Combination of gemcitabine antagonizes antitumor activity of paclitaxel through prevention of mitotic arrest and apoptosis

Abstract

Paclitaxel, the first member of taxanes, is one of the most active chemotherapeutic agents developed in the last decade for the treatment of advanced breast cancer and many other types of solid tumors. The promising clinical activity of paclitaxel has also promoted considerable interest in combining this drug with other antitumor agents. In this study, we assessed the cytotoxic interaction between paclitaxel and gemcitabine administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, DNA fragmentation, and flow cytometric analyses, we found that gemcitabine could significantly antagonize the cytotoxic effects of paclitaxel when tumor cells were exposed to the two drugs simultaneously or exposed to gemcitabine before paclitaxel. However, there was little antagonistic interaction observed when paclitaxel was administered before gemcitabine. Further analyses demonstrated that gemcitabine could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel is administered before gemcitabine. In addition, biochemical examinations revealed that pretreatment or cotreatment of gemcitabine inhibited paclitaxel-induced IκBα degradation and bcl-2 phosphorylation that are believed to play critical roles in the signal pathways leading to apoptotic cell death. These results indicate that the interaction between paclitaxel and gemcitabine is highly schedule dependent. Exposure of tumor cells to gemcitabine before paclitaxel or two drugs simultaneously could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to paclitaxel followed by gemcitabine.