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，并且可以通过化学预防剂抑制胃肠道（GIT）中NOC的形成及其在结肠中的致癌作用。目的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。在第7天，将通过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%的亚硝酸钠可使粪便中NOC的排泄量增加15倍。我们将研究连续降低亚硝酸盐水平对粪便NOC产量的影响，测定不同GIT节段在喂食和不喂食亚硝酸盐时的NOC;研究硝酸盐对粪便NOC的影响;研究抑酸剂奥美拉唑对喂食和不喂食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喂食，以了解亚硝酸盐是否与法兰克福香肠衍生的NOC前体（NOCP）反应;在日粮中添加1、2、4%氯化血红素和亚硝酸盐。目标二：由于抗坏血酸盐抑制酸催化的胃亚硝化，我们将测试在饮食中喂食3个抗坏血酸盐剂量与水中的亚硝酸盐，并测试1个抗坏血酸盐剂量单独或与亚硝酸盐加“氯化血红素”、亚硝酸盐加法兰克福香肠或单独法兰克福香肠。目标3：我们将测试抗坏血酸和5种膳食多酚对法兰克福香肠衍生的NOCP的化学亚硝化产生NOC的抑制作用，并研究多酚在饮食中给予饮用水中含有和不含亚硝酸盐的小鼠对粪便NOC排泄的影响。目的4：从部分纯化的法兰克福香肠NOCP中制备的NOC对鼠伤寒沙门氏菌TA-100具有直接致突变性。我们将对从喂食商业饲料的大鼠的纯化粪便NOCP中获得的NOC进行类似试验。目标5：我们将测试源自法兰克福香肠的NOCP的NOC在喂食接受西方饮食的A/J小鼠> 6周时诱导结肠肿瘤的能力。在开始治疗后15或30周，将评价结肠的异常隐窝病灶和肿瘤。在用氧化偶氮甲烷或从大鼠粪便中的NCOP获得的NOC处理后，将对其他小鼠进行类似的评价。总体结果将表明粪便NOC水平如何控制和降低，以及粪便NOC是否会诱发结肠癌。