Chemoprevention of Colonic NOC Formation and Action

结肠 NOC 形成和作用的化学预防

• 批准号: 7108559
• 负责人: SIDNEY S MIRVISH
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-12 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108559
• 关键词: ascorbate; cancer prevention; carcinogenesis inhibitor; chemical carcinogenesis; chemoprevention; colon neoplasms; drug screening /evaluation; excretion; flavonoids; gastrointestinal toxin absorption; heme; laboratory mouse; nitrates; nitroso compounds; nutrition related neoplasm /cancer; omeprazole; pathogenic diet; vitamin therapy

DESCRIPTION (provided by applicant): We propose that N-nitroso compounds (NOC) in colon contents are a significant cause of colon cancer and that NOC formation in the gastrointestinal tract (GIT) and their carcinogenic action in colon can be inhibited by chemopreventive agents. Experiments in Aims 1-3 will use Swiss mice that receive semipurified diet and are treated for 7 days. On day 7, 24-h feces or GIT sections will be analyzed for NOC by our standard method. Aim 1: We found that feeding 1% sodium nitrite in drinking water increased fecal NOC excretion 15 times. We will study effect of successively lower levels of nitrite on fecal NOC output, determine NOC in different GIT sections when nitrite is fed or not fed; study effect of nitrate on fecal NOC; study effect of acid suppressant omeprazole on gastric and fecal NOC in mice fed or not fed nitrite; feed nitrite with frankfurters to find out whether nitrite reacts with frankfurter-derived NOC precursors (NOCP); and feed 1, 2 and 4% hemin in diet with nitrite. Aim 2: Because ascorbate inhibits acid-catalyzed gastric nitrosation, we will test reduction of fecal NOC level on feeding 3 ascorbate doses in diet with nitrite in water, and test 1 ascorbate dose given alone or with nitrite plus "hemin, nitrite plus frankfurters or frankfurters alone. Aim 3: We will test inhibition by ascorbate and 5 dietary polyphenols of the chemical nitrosation of frankfurter-derived NOCP to give NOC, and study effect of polyphenols, given in diet to mice with and without nitrite in drinking water, on fecal NOC excretion. Aim 4: NOC produced from partially purified NOCP in frankfurters were directly mutagenic in Salmonella typhimurium TA-100. We will conduct similar tests on NOC derived from purified fecal NOCP from rats fed commercial diet. Aim 5: We will test NOC derived from frankfurter-derived NOCP for ability to induce colonic tumors when fed to A/J mice receiving a Western diet for > 6 weeks. At 15 or 30 weeks after beginning treatment, colons will be evaluated for aberrant crypt foci and tumors. Other mice will be evaluated similarly after treatment with azoxymethane or with NOC obtained from NCOP from rat feces. Overall results will indicate how fecal NOC levels are controlled and can be reduced, and whether fecal NOC can induce colon cancer.

描述（由申请人提供）：我们提出，结肠含量的N-亚硝基化合物（NOC）是结肠癌的重要原因，并且在胃肠道（GIT）中的NOC形成及其在结肠中的致癌作用可以抑制化学抗性剂。 AIMS 1-3中的实验将使用接受半纯化饮食并进行7天治疗的瑞士小鼠。在第7天，将通过我们的标准方法分析NOC的24小时粪便或GIT部分。 AIM 1：我们发现，在饮用水中喂食1％亚硝酸钠增加了15倍的粪便NOC排泄。我们将研究依次较低的亚硝酸盐水平对粪便NOC输出的影响，确定当喂食或不喂食的亚硝酸盐时，不同的GIT切片中的NOC；硝酸盐对粪便NOC的研究作用；奥美拉唑抑制酸的研究对喂养或未喂亚硝酸盐的小鼠胃和粪便NOC的研究作用；用法兰克福喂养亚硝酸盐，以找出亚硝酸盐是否与法兰克福衍生的NOC前体（NOCP）反应；和亚硝酸盐的饮食中的1、2和4％hemin。目标2：由于抗坏血酸抑制酸催化的胃硝化化，我们将测试粪便NOC水平的降低，以在水中用亚硝酸盐饮食中的3种抗坏血酸剂量，并测试1个单独给出的抗坏血酸剂量，单独或用硝酸盐加上硝酸盐加上“ hemin，nitrite plus frangfurters and Frankfurters或Frankfurter或Frankfurter或Frankfurter 3：我们将饮食3：我们siet 3：我们siet 3：我们均可进行。法兰克福衍生的NOC的化学硝化作用，具有NOC，以及在饮食中有多酚的研究作用，在饮用水中没有亚硝酸盐，对粪便NOC的排泄物4：由Frandim in Frandium in saluim saluim saluim nim unif tes-saluim nocim nocim s salmen nocim nocim noce noc noc noc。从喂养商业饮食的大鼠纯化的NOCP中，我们将测试来自法兰克福衍生的NOCP的NOC，以诱导结肠肿瘤的能力，当时在15或30周内接受西方饮食的A/J小鼠开始治疗。其他小鼠在用甲氧基烷或从大鼠粪便中获得的NCOP进行治疗后，将对其他小鼠进行类似的评估。总体结果将表明如何控制粪便NOC水平并可以降低，以及粪便NOC是否可以诱导结肠癌。