SUCCESSFUL TREATMENT OF RADIATION-INDUCED FIBROSIS USING CU ZN-SOD AND MN-SOD - AN EXPERIMENTAL-STUDY/

Purpose: To establish how far liposomal copper/zinc superoxide dismuta se (Cu/Zn-SOD) and manganese superoxide dismutase (Mn-SOD), respective ly, reduce radiation-induced fibrosis (RIF), using a well-characterize d pig model of RIF permitting the design of a controlled laboratory ex periment. Methods and Materials: In this model of acute localized gamm a irradiation simulating accidental overexposure in humans, three grou ps of five large white pigs were irradiated using a collimated Ir-192 source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of subcutaneous fibrosis involving skin and skeletal muscle developed 6 months after i rradiation. One experimental group of five pigs was then injected i.m. with 10 mg/10 kg b.wt. of Cu/Zn-SOD, twice a week for 3 weeks, and an other experimental group of five was infected with 10 mg/10 kg b.wt. o f Mn-SOD, three times a week for 3 weeks. Five irradiated control pigs were injected with physiological serum. Animals were assessed for cha nges in the density of the palpated fibrotic block and in the dimensio ns of the projected cutaneous surface. Block depth was determined by u ltrasound. Physical and sonographic findings were confirmed by autopsy 12-14 weeks after completing SOD injections. The density, length, wid th, and depth of the fibrotic block, and the areas and volume of its p rojected cutaneous surface were compared before treatment, 1, 3, and 6 weeks thereafter, and at autopsy, 12-14 weeks after treatment ended. Results: The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. Whether they were given Cu/Zn- dr Mn-SOD, significant and roughly equivalent softening and shrinking of the fibrotic block were noted in all treated animals between the f irst week after treatment ended and autopsy, when mean regression was 45% for length and width, 30% for depth, and 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneou s tissue surrounding the residual scar. This replacement of scar tissu e by normal tissue in experimental animals and the 50% decrease in the linear dimensions of the scar were comparable to the results obtained in previous clinical studies and highly significant compared to the c linical and autopsy results for the control animals. Conclusions: Our results are striking and comparable to the results obtained in our pre vious clinical study after liposomal Cu/Zn-SOD treatment. To our knowl edge, this is the first time that two agents have been shown to revers e the radiation-induced fibrotic process in experimental animals and t o permit the regeneration of normal tissue in a zone of well-establish ed postirradiation fibrosis.