MECHANISMS OF INHIBITION OF CHEMICAL CARCINOGENESIS

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; 来自十字花科蔬菜的吲哚-3-甲醇（I3 C）和常见的绿色 植物色素叶绿素本研究将使用两种模型， 大鼠乳腺、肝脏和结肠联合启动的多器官模型 致癌作用，和虹鳟鱼多器官模型，肝，胃， 以及由强环境因子诱发的鱼鳔肿瘤 二苯并（a，l）芘。I3 C是已知的最突出的植物抗雌激素， 在许多动物方案中具有化学保护性，并受到极大的关注 作为一种潜在的非遗传毒性抑制剂， 癌不幸的是，我们和其他人已经表明I3 C是一种肿瘤促进剂， 在某些模型和协议中，I3 C已经进入了一些 私人支持的临床试验。也许更令人担忧的是，I3 C 也正在准备向公众推销的“健康 食品工业”。因此，对于肿瘤和肿瘤坏死因子治疗存在明确和迫切的需求。 机制研究，例如I3 C对乳腺的潜在保护益处 癌症可以更清楚地衡量其促进活动， 肝癌和结肠癌具体目标1将在 多器官大鼠模型，而目标3扩展了我们对I3 C的认识 在鳟鱼多器官模型中作为阻断剂的功效。一个独特 鳟鱼模型的特点，我们在这里利用，是负担得起的 具有统计学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 靶器官DNA加合物，细胞增殖，特异性ras诱导 基因突变和最终肿瘤结局（精确测定的TD 50 价值观）。 目的2：研究I3 C阻断机制与细胞凋亡的关系。 鳟鱼和哺乳动物在目前的赠款期间，我们使用鳟鱼模型， 首次表明，叶绿素（CHL），一种常见的食品级 叶绿素衍生物，具有有效的剂量响应性阻断活性 抗黄曲霉毒素B1遗传毒性和肝癌。最近的研究还 揭示了CHL在啮齿动物中对皮肤肿瘤的保护作用;然而， 有一些证据表明结肠肿瘤的促进作用。 目标4调查 CHL和天然叶绿素的机制和分子剂量学 化学预防，而目标1研究引发剂特异性的问题， 结肠肿瘤促进。这次更新，沿着一个单独的R-29（RHD）和 R 01（LFB），旨在提供额外的剂量-效应、风险-获益和 我们认为，如果I3 C和叶绿素能够 进行临床试验。

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.