Antimutagenic effects of amifostine: clinical implications

The radioprotector S-2-(3-aminopropylamino) ethylphosphorothioic acid (amifostine; WR-2721) was evaluated for its ability to protect against cyclophosphamide-induced mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in mouse splenocytes under conditions that do not interfere with cyclophosphamide's therapeutic effectiveness against fibrosarcoma lung tumors. Mutations at the HPRT locus increase in frequency as a function of the dose of cyclophosphamide used. With a spontaneous mutation frequency in C3H mice of 1.5 x 10(-6), mutation frequencies increased from 6.2 x 10(-6) to 2.0 x 10(-5) as the cyclophosphamide dose increased from 50 to 200 mg/kg. C3H male mice had 3.5 x 10(5) viable fibrosarcoma cells injected into their tail veins. This resulted in an average of 68 tumor colonies per mouse. Four days following injection, animals received cyclophosphamide 100 mg/kg, which provided significant tumor cell killing and a reduction in tumor colony number to an average of less than one per animal. Amifostine at a concentration of 100 mg/kg did not affect cyclophosphamide's therapeutic efficacy. However, amifostine 100 mg/kg was effective in reducing cyclophosphamide-induced HPRT mutation frequency in mice from 160 to 35 per 10(5) viable cells regardless of whether it was administered 30 minutes before or 2 hours after the cyclophosphamide.