Modification of WR-2721 Radiation Protection from Gastrointestinal Injury and Death in Mice by 2-Mercaptopropionylglycine

Abstract

The radioprotective efficiency of S-2-(3-aminopropylamino)-ethyl phosphorothioic acid (WR-2721) and 2-mercaptopropionylglycine (MPG) was studied in Swiss albino mice exposed to whole-body gamma irradiation (15.0 Gy). WR-2721 (150 mg/kg), an optimum dose of MPG (20 mg/kg), or a combination of the two was administered intraperitoneally before irradiation. The radiation protection was assessed on the basis of histological changes in the jejunal mucosa on Day 3 postirradiation, development of gastrointestinal (GI) syndrome, and animal survival. In the irradiated control the number of surviving crypts was reduced to less than 17% of the value for sham-irradiated mice, and there was a complete collapse of villi. Treatment with MPG resulted in survival of about 35% of the crypts, but no notable protection of the villus structure was evident. WR-2721 alone or in combination with MPG protected both crypts and villi. The combination treatment increased the crypt cellularity and villus height significantly. The changes in the intestinal mucosa were directly correlated with the GI syndrome and death. Irradiation in the absence of the protectors resulted in 100% mortality in 10 days preceded by the signs of severe GI syndrome. Each drug individually delayed the onset of radiation sickness and reduced the severity of the signs. While MPG was not able to increase the survival rate of the animals above that of the controls, WR-2721 increased the survival rate at 10 days to 70% and at 30 days to 30%. The combination of WR-2721 with MPG further reduced the death rate from damage to the GI tract, resulting in 95% survival on Day 10; no signs of radiation sickness were noted in these animals. This treatment also increased the 30-day survival to 70%. The combination of the drugs is seen to be superior to the single-drug treatments in reducing GI injury and increasing survival.