MECHANISMS OF INHIBITION OF CHEMICAL CARCINOGENESIS

抑制化学致癌的机制

基本信息

批准号：
2882312
负责人：
GEORGE S BAILEY
金额：
$ 29万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-05-01 至 2001-02-28
项目状态：
已结题

项目摘要

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.

我们的总体目的是建立作用机理和剂量 - 两种饮食植物化学物质的反应风险效益特征；十字花科蔬菜和普通绿色的吲哚-3-甲醇（I3C）植物色素叶绿素。这项研究将使用两种模型乳腺，肝脏和结肠联合启动的大鼠多机构模型致癌作用和带有肝，胃，和有效的环境特工引起的游泳膀胱肿瘤 Dibenzo（A，L）Pyrene。 I3C是已知的最突出的植物抗雌激素，是在许多动物方案中化学保护，并受到了极大的关注作为激素依赖性人乳房的潜在非生物毒性抑制剂癌症。不幸的是，我们和其他人表明I3C是肿瘤启动子在某些模型和协议中，i3c已经输入了一些私人支持的临床试验。也许更担心的是，i3c是还为“健康食品工业”。因此，对肿瘤和机制研究使乳房的潜在I3C保护益处癌症可以更清楚地与其促销活动相比肝癌和结肠癌。具体目标1将在多器官大鼠模型，而AIM 3扩大了我们对I3C的了解在鳟鱼多器官模型中作为阻止代理的功效。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，以量化预测性致癌剂量，抗癌剂量，特异性之间的关系靶器官DNA加合物，细胞增殖，特定RA的诱导基因突变和最终肿瘤结局（正如精确确定的TD50 值）。 AIM 2检查I3C阻塞机制的关系鳟鱼和哺乳动物。在当前的赠款期内，我们使用鳟鱼模型首次展示叶绿素（CHL），一种常见的食物级叶绿素衍生物具有有效的剂量反应性阻断活性针对黄曲霉毒素B1遗传毒性和肝癌。最近的研究揭示啮齿动物防止皮肤肿瘤的CHL保护；但是，再次有一些促进结肠肿瘤的证据。 AIM 4调查 CHL和天然叶绿素的机理和分子剂量法化学预防，而AIM 1研究了发起者特定的问题结肠肿瘤促进。这种续约，以及单独的R-29（RHD）和 R01（LFB），旨在提供额外的剂量反应，风险效益和我们认为，如果I3C和叶绿素是必要的机理研究继续进行临床试验。