DNA DAMAGE INDUCED BY PANCREATROPIC NITROSAMINES

胰亚硝胺引起的 DNA 损伤

• 批准号: 3184806
• 负责人: DEMETRIUS Michael KOKKINAKIS
• 金额: $ 11.62万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3184806
• 关键词: DNA repair; binding proteins; carcinogen testing; chemical addition; chemical carcinogen; chemical carcinogenesis; chemical structure function; dietary aminoacid; dietary proteins; hamsters; kidney neoplasms; laboratory rat; liver neoplasms; lung neoplasms; molecular oncology; nitrosamines; nitroso compounds; nutrition related tag; pancreas neoplasms; radiotracer; toxin metabolism

N-Nitroso-2, 6-dimethylmorpholine (NNDM), N-Nitrosobis(2- oxopropyl)amine (BOP), N-Nitrosobis(2-hydroxypropyl)amine (BHP), and N-Nitroso(2-hydroxypropyl) (2-oxopropyl) amine (HPOP) induce tumors of the pancreas, lungs, gallbladder, kidneys and bladder in hamsters and upper respiratory tract, esophagus, liver, and kidney tumors in rats. Organotropy of these carcinogens depends on dose, sex, frequency and route of administration. Differences between species in pancreas carcinogenesis and between sexes in liver carcinogenesis are marked and useful in the elucidation of the mechanism of action of these carcinogens. It is proposed to study the relationships among metabolism, tissue injury and carcinogenesis in rats and hamsters treated mainly with HPOP, but also with NNDM and BHP. The aims of this study are: 1) Develop the methodology to characterize and quantitate DNA adducts which are formed and persist in various tissues of hamsters and rats during continuous administration of NNDM, BHP and HPOP. 2) Design regimens of continuous administration of these carcinogens which will cause a high incidence of pancreatic tumors. 3) Measure labeling of tissue and DNA of target and nontarget organs during treatment of hamsters and rats with radiolabeled nitrosamines, and also evaluate possible relations between tumor induction and persistence of various DNA adducts. 4) Evaluate the rate of repair of various adducts by measuring the decline of their concentration in DNA and tissues of animals treated either with a single dose of carcinogen or continuously for 7 days. 5) Test the capacity of rats and hamsters to metabolize xenobiotics including the carcinogenic nitrosamines following the treatment period. Also test the activity of phase I and phase II enzymes in the liver and the ability of various tissues to repair 06 MeGuanosine following the treatment with carcinogenic nitrosamines. 6) Investigate the levels of adducts and the rate of their repair in component cells of the pancreas and liver of animals undergoing treatment with HPOP or following such treatment. 7) Examine the effect of low protein diet, methionine-deficient diet and inhibitors of sulfation of HPOP on the carcinogenicity of HPOP in hamsters. Evaluate the effect of such treatment on the formation and repair of DNA adducts in various organs of the animals.

N-亚硝基-2，6-二甲基吗啉(NNDM) N-亚硝基二(2-羟丙基)胺 (BHP)和N-亚硝基(2-羟丙基)(2-氧丙基)胺 (HPOP)诱发胰腺、肺、胆、肾肿瘤 仓鼠的膀胱和上呼吸道，食道， 大鼠肝、肾肿瘤模型。这些化合物的有机亲和性 致癌物质取决于剂量、性别、频率和途径 行政管理。胰腺中物种间的差异 癌的发生和性别之间的肝癌的发生 在阐明作用机制方面有显著的和有用的 这些致癌物质中。建议对它们之间的关系进行研究 在大鼠代谢、组织损伤和癌变之间的关系 仓鼠主要用HPOP治疗，但也用NNDM和 必和必拓。本研究的目的是：1)发展方法论以 表征和定量DNA加合物的形成和 在金黄地鼠和大鼠的各种组织中持续存在 NNDM、必和必拓、HPOP的管理。2)设计方案 持续服用这些致癌物会导致 胰腺肿瘤的高发。3)测量组织的标签 治疗过程中靶器官和非靶器官的DNA 带有放射性标记亚硝胺的仓鼠和大鼠，还有 评估肿瘤诱导和治疗之间可能的关系 各种DNA加合物的持久性。4)评估 通过测量不同加合物的下降来修复各种加合物 在DNA和动物组织中的浓度 单剂致癌物或连续服用7天。5)测试 大鼠和仓鼠代谢外来物质的能力，包括 治疗后的致癌亚硝胺。 还要检测肝脏中I相酶和II相酶的活性 以及不同组织修复06-鸟苷的能力 在用致癌的亚硝胺治疗之后。6) 研究加合物的水平及其修复率 实验动物胰腺和肝脏的组成细胞 用HPOP治疗或在这种治疗之后。7)审查 低蛋白饮食、蛋氨酸缺乏饮食对小鼠的影响 HPOP硫化抑制剂对HPOP致癌性的影响 仓鼠。评估这种治疗方法对患者的影响 小鼠不同器官DNA加合物的形成与修复 动物。