SCHEDULE-DEPENDENT ANTAGONISM OF PACLITAXEL AND CISPLATIN IN HUMAN GASTRIC AND OVARIAN-CARCINOMA CELL-LINES IN-VITRO

Paclitaxel has demonstrated broad clinical activity in a variety of ma lignancies both alone and in combination with other chemotherapeutic a gents. The in vitro cytotoxicity of paclitaxel and cisplatin alone, in combination and in sequence, were evaluated against established human gastric and ovarian carcinoma cell lines using 2-h drug exposure. The combination of cisplatin and paclitaxel was found to be additive or e ven synergistic when paclitaxel was given 24 h prior to cisplatin as d emonstrated by isobologram analysis. However, when both drugs were giv en simultaneously or when cisplatin was given prior to paclitaxel, a s trong antagonistic interaction was observed. This antagonism was evide nt for up to 72 h after a 2-h exposure to cisplatin. Pretreatment with cisplatin caused no alteration in [H-3]paclitaxel uptake in HM2 gastr ic carcinoma cells, but resulted in decreased intracellular retention of paclitaxel. Since cisplatin treatment led to a reduction in cellula r glutathione content in these cells and reduced levels of glutathione have been associated with protection against cytotoxicity of paclitax el, cells were pretreated with L-buthionine sulfoximine (L-BSO). Howev er, depletion of glutathione had no influence on the activity of pacli taxel. A significant accumulation of cells in S-phase was observed 24 h after cisplatin, which resolved after 48 h and resulted in a pronoun ced increase of G(2)M phase. These data demonstrate that the interacti ons of paclitaxel and cisplatin are highly schedule-dependent and appl ications of cisplatin simultaneously with or prior to paclitaxel may r esult in pronounced antagonism. These findings could have implications for the design of further clinical protocols.