Chemoprevention of Colonic NOC Formation and Action

结肠 NOC 形成和作用的化学预防

• 批准号: 7003899
• 负责人: SIDNEY S MIRVISH
• 金额: $ 7.35万
• 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/7003899
• 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，并且化学预防剂可以抑制胃肠道（GIT）中NOC的形成及其在结肠中的致癌作用。目标 1-3 中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，将通过我们的标准方法分析 24 小时粪便或胃肠道切片的 NOC。目标 1：我们发现在饮用水中添加 1% 亚硝酸钠可使粪便 NOC 排泄量增加 15 倍。我们将研究亚硝酸盐水平逐渐降低对粪便NOC输出的影响，确定饲喂或不饲喂亚硝酸盐时不同胃肠道部分的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或未饲喂亚硝酸盐的小鼠胃和粪便 NOC 的影响；将亚硝酸盐与法兰克福香肠一起饲喂，以了解亚硝酸盐是否与法兰克福香肠衍生的 NOC 前体 (NOCP) 发生反应；日粮中添加1%、2%、4%氯化血红素，并添加亚硝酸盐。目标 2：由于抗坏血酸抑制酸催化的胃亚硝化，因此我们将测试在饮食中饲喂 3 剂量的抗坏血酸和水中的亚硝酸盐后，粪便 NOC 水平的降低情况，并测试单独给予 1 剂量的抗坏血酸或与亚硝酸盐加“血红素、亚硝酸盐加法兰克福香肠或单独给予法兰克福香肠”。目标 3：我们将测试抗坏血酸和 5 种膳食的抑制作用 法兰克福衍生的 NOCP 化学亚硝化生成 NOC 的多酚，并研究在饮用水中添加和不添加亚硝酸盐的小鼠饮食中添加多酚对粪便 NOC 排泄的影响。目标 4：从法兰克福香肠中部分纯化的 NOCP 产生的 NOC 对鼠伤寒沙门氏菌 TA-100 具有直接诱变作用。我们将对NOC衍生进行类似的测试 来自喂食商业饮食的大鼠的纯化粪便 NOCP。目标 5：我们将测试源自法兰克福 NOCP 的 NOC 在喂食接受西方饮食的 A/J 小鼠超过 6 周后诱导结肠肿瘤的能力。开始治疗后 15 或 30 周，将对结肠进行异常隐窝病灶和肿瘤的评估。其他小鼠在用氧化偶氮甲烷或从获得的 NOC 治疗后将进行类似的评估。 来自大鼠粪便的 NCOP。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。