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Cell Cycle–Dependent Antagonistic Interactions between Paclitaxel and -Radiation in Combination Therapy

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina

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 -radiation against human tumor cells in vitro.

Experimental Design: Paclitaxel and -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 -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 -radiation interfered with paclitaxel-induced apoptosis. Further analyses indicated that the addition of -radiation resulted in a transient or prolonged cell cycle arrest at G₂ phase, which likely prevented the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. In addition, biochemical examinations revealed that -radiation inhibited paclitaxel-induced IB degradation and bcl-2 phosphorylation and increased the protein levels of cyclin B1 and inhibitory phosphorylation of p34^cdc2.

Conclusions: Our results suggest that -radiation might specifically block the cell cycle at G₂ 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.

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