Protection of spermatogonial survival and testicular function by WR-2721 against high and low doses of radiation.

The radioprotection of normal cells with WR-2721 at doses of radiation extending down to less than 1 Gy was investigated using testicular cells. Survival of stem spermatogonia after single doses of radiation was measured by counts of repopulating tubules and by sperm head counts, with consistent results obtained for both endpoints. Protection factors (PF) obtained by injection of 400 mg/kg WR-2721 at 15 min prior to irradiation decreased from about 1.4 at radiation doses above 10 Gy to 1.0 at 2 Gy. Similarly, the radioprotection by 300 mg/kg WR-2721 was reduced from a PF of about 1.35 when the drug was given prior to a single high dose of radiation to 1.0-1.1 when the drug was given prior to each of 5 daily fractions of 2 Gy. Thus, less protection of testicular stem cells by WR-2721 was observed at lower doses of radiation. This lowered protection may be explained, at least in part, by a direct cytotoxic effect of WR-2721 on testicular stem cells. Protection of differentiated spermatogonia was observed with 400 mg/kg WR-2721; the PF was 1.4 at 1 Gy and decreased at lower doses. The protection of testicular function by WR-2721, as assayed by the return of fertility and the maximum recovered level of sperm production, was compared to the protection of stem cell survival. At about 8 Gy the PF with 400 mg/kg WR-2721 for both functional endpoints was about 1.5, which was not significantly different from the value of 1.3 obtained using the stem cell assays.