SYNERGISTIC INTERACTION BETWEEN CISPLATIN AND TAXOL IN HUMAN OVARIAN-CARCINOMA CELLS IN-VITRO

Taxol, a unique tubulin active agent, was found to demonstrate a marke d schedule-dependent synergistic interaction with cisplatin (DDP) in t he killing of human ovarian carcinoma 2008 cells in vitro as determine d by median effect analysis. The interaction was highly synergistic wh en 19 h taxol exposure was followed by 1 h concurrent exposure to taxo l and DDP. The combination indices (CIs) on this schedule were 0.11 +/ - 0.1, 0.25 +/- 0.15 and 0.39 +/- 0.14 at 20%, 50% and 80% cell kill r espectively. However, the interaction was antagonistic when 1 h exposu re to DDP was followed by 20 h exposure to taxol, or when cells were e xposed to DDP and taxol for Ih concurrently. When taxol preceded DDP, synergy was also observed with the ii-fold DDP-resistant 2008/C135.25 subline, which yielded CI Values of 0.21 +/- 0.02, 0.30 +/- 0.11 and 0.31 +/- 0.17 at 20%, 50% and 80% cell kill respectively. At an IC50 c oncentration, taxol had no effect on [H-3]cis-dichloro(ethylenediamine ) platinum uptake, on the permeability of the plasma membrane or on gl utathione or metallothionein levels in 2008 or 2008/C135.25 cells. Mi totic arrest in these cells was observed only at taxol concentrations well above those required for synergy with DDP, suggesting that the me chanism underlying the synergistic interaction was not a taxol-induced alteration in cell cycle kinetics. Of additional interest was the fac t that the 2008/C135.25 cells were hypersensitive to taxol, and that this was partially explained by an alteration in the biochemical pharm acology of taxol. Although cellular taxol accumulation reached steady state within 2 h in both cell lines, taxol efflux was slower and the t axol was more extensively bound in 2008/C135.25 cells than in 2008 ce lls. In addition, the 2008/C135.25 cells had only 55% of the parental levels of beta-tubulin content. However, in another pair of DDP-sensi tive and -resistant ovarian cell lines no taxol hypersensitivity and n o change in beta-tubulin content was observed, indicating that the DDP -resistant and taxol-hypersensitive phenotypes do not segregate togeth er. We conclude that taxol interacts synergistically with DDP in a man ner that is highly schedule dependent, and that the hypersensitivity o f 2008/C135.25 cells to taxol is unrelated to the mechanism of synerg y. These in vitro observations suggest that drug schedule will be an i mportant determinant of the activity and toxicity of the DDP and taxol drug combination in clinical studies.