In vitro evaluation of schedule-dependent interactions between docetaxel and doxorubicin against human breast and ovarian cancer cells

Docetaxel, a novel member of the taxoid family, has shown greater potency t han paclitaxel in the treatment of advanced breast cancer and certain other solid tumors. The promising clinical activity of docetaxel has also promot ed considerable interest in combining this drug with other antitumor agents . In this study, we assessed the cytotoxic interaction between docetaxel an d doxorubicin administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including DNA fragmentat ion analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and flow cytometric analyses, we found that the antagonistic intera ction occurred when tumor cells were exposed to the two drugs simultaneousl y or exposed to doxorubicin before docetaxel, However, no antagonism was ob served when docetaxel was added before doxorubicin, Further analyses demons trated that doxorubicin could interfere with the cytotoxic effect of doceta xel on both mitotic arrest and apoptotic cell death. In addition, biochemic al examinations revealed that docetaxel could induce phosphorylation of bot h bcl-2 and c-raf-1, but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin, These results indic ate that the interaction between docetaxel and doxorubicin is highly schedu le dependent. Exposure of tumor cells to doxorubicin before docetaxel could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to docetaxel followed by doxorubicin.