Colon cancer is the second leading cause of death from cancer in the United States today whereas cancer of the small intestine is a relatively rare event. Intestinal tumors develop from a series of somatic mutations subsequent to an initiating event such as DNA-alkylation or oxidation. Our primary hypothesis is that the small intestine (SI) and large intestine (LI) respond differently to these two important forms of DNA damage (alkylation and oxidation), which is a key reason for the difference in tumor incidence at these two sites. Our secondary hypothesis is that SI cells are protected from tumor induction because they produce less reactive oxygen species (ROS) and less oxidative damage to DNA and LI cells.
In specific aim # 1 we will inject rats with the DNA alkylating agent azoxymethane and measure in vivo DNA damage, repair and apoptosis in SI and LI over the 48 h period post injection. DNA damage and repair are measured by quantitative immunohistochemistry of O6-methylguanine adducts and its repair enzyme; and apoptosis is detected by the TUNEL assay.
In specific aim #2 we will determine in vivo response to the DNA oxidizing agent dextran sodium sulfate in rat SI and LI within the first 48 h after removal of the oxidizing agent. DNA damage is measured by quantitative immunohistochemistry of 8oxodG adducts; activity of the repair enzyme specific for 8oxodG by an endonuclease assay; and apoptosis by the TUNEL assay.
In specific aim #3 we will determine steady state levels of oxidative DNA damage and ROS generation in SI and LI in young and old rats and whether or not ROS generation in SI and LI is due to differences in mitochondrial electron transport. DNA damage will be assessed by the FLARE assay and ROS production by oxidation of the vital dye 2',7'-dichlorofluorescein in cells incubated with and without electron transport inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061750-08
Application #
6512984
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Okano, Paul
Project Start
1994-08-01
Project End
2004-04-30
Budget Start
2002-05-31
Budget End
2003-04-30
Support Year
8
Fiscal Year
2002
Total Cost
$226,800
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
047006379
City
College Station
State
TX
Country
United States
Zip Code
77845
Hong, Mee Young; Turner, Nancy D; Murphy, Mary E et al. (2015) In vivo regulation of colonic cell proliferation, differentiation, apoptosis, and P27Kip1 by dietary fish oil and butyrate in rats. Cancer Prev Res (Phila) 8:1076-83
Cho, Youngmi; Turner, Nancy D; Davidson, Laurie A et al. (2014) Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation. Exp Biol Med (Maywood) 239:302-10
Cho, Youngmi; Turner, Nancy D; Davidson, Laurie A et al. (2012) A chemoprotective fish oil/pectin diet enhances apoptosis via Bcl-2 promoter methylation in rat azoxymethane-induced carcinomas. Exp Biol Med (Maywood) 237:1387-93
Cho, Youngmi; Kim, Hyemee; Turner, Nancy D et al. (2011) A chemoprotective fish oil- and pectin-containing diet temporally alters gene expression profiles in exfoliated rat colonocytes throughout oncogenesis. J Nutr 141:1029-35
Vanamala, J; Glagolenko, A; Yang, P et al. (2008) Dietary fish oil and pectin enhance colonocyte apoptosis in part through suppression of PPARdelta/PGE2 and elevation of PGE3. Carcinogenesis 29:790-6
Apanasovich, Tatiyana V; Ruppert, David; Lupton, Joanne R et al. (2008) Aberrant crypt foci and semiparametric modeling of correlated binary data. Biometrics 64:490-500
Crim, Kristy Covert; Sanders, Lisa M; Hong, Mee Young et al. (2008) Upregulation of p21Waf1/Cip1 expression in vivo by butyrate administration can be chemoprotective or chemopromotive depending on the lipid component of the diet. Carcinogenesis 29:1415-20
Baladandayuthapani, Veerabhadran; Mallick, Bani K; Young Hong, Mee et al. (2008) Bayesian hierarchical spatially correlated functional data analysis with application to colon carcinogenesis. Biometrics 64:64-73
Hong, Mee Young; Turner, Nancy D; Carroll, Raymond J et al. (2005) Differential response to DNA damage may explain different cancer susceptibility between small and large intestine. Exp Biol Med (Maywood) 230:464-71
Hong, Mee Young; Bancroft, Laura K; Turner, Nancy D et al. (2005) Fish oil decreases oxidative DNA damage by enhancing apoptosis in rat colon. Nutr Cancer 52:166-75

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