In addition to the cytoprotective benefits of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) to normal cells, it also prevents the induction of somatic mutations that can lead to therapy-induced second cancers. The mutagenic effects of cyclophosphamide, an agent that is known to be mutagenic to normal cells, were determined in mouse splenocytes using a mutational assay system. Cyclophosphamide 100 mg/kg increased mutant frequencies 10-fold. In contrast, amifostine 100 mg/kg, whether administered 30 minutes before or 2 hours after cyclophosphamide administration, resulted in eightfold lowered mutant frequencies. To address potential cytoprotective effects on tumors exposed to this dose, amifostine was administered to tumor-bearing mice either 30 minutes before or 2 hours after the administration of cyclophosphamide. Cyclophosphamide (range, 10 to 100 mg/kg) was administered intraperitoneally into mice 4 days following the injection of 3.5 x 10(5) viable fibrosarcoma (FSa) cells. At this time, microcolonies of FSa tumors containing 50 to 200 cells were present in the lung. The number of FSa lung nodules formed at the end of 14 days in control animals was compared with that of animals treated with cyclophosphamide +/- amifostine. No cytoprotection of murine FSa tumors by amifostine was observed across the entire cyclophosphamide dose range tested, regardless of time of administration, demonstrating the utility of amifostine as a chemopreventive drug under conditions that do not allow cytoprotection for tumor cells.