MECHANISMS OF INHIBITION OF CHEMICAL CARCINOGENESIS

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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.