Clinical pharmacology of taxanes as radiosensitizers and the thiol- based radioprotectant amifostine

Although many anticancer agents have been evaluated as radiosensitizing agents in cancer patients, none has demonstrated unequivocal clinical efficacy. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to enhance tumor cell response to ionizing radiation in cell culture studies. The pharmacokinetics and pharmacodynamics of paclitaxel in cancer patients receiving other highly metabolized drugs have not been well described and will be a key consideration in the development of the drug as a radiosensitizing agent. In addition, drug interaction studies demonstrate that administration sequence of paclitaxel with other chemotherapeutic agents, including cisplatin, doxorubicin, and cyclophosphamide, likely will affect its radiosensitizing efficacy. Other drugs that may affect paclitaxel radiosensitizing efficacy include corticosteroids and anticonvulsants; these interactions are particularly important in patients with central nervous system tumors, as is the question of whether paclitaxel can penetrate the blood-brain barrier. Overall, paclitaxel pharmacokinetics appear to favor radiosensitization, and results from an ongoing series of randomized trials should help define the drug's role in this setting. In contrast, amifostine, a sulfhydryl-containing agent, is currently being evaluated as a radioprotectant for normal tissues in patients who are receiving radiation therapy. Recent clinical trials have focused on amifostine's ability to reduce platinum-induced nephrotoxicity, although the drug was originally developed as a radioprotectant. Phase I clinical trials suggest that amifostine may be administered in much lower doses for radioprotection than those required for protection from platinum-induced nephrotoxicity. Amifostine pharmacokinetics support this finding; elimination of the drug may be dose dependent with clearance saturated at high doses, leading to increased risk of toxicity with no added radioprotectant benefit. Large randomized trials evaluating both paclitaxel as a radiosensitizer and amifostine as a radioprotectant are needed to make any firm conclusions regarding efficacy of either drug in modulating cancer therapy.