Combination of taxanes with radiation: Preclinical studies

Treatment regimens consisting of taxanes, a potent class of chemotherapeutic agents, combined with radiotherapy have recently undergone extensive preclinical investigation. The focus was primarily on cell radiosensitization because taxanes arrest cells in the radiosensitive G₂/M phase of the cell cycle. In vitro studies provided ample evidence that taxanes can enhance radiation sensitivity of tumor cells, with enhancement factors ranging from 1.1 to more than 3.0. Additive or subadditive effects were also reported. The outcome of the taxane-radiation interaction in vitro depended on many factors, including cell type, proliferation state of cells, drug concentration, and timing of radiation delivery in relation to drug administration. In vivo studies, although limited, showed that taxanes can strongly enhance tumor radioresponse, producing enhancement factors of 1.2 to more than 2.0. Two major mechanisms of tumor radioenhancement were detected: reoxygenation of radioresistant hypoxic cells and G₂/M arrest. Both occur in tumors that respond to taxanes by mitotic arrest and apoptosis. Only G₂/M arrest occurs in tumors that display only mitotic arrest. Compared with tumor radioresponse, normal tissue radioresponse was much less affected by taxanes. On a molecular level, taxanes activate a number of genes, but it appears that their effects are mainly p53-independent and primarily involve phosphorylation of the Bcl-2 gene. Overall, preclinical studies show that taxanes can enhance radiation sensitivity of tumor cells, potentiate tumor response, and increase the therapeutic ratio of radiotherapy. The cellular and molecular effects of taxanes may be useful in designing optimal treatment schedules for clinical trials.