Patients undergoing x-ray therapy to the pelvis have intestinal symptoms proportional to the volume treated and the dose delivered. WR-2721, S-2 (3-aminopropylaminoethyl) phosphorothioic acid, is an organic thiophosphate compound that selectively protects normal tissues against radiation effects. A Phase I/II study was done to test the ability of topical application of WR-2721 to protect the mucosa of the rectosigmoid from radiation damage. Thirty-one patients were enrolled in this study, of which, seven were control subjects. Twenty-four patients received WR-2721 daily, in enema form, 45 minutes before treatment. The patients were assigned by groups of three to receive increasing doses of WR-2721 beginning with 100 mg/enema to 450 mg/enema. Rectal mucosal biopsies were obtained within the treated field before, during, and at the end of therapy. The degree of damage to the rectal mucosa was scored on the basis of a 0 to 4 scale (with 0, least damage to 4, most damage) as determined by the percentage of damaged mucosal crypt glands. The patients' symptoms were recorded once a week during the entire course of therapy. The biopsy scores of the control group were slightly higher than those of the treatment groups; however, this difference did not appear to be significant. In the treated groups, there was a slight decrease in the biopsy scores with increasing doses of WR-2721, but this trend was not sustained. There were no differences among any of the groups in the symptoms experienced during the course of therapy. This study showed that WR-2721 could be administered safely in enema form in doses ranging from 100 to 450 mg/enema, but this drug did not protect the rectosigmoid mucosa from radiation damage at the doses administered.