OBJECTIVE To evaluate the radioprotectant effects of the 21-aminosteroid U-74389G on the rat C6 glioma model after stereotactic radiosurgery. Because radiosurgery causes both tumor cytotoxicity, as well as regional brain edema, we hypothesized that this drug might exhibit advantageous or deleterious effects on healthy and neoplastic tissue. METHODS Rats were implanted with 10(6) C6 glioma cells into the right frontal brain and randomized to a Control Group (n = 18), radiosurgery on Day 14 (50% isodose = 35 Gy) (n = 15), or radiosurgery preceded by a single 15 mg/kg intravenous dose of 21-aminosteroid (n = 27). All animals were killed by 90 days and evaluated for survival, tumor size, the presence or absence of regional parenchymal edema, or radiation-induced vasculopathy. RESULTS After tumor implantation, median survival in the Control Group was 23 days. Significant improvements in median survival were noted after RS alone (median, 31 days; p = 0.02), and RS plus 21-aminosteroid (median, 59 days; p < 0.0001). In the Control Group, mean tumor diameter was 5.4 mm. After RS alone, the mean diameter was 3.2 mm (p = 0.002), and after RS plus 21-aminosteroid, 2.9 mm (p = 0.0002). In the Control Group, the tumor grew as a hypercellular, compact mass. Only 3 of 18 animals had peritumoral edema. In contrast, 7 of 15 animals in the RS group had evidence of edema (p = 0.006), but rats that received 21-aminosteroid showed no increase compared to controls (p = 0.38). Similarly, 6 of 15 animals that had radiosurgery alone showed evidence of vasculopathy (p = 0.005) compared to no animals in the control group and only 2 of 27 aminosteroid-treated animals. CONCLUSIONS The 21-aminosteroid U-74389G exhibits a radioprotectant effect on normal brain tissue, but does not appear to protect the tumor in an in vivo rat radiosurgery model. We believe that the observed beneficial effects on healthy brain led to significant prolongation of animal survival; perhaps, by limiting the adverse effects of high-dose radiosurgery. This radioprotectant should now be evaluated in randomized clinical trials in patients with malignant brain tumors.