The overall aim is to enhance our understanding of the mechanisms of anti-carcinogenesis by synthetic and naturally occurring compounds, and their possible impact on human cancer. This becomes especially important in view of the results from our laboratory and others that some putative food-borne inhibitors in the human diet actually enhance tumor response experimentally. Much of the work will use a component of brassica vegetables, indole-3-carbinol (I3C), as a model for blocking agents which can also promote. We will use the rainbow trout, which has proven responsive to a number of carcinogens and inhibitors, and is especially valuable for inhibitor studies for three reasons: a) Mechanism studies in this non-mammalian vertebrate broadens our data base for extrapolation to man; b) Its economies and sensitivity permit a great range of tumor studies for investigating fundamental concepts of anti-carcinogenesis at modest cost. Many of the proposed studies would be economically unrealistic, or unfeasible for rare metabolites, in traditional rodent models. c) Use of alternative vertebrates where sound and feasible reduces use of mammalian test animals.
Specific aims are: 1) Conduct tumor studies using aflatoxin B1 (AFB1) and two selected inhibitors, to rigorously establish the relationships between applied carcinogen dose, inhibitors, to rigorously establish the relationships between applied carcinogen dose, inhibitor dose, peak target tissue DNA adduct formation, and final tumor response in trout. 2) Investigate and quantitate changes in responsiveness to tumor inhibitors with increasing age, and the role of altered carcinogen pharmacokinetics, metabolism, and DNA adduct formation in this process. 3) Extend previous investigations into the detailed mechanisms of 13C inhibition of AFB1 carcinogenesis. Synthesize radiolabeled 13C and investigate its metabolism in vivo and in isolated cells. Where possible test metabolite(s) for ability to alter carcinogen metabolism and inhibit DNA adduct formation. Determine I3C effects on specific trout hepatic and intestinal phase III detoxifying activites. 4) Investigate mechanisms of promotion by 13C and quantitatively assess its potencies for promotion versus inhibition. Conduct structure/function tumor studies for promotion or inhibition by 13C analogues. Determine 13C effects on target cell proliferation, ornithine decarboxylase activity, intercellular communication, and/or DNA damage. 5) Expand the data base of inhibitor/carcinogen testing in the trout model, each with specific rationale under test, using protocols which detect promotion or inhibition. Initiate mechanism studies where inhibition or promotion occur.
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