Our overall aims are to elucidate anticarcinogenic mechanisms for selected blocking to better evaluate the potential impact of such dietary factors on human Aim 2 focuses on anti-initiation mechanisms, with initial emphasis on the common dietary factors indole-3-carbinol (I3C) and chlorophylls.
Aim 1 addresses the almost total lack of truly quantitative information on the relationship between inhibitor dose and carcinogen potency (i. e. TD50 value), or whether inhibitor effects at high carcinogen dose and tumor response apply at lower doses and incidences more reflective of human cancer. We address these issues through 9000-animal molecular dosimetry tumor studies that quantify relationships between carcinogen dose, modulator dose, altered DNA adduction, and final tumor outcome as reflected in inhibitor-altered TD50 values. The data thus determine if reduced DNA adduction alone quantitatively accounts for, and predicts, reduced tumor outcome, and also measure """"""""percent inhibition"""""""" vs. inhibitor dietary concentration. Unfortunately, in some protocols many """"""""anticarcinogens"""""""" show co-carcinogenesis or promotion, or are limited by a low potency/toxicity ratio.
Aims 1 and 3 investigate tumor dose-response and DNA adduction relationships for such agents, and examine combined chemoprevention protocols to overcome some of these limitations. We also address a common shortcoming in previous combined inhibitor studies, which lack any statistical measure of synergism or antagonism. Much of our proposed work uses I3C as a model natural blocking agent that also can promote. We believe it fundamentally important to understand mechanisms of such ambivalent factors, and to derive dose-response approaches to quantify relative inhibitory benefit vs. promotional risk. Finally, Aim 4 proposes tumor modulation studies using 3 new dietary factors, to modestly expand the data base beyond rodent models for future comparative mechanism studies. Our animal model, the rainbow trout, has unique value for the proposed studies for two principal reasons: 1) comparative mechanism studies are essential for confidant extrapolation of relevant inhibitory mechanisms to humans, and 2) the economies and sensitivity of the model permit a great range and complexity in tumor study design, which allows us to approach fundamental concepts of anticarcinogenesis of high statistical demand at a relatively modest budget. Many of our proposed experiments would be economically unrealistic, and in the case of rare carcinogens or modulators, not feasible with rodent models.
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