Comparative Mechanisms of Cancer Chemoprevention

描述(由申请人提供)： 这一修订后的计划项目侧重于通过选定的一组植物化学物质：叶绿素、吲哚-3-甲醇和茶多酚来进行癌症化学预防。已知这些化合物中的每一种在某些动物模型中都具有保护作用；然而，分子机制和剂量反应问题尚未完全确定，联合化学预防方法受到的关注相对较少，对肿瘤增强的潜力(例如，吲哚-3-甲醇)尚未完全了解，母亲暴露于这些药物在胎儿健康风险中的作用尚未被探索。拟议的研究将在标准大鼠模型(乳腺、肝脏)、基因敲除和同源基因小鼠模型(结肠、肺)和多器官虹鲑鱼模型(胃、肝脏)中系统地检查这些阻滞剂和抑制剂预防癌症的分子机制，以及在人类细胞培养模型中的研究。这种比较方法的结果将被转化为三个生物标记物干预和人类志愿者的生物利用度研究。总而言之，该计划项目的总体目标是在选定的动物模型中进行高度交互的机制、肿瘤发生和剂量-反应研究，每个模型在癌症化学预防研究中都具有特定的优势，并将最有希望的结果转化为可能在人类群体中证明化学预防前景的初步人类研究。这一目标将通过三个互补的协同项目来实现：1)作为跨物种阻滞剂的叶绿素(G.Bailey，PI)；2)经胎盘的化学保护和GI生物利用度(D.Williams，PI)；以及3)茶的a-连环蛋白途径和化学保护(R.Dashwood，PI)。调查人员将得到行政核心(G.Bailey，主任)和服务核心(R.Dashwood，主任)的协助，前者负责监督项目间会议，并提供预算、报告和外部咨询需求，后者提供选定的动物、预备化学、统计和其他服务。乔治·贝利博士将担任该计划项目的首席研究员。

DESCRIPTION (provided by applicant): This amended program project focuses on cancer chemoprevention by a selected set of phytochemicals: the chlorophylls, indole-3-carbinol, and tea polyphenols. Each of these in natural or derivative form is known to have protective efficacy in some animal models; however, molecular mechanisms and dose-response issues are not fully defined, combined chemopreventive approaches have received relatively little attention, the potential for tumor enhancement (by indole-3-carbinol, for example) is not fully understood, and the role of maternal exposure to these agents in fetal health risk has not been explored. The proposed studies will provide a systematic examination of the molecular mechanisms of cancer chemoprevention by these blocking agents and suppressing agents in standard rat models (mammary, liver), knockout and congenic mouse models (colon, lung), and a multi-organ rainbow trout model (stomach, liver), along with studies in human cell culture models. The results of this comparative approach will be translated into three biomarker intervention and bioavailability studies in human volunteers. In summary, the overall aim of this program project is to conduct highly interactive mechanism, tumorigenesis, and dose-response studies in selected animal models, each having specific advantages for cancer chemoprevention research, and to translate the most promising results into initial human studies that may demonstrate chemoprevention promise in human populations. This goal will be achieved through three complementary, synergistic projects: 1) Chlorophylls as Trans-Species Blocking Agents (G. Bailey, PI); 2) Transplacental Chemoprotection and GI Bioavailability (D. Williams, PI); and 3) The a-Catenin Pathway and Chemoprotection by Tea (R. Dashwood, PI). Investigators will be aided by an Administrative Core (G. Bailey, Director), which oversees inter-project meetings and provides budgetary, reporting, and external advisory needs, and a Service Core, which provides selected animal, preparative chemistry, statistical, and other services (R. Dashwood, director). Dr. George Bailey will serve as Principal Investigator for the program project.