Radioprotection in rat spinal cord with WR-2721 following cerebral lateral intraventricular injection.
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.
D004999:Amifostine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D007276:Injections, Intraventricular; D009946:Organothiophosphorus Compounds / Q000627:therapeutic use*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000528:radiation effects*
D009946:Organothiophosphorus Compounds; D011837:Radiation-Protective Agents; D004999:Amifostine