Taxol and discodermolide represent a synergistic drug combination in humancarcinoma cell lines

Recently, three natural products have been identified, the epothilones, ele utherobin, and discodermolide, whose mechanism of action is similar to that of Taxol in that they stabilize microtubules and block cells in the mitoti c phase of the cell cycle. In this report, we have compared and contrasted the effects of these new agents in Taxol-sensitive and-resistant cell Lines . We also have taken advantage of a human lung carcinoma cell line, A549-T1 2, that was isolated as a Taxol-resistant cell line and found to require lo w concentrations of Taxol (2-6 nu) for normal cell division. This study the n examined the ability of these new compounds to substitute for Taxol in su staining the growth of A549-T12 cells, Immunofluorescence and flow cytometr y have both indicated that the epothilones and eleutherobin, but not discod ermolide, can substitute for Taxol in this Taxol-dependent cell line, In A5 49-T12 cells, the presence of Taxol significantly amplified the cytotoxicit y of discodermolide, and this phenomenon was not observed in combinations o f Taxol with either the epothilones or eleutherobin, Median effect analysis using the combination index method revealed a schedule-independent synergi stic interaction between Taxol and discodermolide in four human carcinoma c ell lines, an effect that was not observed between Taxol and epothilone B, Flow cytometry revealed that concurrent exposure of A549 cells to Taxol and discodermolide at doses that do not induce mitotic arrest caused an increa se in the hypodiploid population, thereby indicating that a possible mechan ism for the observed synergy is the potentiation of apoptosis, Our results suggest that Taxol and discodermolide may constitute a promising chemothera peutic combination.