The mineral selenium (Se) prevents tumor development in experimental animals. Many epidemiological studies suggest that dietary Se is inversely correlated to human carcinogenesis. Recently, a double-blind study using moderate doses of Se has demonstrated a significant reduction in human cancer incidence at several sites, including lung, prostate and intestine. Most rodent experimental studies that have employed Se as a chemopreventive agent have relied on the use of pharmacological doses of Se to prevent tumor induction mediated by chemical carcinogens. The relevance of these studies to human carcinogenesis is unclear, and despite decades of research, these studies have failed to elucidate the mechanism of action of Se in chemoprevention. This proposal is based on a novel approach to determine the role of Se in human chemoprevention using the mouse as a model system. We hypothesize that the role of Se in human chemoprevention can be replicated in the mouse with the use of physiological levels of Se and that these effects will be most relevant to human carcinogenesis with the use mouse strains carrying defined mutations in genes involved in human carcinogenesis. We will test the role of dietary Se in the Min model of familial adenomatous polyposis (FAP) and the Mlh1-/-mouse model of human hereditary nonpolyposis colorectal cancer (HNPCC) that we have recently developed. Additionally, we hypothesize that at physiological doses of Se, chemoprevention mechanisms are mediated through alterations in the level of oxidative stress. We will determine if modulation of oxidative stress by Se affects tumor development through a direct effect on genomic stability, or indirectly through the inhibition of pathways that are normally induced by oxidants in the intestine, such as cyclooxygenase-2 (COX-2).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078723-02
Application #
2896630
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1998-09-22
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Genetics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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