Protection of Normal Tissue against Late Radiation Injury by WR-2721

The ability of WR-2721 to protect against late radiation damage has been studied in skin, muscle, and vascular tissues of rats. Animals treated with and without WR-2721 (200 mg/kg) received irradiation to the left hind limb (2000-8000 rad); representative groups were killed at intervals ranging from 72 hr to 6 months. Acute skin reactions graded over the 6-month period were decreased by the drug with a dose-modifying factor (DMF) of 1.5. Late effects were markedly diminished in drug-protected animals. Graded skin reactions were widely separated at 6 months, and a DMF could not be calculated. At the time of sacrifice radiation atrophy of skeletal muscle was significantly reduced in drug-treated animals, as measured by changes in the cross-sectional diameters of muscle fibers (P = ≤0.05). Although this method yielded some scatter in the data, protection at the 3- and 6-month intervals indicated a DMF of 1.5-2.0. Radiation vascular injury was evaluated by measuring tissue blood flow using radioactive microsphere concentration in the left and right (irradiated and nonirradiated) hind limbs. At all dose levels significant radiation injury occurred in non-drug-treated animals when compared with controls (P = ≤0.05-0.001), while drug-treated animal flows were not significantly different from normal. Comparison of all drug-treated and non-drug-treated animals showed significant protection (P = ≤0.05). The time pattern of injury in non-drug-treated rats was biphasic, with significant damage occurring at 72 hr and 1 week, returning to normal between 1 and 3 months, but showing significant late damage at 6 months (P = ≤0.001). Again, this injury pattern did not appear in WR-2721-treated rats. Thus the ability of WR-2721 to protect against acute and chronic radiation injury in vessels, skin, and muscle indicates that an increased therapeutic gain can be expected when this drug is used in clinical radiation therapy.