ACTIVITY-DEPENDENT AND SCHEDULE-DEPENDENT INTERACTIONS OF PACLITAXEL,ETOPOSIDE AND HYDROPEROXY-IFOSFAMIDE IN CISPLATIN-SENSITIVE AND CISPLATIN-REFRACTORY HUMAN OVARIAN-CARCINOMA CELL-LINES

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 2 h exposure to paclitaxel, hydrop eroxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-re fractory human ovarian carcinoma cell lines using isobologram analysis , The combinations of either paclitaxel-hydroperoxy-ifosfamide or pacl itaxel-etoposide were found to be additive or synergistic when the dru gs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etopos ide or hydroperoxy-ifosfamide were given before paclitaxel; antagonist ic interactions were observed. With regard to etoposide this antagonis m was evident for up to 24 h. In agreement with our data with the sche dule-dependent interactions of paclitaxel and cisplatin in human gastr ic and ovarian carcinoma cell lines, these data demonstrate that the i nteractions of paclitaxel, etoposide and hydroperoxy-ifosfamide are al so highly schedule dependent and applications of etoposide or ifosfami de before paclitaxel may result in pronounced antagonism. These Ending s could have implications for the design of further clinical protocols .