The radioprotective effects of nitric oxide synthase inhibitor T1023 on normal and malignant tissues

The aim of this research was to study ability of the new NOS inhibitor, N,S-substituted isothiourea (compound T1023), to effectively and selectively protect the normal somatic tissues from radiation-induced adverse effects. Methods of investigation included the study of T1023 influence on the development of skin acute radiation damage and antitumor effects of g-radiation on intact mice and on the models of solid Ehrlich carcinoma (CE) for studying radiotherapy-induced effects; comparative estimation of the radioprotective efficacy and selectivity of T1023 and amifostine in normal tissues. The results of the experiments showed that T1023 at the optimal dose for prevention of ARS development (75 mg/kg), significantly reduced the radiation-induced alteration of the skin and underlying tissues, as well as the severity of acute radiation burns. DRF for acute radiation-induced skin reaction is 1.46. It is important to stress that no radioprotective effect of T1023 on the CE tissues, growing on the irradiated limb of animals was observed, the NOS inhibitor did not reduce the therapeutic effectiveness of radiation therapy. Amifostine (250 mg/kg) and T1023 (75 mg/kg), used in optimal radioprotective doses, were equally effective for selective protection of normal tissues. However, optimal dose of T1023 was twice as safe (26% LD16) than amifostine (50% LD16). T1023 manifests protective efficacy and selective protection of normal somatic tissues from radiation-induced damage at relatively safe doses. The protective properties of T1023 allow us to continue the study of this compound as the basis for development of an effective and safe pharmacological agent for the prevention of adverse effects of radiotherapy.