Beneficial effects of the radioprotectant 21-aminosteroid U-74389G in a radiosurgery rat malignant glioma model

Purpose: To evaluate the radioprotectant effects of the 21-aminosteroid U-7 4389G on the rat C6 glioma model after stereotactic radiosurgery. Because r adiosurgery 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 fron tal brain and randomized to a Control Group (n = 18), radiosurgery on Day 1 4 (50% isodose = 35 Gy) (n = 15), or radiosurgery preceded by a single 15 m g/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 a lone (median, 31 days; p = 0.02), and RS plus 21-aminosteroid (median, 59 d ays; p < 0.0001). In the Control Group, mean tumor diameter was 5.4 mm. Aft er 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 alon e 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 effect s on healthy brain led to significant prolongation of animal survival; perh aps, by limiting the adverse effects of high-dose radiosurgery. This radiop rotectant should now be evaluated in randomized clinical trials in patients with malignant brain tumors. (C) 1999 Elsevier Science Inc.