After several decades of preclinical and clinical research, the first approved 
radioprotective drug, amifostine, is being used in clinical practice. Amifostine 
has been shown to specifically protect normal tissues from damage caused by 
radiation and chemotherapy. An inactive prodrug, amifostine is converted to an 
active thiol by dephosphorylation by alkaline phosphatase in the normal 
endothelium. The hypovascularity and acidity of the tumor environment and the 
differential expression of alkaline phosphatase in normal and neoplastic tissues 
contribute to its cytoprotective selectivity. The cytoprotective mechanism of 
amifostine is complicated, involving free-radical scavenging, DNA protection and 
repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug 
Administration has approved the i.v. use of amifostine to reduce the cumulative 
renal toxicity associated with repeated administration of cisplatin in patients 
with advanced ovarian cancer and to reduce the incidence of moderate to severe 
xerostomia in patients undergoing postoperative radiation treatment for head and 
neck cancer, where the radiation port includes a substantial portion of the 
parotid glands. Nonetheless, amifostine has potential applications in many other 
oncologic settings. Novel schedules and routes of administration are under 
investigation and may further simplify the use of amifostine, reduce any 
undesired effects, and considerably broaden its applications. This review 
summarizes the clinical experience with amifostine and provides insight into 
future clinical directions.