Radioprotective and tumor antiangiogenic effect of the novel synthetic superoxide dismutase (SOD) mimetic compounds

We have developed and tested several synthetic superoxide dismutase (SOD) mimetic metalloporphyrin compounds to determine their ability to protect/ameliorate radiation-induced (RT) normal tissue injury, and, at the same time, to produce significant anti-tumor activity. In rats with R3230 AC mammary adenocarcinoma tumors, a significant inhibition of tumor growth was observed after intraperitoneal administration of 6mg/kg of manganese(III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2PyP). Furthermore, rats that received MnTE-2PyP had a significant inhibition of the postradiation tumor regrowth. Animals pretreated with MnTE-2PyP (6mg/kg intraperitoneal) 24h before implantation of R3230 mammary adenocarcinoma show a significant inhibition of tumor angiogenesis. MnTE-2-PyP significantly delayed development of RT-induced lung injury in rats after 28Gy of right hemithoracic irradiation. The magnitude of the change in breathing rate is, on average, reduced by 30%, indicating the ability of MnTE-2PyP to significantly reduce the severity of RT-induced lung injury. Six months after the treatment, a significant increase in hydroxyproline content per gram of dry or wet lung was observed in animals receiving radiation only. Administration of 6mg/kg of MnTE-2-PyP before RT resulted in a significant reduction in hydroxyproline content. Furthermore, we have found a significant association between the radioprotective effect of MnTE-2-PyP and changes in plasma levels of transforming growth factor-β. This association suggests a possible role of SOD mimetics in activation/regulation of cytokines that are involved in development of radiation-induced lung injury. This new strategy of utilizing a single compound with antitumor activity to simultaneously protect normal tissues could allow a higher dose of radiation to be delivered to the tumor without increasing the risk of complications, and could further improve breast-conserving cancer therapy.