Radioprotectants: Pharmacology and clinical applications of amifostine

Amifostine (Ethyol, ALZA Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) is a phosphorylated cysteamine derivative that was originally developed by the US Army Walter Reed Institute (Washington, DC) as a radioprotectant. Amifostine, a prodrug, is metabolized by the enzyme alkaline phosphatase to an active sulfhydryl compound (WR-1065) capable of scavenging radiation-generated free radicals and preventing cell damage. The disulfides of WR-1065 are structurally analogous to endogenous polyamines, which can bind to DNA molecules and stabilize them in a compact form less vulnerable to damage by cytotoxic agents. Preclinical and clinical studies show that amifostine is a selective radioprotectant that reduces both early and late radiation-induced toxicities to normal tissues while leaving tumor cells exposed to the cytotoxic effects of radiation. Preclinical data indicate that amifostine could reduce the risk of secondary cancers caused by radiation and certain forms of chemotherapy.