RADIOPROTECTION BY WR-151327 AGAINST THE LATE NORMAL TISSUE-DAMAGE INMOUSE HIND LEGS FROM GAMMA-RAY RADIATION

Purpose: To evaluate the protective effect of WR-151327 on late radiat ion-induced damage to normal tissues in mice. Methods and Materials: T he right hind legs of mice with or without WR-151327 administration (4 00 mg/kg) were Cs-137 gamma rays. Leg contracture and skin shrinkage a ssays were performed at 380 days after irradiated with irradiation. Th e mice were killed on day 400 postirradiation and histological section s of the legs were made. The thickness of the dermis, epidermis, and s kin (dermis plus epidermis) was measured. The muscular area of the leg s and the posterior knee angle between the femur and tibia were also m easured. The left hind legs were similarly assessed as nonirradiated c ontrols. Group means and standard deviations were calculated and dose- response curves were drawn for every endpoint. Then, the dose modifyin g factor (DMF) for each endpoint and the correlations among endpoints were determined. Results: Late damage assayed by leg contracture and s kin shrinkage progressed with increasing radiation dose. However, it w as reduced by drug treatment. The significant effect was indicated for skin shrinkage by a DMF of 1.8 at 35%. The DMF for leg contracture wa s 1.3 at 6 mm. In the irradiated legs, epidermal hyperplasia and derma l fibrosis in the skin, muscular atrophy, and extension disturbance of the knee joint were observed. These changes progressed with increasin g radiation dose. Skin damage assayed by the present endpoints was als o reduced by drug treatment by DMFs of 1.4 to 1.7. However, DMFs for d amage to the muscle and knee were not determined because no isoeffect was observed. There were good correlations between leg contracture or skin shrinkage and the other endpoints in both untreated and drug-trea ted mice. Conclusions: WR-151327 has the potential to protect against radiation-induced late normal tissue damage.