Radioprotective and tumor antiangiogenic effect of the novel synthetic superoxide dismutase (SOD) mimetic compounds
© BioMed Central Ltd 2001
Received: 10 May 2001
Published: 31 May 2001
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.