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 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). Notably, delaying administration of the Tempol diet 1 month after TBI could also enhance survival. 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. Currently, to better define the timing of TP treatment with regard to survival enhancement and reduction in carcinogenesis, groups of C3H mice were exposed to 3 Gy TBI (3 Gy control on regular diet) and TP food supplementation was initiated at time 0, 1, 2, 3, or 6 months post-IR (n = 100/group). Likewise, we are testing the hypothesis that the survival advantage and reduction in hematopoietic cancers following 3 Gy TBI afforded by TP food supplementation can be achieved with short durations of TP treatment. To test this hypothesis, groups of C3H mice were exposed to 3 Gy TBI (3 Gy control on regular diet) and TP food supplementation was initiated immediately post-IR. The TP diet will either be continued for the full 400 days or will be changed to the control diet at 1, 2, 3, or 6 months post-IR (n = 100/group). These are long-term studies as mice will be followed to 400 days post-IR for survival assessment. Both of these studies were initiated in 2013. Lastly, studies are on-going 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 are currently analyzing 106 urine metabolites acquired from 100 mice over a two year period. Preliminary principle component analysis (PCA) using over 7000 metabolites indicates that the metabolite profile of control animals can be clearly separated from IR exposed animals. Considerable more data analysis will be required. 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.
|Cook, John A; Chandramouli, Gadisetti V R; Anver, Miriam R et al. (2016) Mass Spectrometry-Based Metabolomics Identifies Longitudinal Urinary Metabolite Profiles Predictive of Radiation-Induced Cancer. Cancer Res 76:1569-77|
|Mitchell, James B; Anver, Miriam R; Sowers, Anastasia L et al. (2012) The antioxidant tempol reduces carcinogenesis and enhances survival in mice when administered after nonlethal total body radiation. Cancer Res 72:4846-55|