taxol), a taxane, and vinorelbine (VRB), a semisynt
hetic 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 StMl11a. The SRB (sulphorhodamine B) assay was used ao determine
growth inhibition. Possible drug-drug interaction at the cellular leve
l was assessed by constructing Isoboles (Isobologram analysis) and app
lying the concept of an 'envelope of additivity'. Both agents were act
ive in the nanomolar range at clinically achievable concentrations, Th
e 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 StMl11a 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 ob
served with particularly low concentrations of paclitaxel (3 nM) and V
RB (0.01 nM). A few points were located within the envelope of additiv
ity or in the subadditive (antagonism) region of the isobole. An overa
ll synergy was also found if the data were analysed by the median effe
ct analysis. The effect of these agents on the cytoskeleton and ultras
tructure 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 concent
rations. (C) 1997 Elsevier Science Ltd.