Activity- and schedule-dependent interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive and -refractory human ovarian carcinoma cell lines

Abstract

Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of a 2 h exposure to paclitaxel, hydroperoxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-refractory human ovarian carcinoma cell lines using isobologram analysis. The combinations of either paclitaxel-hydroperoxy-ifosfamide or paclitaxel-etoposide were found to be additive or synergistic when the drugs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etoposide or hydroperoxy-ifosfamide were given before paclitaxel, antagonistic interactions were observed. With regard to etoposide this antagonism was evident for up to 24 h. In agreement with our data with the schedule-dependent interactions of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines, these data demonstrate that the interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide are also highly schedule dependent and applications of etoposide or ifosfamide before paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.