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.