Protection against Radiation-Induced Carcinogenesis

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Our previous study (conducted over a 4-year period) used both female C3H and CBA mice that were exposed to total body dose of radiation of 3 Gy with or without Tempol (TP) supplementation in the animal's food. Immediately following the radiation exposure, animals were be placed on either control or TP-containing food. The groups included: a) no radiation, control food, b) 3 Gy, control food, c) no radiation, TP food, and d) 3 Gy, TP food. Animals (1200 mice) were monitored for their entire lifespan and upon development of a tumor or when a humane endpoint was reached mice were euthanized, necropsied, and evaluated pathologically for the presence of tumor and cause of death. Chronic supplementation of TP in the diet of mice was found to reduce body weight without toxicity, decreased cancer, and extended survival when administered after non-lethal total body radiation (TBI). Tempol reduced the incidence of hematopoietic neoplasms (lymphomas) in both mouse strains; whereas, both the onset and incidence of non-hematopoietic neoplasms were reduced in CBA mice. To better understand mechanisms associated with these findings we have conducted year-long studies collecting tissue for assessment of genomic instability tissues and cytokine induction and these tissues are currently under study. We have also focused the past year on studies to determine if metabolites in the urine of mice receiving whole body radiation can predict for radiation-induced cancer induction prior to the observation of tumor mass. We have analyzed 106 urine metabolites acquired from 100 mice over a two year period (n = 25 0 Gy control; n = 75 5.4 Gy). Tumor pathology data for each mouse analyzed is available. Principle component analysis (PCA) using over 7000 metabolites indicates that the metabolite profile of control animals can be clearly separated from radiation exposed animals as early as 3 months post-TBI that predict for tumor induction. Further, the alteration in urine metabolites in irradiated mice can also distinguish between hematopoietic and solid tumors. Lastly, the urine metabolite profile of TBI treated mice at 6 months of age more resemble the profile of aged control mice (18 months of age). This study will be replicated beginning in the fall. Collectively, the results to date encourage further evaluation of Tempol as a chemopreventive, to reduce the incidence of radiation-induced second malignancies after a course of definitive radiation therapy. Tempol may also find applications to reduce the risk of cancers in populations exposed to non-lethal radiation due to nuclear accidents or terrorist attacks. Changes in urine metabolite profiles following radiation may provide a means to predict for radiation-induced cancer induction.