MECHANISMS OF INHIBITION OF CHEMICAL CARCINOGENESIS

抑制化学致癌的机制

• 批准号: 2376773
• 负责人: GEORGE S BAILEY
• 金额: $ 35.94万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-05-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2376773
• 关键词: Cruciferae; DNA damage; adduct; aflatoxins; alternatives to animals in research; apoptosis; benzopyrenes; breast neoplasms; cancer risk; carcinogenesis inhibitor; cell cycle; chemical carcinogenesis; chemoprevention; chlorophyll; colon neoplasms; dosage; gene mutation; indoles; laboratory rat; liver neoplasms; nutrient interaction; nutrition related neoplasm /cancer; nutrition related tag; trout /salmon; tumor promoters

Our overall aim is to establish the mechanisms of action and the dose- response risk-benefit characteristics for two dietary phytochemicals; indole-3-carbinol (I3C) from cruciferous vegetables, and the common green plant pigment chlorophyll. Two models will be used for this research, a rat multiorgan model for joint initiation of mammary, liver, and colon carcinogenesis, and a rainbow trout multi-organ model with liver, stomach, and swim bladder tumors elicited by the potent environmental agent dibenzo(a,l)pyrene. I3C is the most prominent plant antiestrogen known, is chemoprotective in many animal protocols, and has received great attention as a potential non-genotoxic inhibitor of hormone-dependent human breast cancer. Unfortunately, we and others have shown I3C to be a tumor promoter in certain models and protocols, yet I3C has already been entered in some privately supported clinical trials. Of perhaps greater concern, I3C is also being prepared for marketing to the general public by the "health food industry". Thus there is a clear and compelling need for tumor and mechanism studies such that potential I3C protective benefits for breast cancer can be more clearly weighed against its promotional activity in liver and colon cancer. Specific Aim 1 will conduct such experiments in the multi-organ rat model, while Aim 3 expands our knowledge of I3C efficacy as a blocking agent in the trout multi-organ model. A unique feature of the trout model, which we exploit here, is the affordability of statistically challenging tumor study designs to quantify the predictive relationships between carcinogen dose, anticarcinogen dose, specific target organ DNA adducts, cell proliferation, induction of specific ras gene mutations, and final tumor outcome (as precisely determined TD50 values). Aim 2 examines the relationship of I3C blocking mechanisms in trout and mammals. In the current grant period we used the trout model to show for the first time that chlorophyllin (CHL), a common food-grade chlorophyll derivative, has potent, dose-responsive blocking activity against aflatoxin B1 genotoxicity and liver cancer. Recent studies also reveal CHL protection in rodents against skin tumors; again, however, there is some evidence for colon tumor promotion. Aim 4 investigates mechanisms and molecular dosimetry of CHL and native chlorophyll chemoprevention, while Aim 1 investigates the issue of initiator-specific colon tumor promotion. This renewal, along with a separate R-29 (RHD) and R01 (LFB), aim to provide the additional dose-response, risk-benefit, and mechanism studies that we believe necessary if I3C and chlorophylls are to proceed toward clinical trials.

我们的总体目标是建立作用机制和剂量 两种膳食植物化学物质的反应风险效益特征； 来自十字花科蔬菜和常见绿色植物的吲哚-3-甲醇 (I3C) 植物色素叶绿素。本研究将使用两个模型，一个 乳腺、肝脏和结肠联合启动的大鼠多器官模型 致癌作用，以及虹鳟鱼多器官模型，包括肝脏、胃、 和由强效环境剂引起的鱼鳔肿瘤 二苯并(a,l)芘。 I3C 是已知最突出的植物抗雌激素， 在许多动物方案中具有化学保护作用，并受到高度关注 作为激素依赖性人类乳腺的潜在非基因毒性抑制剂 癌症。不幸的是，我们和其他人已经证明 I3C 是肿瘤促进剂 在某些型号和协议中，但 I3C 已在某些型号和协议中进入 私人支持的临床试验。也许更值得关注的是，I3C 是 还准备通过“健康”向公众进行营销 食品工业”。因此，对于肿瘤和 机制研究表明 I3C 对乳房的潜在保护作用 可以更清楚地衡量癌症与其促销活动 肝癌和结肠癌。具体目标 1 将在 多器官大鼠模型，而 Aim 3 扩展了我们对 I3C 的了解 作为鳟鱼多器官模型中的阻断剂的功效。一个独特的 我们在这里利用的鳟鱼模型的特征是 统计上具有挑战性的肿瘤研究设计来量化预测 致癌物剂量、抗癌物剂量、特异性之间的关系 靶器官 DNA 加合物、细胞增殖、特异性 ras 的诱导 基因突变和最终肿瘤结果（精确测定的 TD50 值）。 目标 2 检查 I3C 阻塞机制的关系 鳟鱼和哺乳动物。在当前的资助期内，我们使用鳟鱼模型 首次证明常见食品级叶绿素（CHL） 叶绿素衍生物，具有有效的剂量反应性阻断活性 抗黄曲霉毒素 B1 遗传毒性和肝癌。最近的研究还 揭示 CHL 对啮齿类动物对抗皮肤肿瘤的保护作用；然而，再次， 有一些证据表明结肠癌会促进。 目标 4 调查 CHL 和天然叶绿素的机制和分子剂量测定 化学预防，而目标 1 调查引发剂特异性问题 结肠肿瘤促进。此次更新以及单独的 R-29 (RHD) 和 R01（LFB），旨在提供额外的剂量反应、风险效益和 如果 I3C 和叶绿素要 继续进行临床试验。