Kondziolka D, Mori Y, Martinez A J, McLaughlin M R, Flickinger J C, Lunsford L D
Department of Neurological Surgery, University of Pittsburgh, PA, USA.
Int J Radiat Oncol Biol Phys. 1999 Apr 1;44(1):179-84. doi: 10.1016/s0360-3016(98)00552-5.
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.
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.
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.
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.
评估21 -氨基类固醇U - 74389G在立体定向放射外科手术后对大鼠C6胶质瘤模型的辐射防护作用。由于放射外科手术会导致肿瘤细胞毒性以及局部脑水肿，我们推测这种药物可能对健康组织和肿瘤组织产生有利或有害的影响。
将10⁶个C6胶质瘤细胞植入大鼠右额叶脑内，随机分为对照组（n = 18）、第14天进行放射外科手术组（50%等剂量线 = 35 Gy）（n = 15）或在放射外科手术前静脉注射单次15 mg/kg 21 -氨基类固醇组（n = 27）。所有动物在90天内处死，评估其生存情况、肿瘤大小、是否存在局部实质水肿或放射性血管病变。
肿瘤植入后，对照组的中位生存期为23天。单独放射外科手术后中位生存期有显著改善（中位值，31天；p = 0.02），放射外科手术加21 -氨基类固醇组（中位值，59天；p < 0.0001）。在对照组中，平均肿瘤直径为5.4 mm。单独放射外科手术后，平均直径为3.2 mm（p = 0.002），放射外科手术加21 -氨基类固醇后为2.9 mm（p = 0.0002）。在对照组中，肿瘤生长为细胞密集的紧实肿块。18只动物中只有3只出现瘤周水肿。相比之下，放射外科手术组15只动物中有7只出现水肿迹象（p = 0.006），但接受21 -氨基类固醇的大鼠与对照组相比未出现增加（p = 0.38）。同样，单独进行放射外科手术的15只动物中有6只出现血管病变迹象（p = 0.005），而对照组无动物出现，27只接受氨基类固醇治疗的动物中只有2只出现。
21 -氨基类固醇U - 74389G对正常脑组织具有辐射防护作用，但在体内大鼠放射外科手术模型中似乎不能保护肿瘤。我们认为观察到的对健康脑的有益作用导致动物生存期显著延长；也许是通过限制高剂量放射外科手术的不良反应。这种辐射防护剂现在应该在恶性脑肿瘤患者的随机临床试验中进行评估。
