Exploration of platinum-based dose-intensive chemotherapy strategies with amifostine (Ethyol)

The preclinical evaluation of amifostine confirms selective protection of normal tissues against toxicity due to cisplatin therapy while maintaining the antitumour effects. The mechanism of protection relates to the selective uptake of the free thiol, amifostine, into normal tissue compared with tumour tissue, intracellular binding and therefore detoxification of anticancer drugs, as well as through the scavenging of oxygen free radicals. Although vigorous hydration schedules have helped to alleviate nephrotoxicity, ototoxicity and cumulative dose-related peripheral neuropathy, these side effects remain important dose-limiting toxicities related to cisplatin therapy. The preclinical and clinical results to date demonstrate that amifostine can protect against cisplatin toxicities, in particular nephrotoxicity. Recent studies have demonstrated that higher single and cumulative cisplatin doses have an important impact on survival outcome; however, the improvement in survival comes at the cost of increased acute and cumulative haematological, renal and neurological toxicities that can result in serious morbidity. The role of amifostine as a unique supportive measure to reduce these toxicities offers the possibility of improving the quality of life of patients receiving chemotherapy.