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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034732-10
Application #
3172512
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1983-05-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
10
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Oregon State University
Department
Type
Schools of Earth Sciences/Natur
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
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Chen, Maria J; Chiou, P Peter; Yang, Bih-Ying et al. (2004) Development of rainbow trout hepatoma cell lines: effect of pro-IGF-I Ea4-peptide on morphological changes and anchorage-independent growth. In Vitro Cell Dev Biol Anim 40:118-28
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Xu, M; Orner, G A; Bailey, G S et al. (2001) Post-initiation effects of chlorophyllin and indole-3-carbinol in rats given 1,2-dimethylhydrazine or 2-amino-3-methyl- imidazo. Carcinogenesis 22:309-14
Breinholt, V; Arbogast, D; Loveland, P et al. (1999) Chlorophyllin chemoprevention in trout initiated by aflatoxin B(1) bath treatment: An evaluation of reduced bioavailability vs. target organ protective mechanisms. Toxicol Appl Pharmacol 158:141-51
Oganesian, A; Hendricks, J D; Pereira, C B et al. (1999) Potency of dietary indole-3-carbinol as a promoter of aflatoxin B1-initiated hepatocarcinogenesis: results from a 9000 animal tumor study. Carcinogenesis 20:453-8
Hayashi, T; Schimerlik, M; Bailey, G (1999) Mechanisms of chlorophyllin anticarcinogenesis: dose-responsive inhibition of aflatoxin uptake and biodistribution following oral co-administration in rainbow trout. Toxicol Appl Pharmacol 158:132-40

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