Protection against Radiation-Induced Carcinogenesis

防止辐射诱发的致癌作用

• 批准号: 8349242
• 负责人: James Mitchell
• 金额: $ 32.13万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349242
• 关键词: Acute; Animal Feed; Animals; Awareness; Caloric Restriction; Chemopreventive Agent; Chronic; Control Groups; Data; Diet; Dose; External Beam Radiation Therapy; Face; Female; Food; Food Supplementation; Funding; Government Agencies; Hematopoietic; Hematopoietic Neoplasms; Human; Inbred C3H Mice; Inbred CBA Mice; Incidence; Intensity-Modulated Radiotherapy; Longevity; Lymphoma; Malignant Neoplasms; Mediating; Modification; Monitor; Mouse Strains; Mus; Normal tissue morphology; Nuclear; Patients; Population; Process; Radiation; Radiation Injuries; Radiation Oncology; Radiation-Induced Cancer; Radiation-Protective Agents; Reagent; Risk; Second Primary Neoplasms; Solid Neoplasm; Staining method; Stains; Supplementation; Survivors; Testing; Time; Urine; Weight; Whole-Body Irradiation; cancer risk; carcinogenesis; dosimetry; effective intervention; experience; food consumption; interest; irradiation; research and development; stem; tempol; tumor; tumorigenesis

Two strains of mice were used in this project. Female C3H and CBA mice were exposed to a 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 include: a) no radiation, control food, b) 3 Gy, control food, c) no radiation, TP food, and d) 3 Gy, TP food. For C3H mice, one additional group was added receiving 3 Gy total body irradiation where the administration of the TP containing food was delayed one month post-irradiation. Preliminary data show TP food supplementation after radiation: a) did not alter food consumption compared to animals on a control food diet, b) compared to animals on control food diet, the TP diet resulted in decreased weights in both mouse strains (40% for C3H and 20% for CBA), and c) TP food supplementation post-radiation significantly enhanced the survival of both mouse stains. Median survival values for 0 Gy, 3 Gy, 0 Gy TP, and 3 Gy TP for C3H mice was 706, 434, 764, and 670 days, respectively. For CBA mice median survival values for 0 Gy, 3 Gy, 0 Gy TP, and 3 Gy TP for C3H mice was 901, 660, 939, and 782 days, respectively. The incidence of hematopoietic neoplasms (predominantly lymphomas) was significantly reduced in both mouse strains by TP treatment and both the onset and incidence of solid neoplasms was significantly reduced in CBA mice treated with TP. These preliminary data would encourage further research and development of TP as a chemopreventive agent. The second hypothesis is also being tested that mice protected from lethal total body irradiation by administration of a radioprotector immediately before radiation exposure will experience an elevated risk of cancer induction. Mice were exposed to a total body radiation dose of 10.8 Gy, a radiation dose that results in 100% lethality. Ten minutes prior to the 10.8 Gy exposure the animals will be injected with a radioprotector. The control for this group, another set of animals was exposed to 5.4 Gy total body irradiation. This radiation dose was derived from the radiation dose modification factor (2) when the radioprotector is administered 10 min before total body irradiation. These animals will also be followed for their entire lifespan for tumor induction as outlined above. Preliminary data show that the median survival for mice receiving 0, 5.4 or 10.8 Gy were 706, 460, and 491 days, respectively. There was no difference between the 5.4 and 10.8 Gy groups (p = 0.42); however, the median survival of both irradiated groups was significantly shorter compared to unirradiated mice (p < 0.0001). Cancer incidence (hematopoietic plus solid tumors) was similar between the 5.4 and 10.8 Gy groups and was significantly greater than for unirradiated controls. However, the ratio of hematopoietic to solid tumors differed between the two groups, with the 5.4 Gy group having a higher incidence of hematopoietic neoplasms compared to the 10.8 Gy group (1.8 fold). A greater incidence of solid tumors was observed in the 10.8 Gy group. These preliminary results suggest that mice protected from lethal whole body radiation have a shortened lifespan, due in large part, to cancer induction post-radiation compared to unirradiated controls. Lastly studies have been initiated 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.

本项目使用了两种小鼠。雌性C3H和CBA小鼠在动物食物中添加或不添加Tempol时暴露于3 Gy的全身辐射剂量。在辐射暴露后，动物们立即被放置在对照或含有tp的食物上。组分为：a)无辐射，对照食品；b) 3 Gy，对照食品；c)无辐射，TP食品；d) 3 Gy， TP食品。对于C3H小鼠，另增加一组接受3gy全身照射，其中含TP的食物在照射后延迟一个月给药。初步数据显示，辐射后补充TP食物：a)与对照组相比，没有改变食物摄入量；b)与对照组相比，TP饮食导致两种小鼠品系的体重下降（C3H为40%，CBA为20%）；c)辐射后补充TP食物显著提高了两种小鼠品系的存活率。0 Gy、3 Gy、0 Gy TP和3 Gy TP对C3H小鼠的中位生存值分别为706天、434天、764天和670天。CBA小鼠0 Gy、3 Gy、0 Gy TP和3 Gy TP对C3H小鼠的中位生存值分别为901、660、939和782天。两种小鼠品系经TP治疗后，造血肿瘤（主要是淋巴瘤）的发病率均显著降低，CBA小鼠经TP治疗后，实体瘤的发病和发病率均显著降低。这些初步数据将鼓励TP作为化学预防剂的进一步研究和开发。第二种假设也正在验证中，即在暴露于辐射之前立即给予放射性保护剂以保护小鼠免受致命的全身照射，从而使其患癌症的风险增加。小鼠暴露在10.8 Gy的全身辐射剂量下，这一辐射剂量导致100%的死亡率。在10.8 Gy辐射前10分钟，这些动物将被注射放射性保护剂。作为对照组，另一组动物接受5.4戈瑞的全身辐射。该辐射剂量是在全身照射前10分钟使用放射性保护器时，由辐射剂量修正因子(2)得出的。如上所述，这些动物也将在其整个生命周期内进行肿瘤诱导。初步数据显示，接受0、5.4和10.8 Gy辐射的小鼠的中位生存期分别为706、460和491天。5.4 Gy组与10.8 Gy组间无差异（p = 0.42）；然而，与未照射小鼠相比，两组小鼠的中位生存期均显著缩短（p < 0.0001）。癌症发病率（造血和实体瘤）在5.4和10.8 Gy组之间相似，显著高于未照射对照组。然而，两组之间造血肿瘤与实体肿瘤的比例存在差异，与10.8 Gy组相比，5.4 Gy组的造血肿瘤发生率更高（1.8倍）。10.8 Gy组实体瘤发生率较高。这些初步结果表明，与未受辐射的对照组相比，受到全身致命辐射保护的小鼠寿命缩短，这在很大程度上是由于辐射后的癌症诱导。最后，在观察肿瘤肿块之前，研究人员已经开始确定接受全身辐射的小鼠尿液中的代谢物是否可以预测辐射诱导的癌症诱导。