Cell cycle-dependent antagonistic interactions between paclitaxel and gamma-radiation in combination therapy.

PURPOSE: The promising clinical activity of paclitaxel, a naturally occurring antimicrotubule agent, has promoted considerable interest in combining this drug with radiation therapy, but it remains unclear whether such a combination would increase the therapeutic efficacy. This study is to assess the potential interactions between paclitaxel and gamma-radiation against human tumor cells in vitro. EXPERIMENTAL DESIGN: Paclitaxel and gamma-radiation were administered in three different sequences designated as pre-radiated, co-radiated, and post-radiated to BCap37 (human breast cancer cell line) and KB (human epidermoid carcinoma cell line) cells. The cytotoxic interactions between and mutual influences of these two agents on their antitumor activities were analyzed by a series of assays including cytotoxic, morphological, and biochemical examinations. RESULTS: The combination of paclitaxel and gamma-radiation did not produce a synergistic or additive effect. Instead, the overall in vitro cytotoxicity of these combinations was much lower than that of paclitaxel treatment alone. DNA fragmentation and flow cytometric assays showed that the addition of gamma-radiation interfered with paclitaxel-induced apoptosis. Further analyses indicated that the addition of gamma-radiation resulted in a transient or prolonged cell cycle arrest at G(2) phase, which likely prevented the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. In addition, biochemical examinations revealed that gamma-radiation inhibited paclitaxel-induced IkappaBalpha degradation and bcl-2 phosphorylation and increased the protein levels of cyclin B1 and inhibitory phosphorylation of p34(cdc2). CONCLUSIONS: Our results suggest that gamma-radiation might specifically block the cell cycle at G(2) phase, which in turn prevents the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. Therefore, it eventually results in a cell cycle-dependent antagonistic effect on the antitumor activity of paclitaxel. This finding may be relevant to the clinical application of combination therapy with paclitaxel and radiation.