Amifostine (
Ethyol), an inorganic
thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation and chemotherapeutic agents, thus preserving the efficacy of
radiotherapy and
chemotherapy. This review summarizes the preclinical data and clinical experience with
amifostine, and provides insight into future clinical directions.
Amifostine, an inactive
pro-drug, is transformed to an active
thiol after dephosphorylation by
alkaline phosphatase found in the normal endothelium. The absence of
alkaline phosphatase in the tumoral endothelium and stromal components, and the hypovascularity and acidity of the
tumor environment, may explain its cytoprotective selectivity. The cytoprotective mechanism of
amifostine is complicated, involving
free radical scavenging,
DNA protection and repair acceleration, and induction of cellular hypoxia.
Intravenous administration of
amifostine 740-900 mg/m(2) before
chemotherapy and 250-350 mg/m(2) before each
radiotherapy fraction are widely used regimens. The US Food and Drug Administration has approved the use of
amifostine as a cytoprotector for
cisplatin chemotherapy and for radiation-induced
xerostomia. Ongoing trials are being conducted to determine the efficacy of
amifostine in reducing radiation-induced
mucositis and other toxicities. Novel schedules and routes of administration are under investigation, and may further simplify the use of
amifostine and considerably broaden its applications.