Spence A M, Krohn K A, Edmondson S W, Steele J E, Rasey J S
Int J Radiat Oncol Biol Phys. 1986 Aug;12(8):1479-82. doi: 10.1016/0360-3016(86)90198-7.
The capacity of WR-2721 to provide radioprotection in central nervous system (CNS) tissue was assessed in F-344 rats irradiated with Cs-137 to the cervical spinal cord 45 min following injection of either 0.33 mg (0.60 X LD50) of WR-2721 or carrier solution in the right lateral cerebral ventricle. The radiation dose groups were 20, 26, 32, or 38 Gy; the dose rate was 1.48 Gy/min. Following irradiation, the time in weeks to forelimb and hindlimb paralysis was measured and statistical significance was assessed by means of the log rank sum test. The median times in weeks to forelimb paralysis in control vs. WR-2721-treated rats were, respectively, 20 vs. 22 at 38 Gy, 19 vs. 31 at 32 Gy (p less than 0.01), 23 vs. 28 at 26 Gy (p less than 0.01), and 49 vs. 60 at 20 Gy (p less than 0.01). The median times to hindlimb paralysis in control vs. WR-2721-treated rats were respectively, 20 vs. 29 at 38 Gy (p less than 0.001), 20 vs. 35 at 32 Gy (p less than 0.01), 23 vs. 34 at 26 Gy (p less than 0.001), and 58 vs. 65 at 20 Gy (p less than 0.01). From these results, we calculated the DMF for forelimb paralysis to be 1.3 and for hindlimb paralysis, 1.6. Histological studies from selected spinal cords from symptomatic killed rats showed petechial hemorrhages, rare microvascular thrombi, and scattered microinfarcts in both gray and white matter. In the white matter columns, there were scattered microfoci of demyelination. The histological findings did not differ between the control and WR-2721-treated groups, but were worse in the higher dose groups. These data indicate that WR-2721 has the capacity to be radioprotective in CNS tissues, when it is administered by a route that bypasses the blood-brain barrier.
在F-344大鼠中评估了WR-2721对中枢神经系统（CNS）组织的辐射防护能力。给大鼠右侧侧脑室注射0.33毫克（0.60×LD50）的WR-2721或载体溶液，45分钟后用Cs-137照射大鼠颈脊髓。辐射剂量组分别为20、26、32或38 Gy；剂量率为1.48 Gy/分钟。照射后，测量前肢和后肢麻痹出现的周数，并通过对数秩和检验评估统计学意义。对照组与接受WR-2721治疗的大鼠前肢麻痹的中位周数分别为：38 Gy时，20周对22周；32 Gy时，19周对31周（p＜0.01）；26 Gy时，23周对28周（p＜0.01）；20 Gy时，49周对60周（p＜0.01）。对照组与接受WR-2721治疗的大鼠后肢麻痹的中位周数分别为：38 Gy时，20周对29周（p＜0.001）；32 Gy时，20周对35周（p＜0.01）；26 Gy时，23周对34周（p＜0.001）；20 Gy时，58周对65周（p＜0.01）。根据这些结果，我们计算出前肢麻痹的剂量防护系数（DMF）为1.3，后肢麻痹的DMF为1.6。对有症状并处死的大鼠选取部分脊髓进行组织学研究，结果显示灰质和白质均有瘀点性出血、罕见的微血管血栓以及散在的微梗死灶。在白质柱中，有散在的脱髓鞘微病灶。对照组与接受WR-2721治疗的组之间组织学结果无差异，但在高剂量组中情况更严重。这些数据表明，当通过绕过血脑屏障的途径给药时，WR-2721具有对CNS组织的辐射防护能力。
