Protection against Radiation-Induced Carcinogenesis

我们之前的研究(为期4年)使用了雌性C3H和CBA小鼠，这些小鼠在动物的食物中添加或不添加Tempoll(TP)的情况下，暴露于3Gy体总剂量的辐射。在辐射暴露后，立即将动物置于对照组或含TP的食物中。组包括：a)不照射，对照食物；b)3Gy，对照食物；c)不照射，TP食物；d)3Gy，TP食物。对动物(1200只小鼠)的整个生命周期进行监测，在发生肿瘤或达到人道终点时，对小鼠进行安乐死、尸检，并对其是否存在肿瘤和死因进行病理学评估。在小鼠饮食中长期补充茶多酚被发现在非致命性全身辐射(TBI)后服用时，可以减轻体重，没有毒性，减少癌症，并延长生存时间。在两个品系的小鼠中，坦普尔降低了造血肿瘤(淋巴瘤)的发生率；而在CBA小鼠中，非造血肿瘤的发病率和发病率都降低了。为了更好地了解与这些发现相关的机制，我们进行了长达一年的研究，收集组织用于评估基因组不稳定性、组织和细胞因子诱导，这些组织目前正在研究中。在过去的一年里，我们还专注于研究，以确定接受全身辐射的小鼠的尿液中的代谢物是否可以在观察肿瘤质量之前预测辐射诱发癌症的发生。我们分析了两年期间从100只小鼠身上获得的106种尿代谢物(n=250Gy对照组；n=755.4Gy.)分析的每只小鼠的肿瘤病理数据都是可用的。主成分分析(PCA)对7000多种代谢物的分析表明，对照动物的代谢物与辐射暴露动物的代谢物图谱早在脑损伤后3个月就可以清晰地分离出来，从而预测了肿瘤的诱发。此外，受照小鼠尿液代谢产物的变化也可以区分造血性肿瘤和实体肿瘤。最后，脑外伤治疗组小鼠在6个月龄时的尿代谢物谱更接近于老年对照组小鼠(18个月龄)。这项研究将从秋季开始重复进行。总而言之，迄今为止的结果鼓励进一步评估坦波尔作为一种化学预防措施，以减少在一个明确的放射治疗疗程后由辐射引起的第二种恶性肿瘤的发生率。坦波尔还可能找到降低因核事故或恐怖袭击而暴露于非致命性辐射的人群患癌症风险的应用程序。辐射后尿代谢物的变化可能为预测辐射致癌提供一种手段。

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.