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）：我们提出结肠内容物中的n -亚硝基化合物（NOC）是结肠癌的重要原因，并且NOC在胃肠道（GIT）中的形成及其在结肠中的致癌作用可以被化学预防药物抑制。Aims 1-3的实验将使用接受半纯化饮食并治疗7天的瑞士小鼠。第7天，用我们的标准方法分析24小时粪便或GIT切片的NOC。目的1：我们发现在饮用水中添加1%亚硝酸钠使粪便NOC排泄量增加15倍。我们将研究连续降低亚硝酸盐水平对粪便NOC输出的影响，确定投喂和不投喂亚硝酸盐时不同GIT区段的NOC；研究硝酸盐对粪便NOC的影响；研究抑酸剂奥美拉唑对饲喂和未饲喂亚硝酸盐小鼠胃和粪便NOC的影响；在法兰克福香肠中添加亚硝酸盐，观察亚硝酸盐是否与法兰克福香肠衍生NOC前体（NOCP）发生反应；在饲料中添加1、2、4%血红蛋白和亚硝酸盐。目的2：由于抗坏血酸抑制酸催化的胃亚硝化作用，我们将测试在水中添加3剂量抗坏血酸和亚硝酸盐对粪便NOC水平的降低，并测试1剂量抗坏血酸单独或与亚硝酸盐加血红素，亚硝酸盐加法兰克福香肠或单独法兰克福香肠。目的3：我们将测试抗坏血酸和5种膳食多酚对法兰克福衍生NOCP的化学亚硝化作用的抑制作用，并研究多酚对小鼠粪便NOC排泄的影响，这些小鼠在饮用水中添加和不添加亚硝酸盐。目的4：由部分纯化的法兰克福香肠NOCP生产的NOC对鼠伤寒沙门氏菌TA-100具有直接诱变作用。我们将对从饲喂商业饲料的大鼠的纯化粪NOCP中提取的NOC进行类似的试验。目的5：我们将测试从法兰克福香肠衍生的NOCP中提取的NOC诱导结肠肿瘤的能力，并将其喂给接受西方饮食的A/J小鼠60至6周。在开始治疗后15或30周，结肠将评估异常隐窝灶和肿瘤。其他小鼠在用偶氮甲烷或从大鼠粪便中提取的NCOP获得的NOC治疗后也将进行类似的评估。总体结果将表明如何控制和降低粪便NOC水平，以及粪便NOC是否会诱发结肠癌。