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.
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