Abstract

The long-term goal of this project is to provide a mechanistic basis for the prevention of esophageal adenocarcinoma (EAC). In the previous grant period, a surgical model esophagogastroduodenal anastomosis (EGDA) was developed and characterized. Our results helped us to develop the present hypothesis that reactive oxygen species and excessive arachidonic acid metabolites, which are produced due to reflux-induced inflammation, are major factors driving esophageal adenocarcinogenesis. In this application, we plan to test this hypothesis and examine related chemoprevention approaches with the following specific aims: 1. To test the hypothesis that oxidative stress is a major driving force for esophageal adenocarcinogenesis by studying the effect of antioxidant nutritional status (by manipulating dietary levels of vitamin E) or supplementation with N-acetyl cysteine on EAC formation and related biochemical and histological changes in the rat EGDA model. 2. To examine the contribution of aberrant arachidonic acid (AA) metabolism, especially the overproduction of prostaglandin E2 and leukotriene B4, to esophageal adenocarcinogenesis by analyzing key enzymes, metabolites, and receptors in rat tissues. Functional studies in explant and cell cultures will be carried out with respective enzyme inhibitors and receptor antagonists for selecting potential chemopreventive agents. 3. To determine the effectiveness of specific inhibitors of AA metabolism and receptor antagonists (identified in Aim 2) as chemopreventive agents against tumorigenesis in the rat EGDA model. The effects of these agents on short-term biochemical markers and inflammation will be correlated with inhibition of tumorigenesis to gain mechanistic information. Combination of agents will be studied systematically to develop effective chemopreventive approaches. These studies are expected to fully elucidate the roles of oxidative stress and aberrant AA metabolism in the formation of EAC and help develop effective agents for its prevention.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075683-09
Application #
7177541
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Malone, Winfred F
Project Start
1998-04-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2009-01-31
Support Year
9
Fiscal Year
2007
Total Cost
$275,212
Indirect Cost

  Institution

Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901

  Publications

Hao, Jing; Zhang, Bin; Liu, Ba et al. (2009) Effect of alpha-tocopherol, N-acetylcysteine and omeprazole on esophageal adenocarcinoma formation in a rat surgical model. Int J Cancer 124:1270-5
Hao, Jing; Liu, Ba; Yang, Chung S et al. (2009) Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice. BMC Gastroenterol 9:59
Chen, Xiaoxin; Qin, Rong; Liu, Ba et al. (2008) Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol 8:1
Liu, Tong; Zhang, Xinyan; So, Chi-Kwong et al. (2007) Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis 28:488-96
Chen, Xiaoxin; Wang, Su; Wu, Nan et al. (2004) Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis. Clin Cancer Res 10:6703-9
Su, Yinghao; Chen, Xiaoxin; Klein, Michael et al. (2004) Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus. Lab Invest 84:753-65
Chen, Xiaoxin; Li, Ning; Wang, Su et al. (2003) Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin. J Natl Cancer Inst 95:1053-61
Chen, Xiaoxin; Li, Ning; Wang, Su et al. (2002) Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and alpha-difluoromethylornithine on tumorigenesis in a rat surgical model. Carcinogenesis 23:2095-102
Chen, Xiaoxin; Ding, Yu; Liu, Chang-Gong et al. (2002) Overexpression of glucose-regulated protein 94 (Grp94) in esophageal adenocarcinomas of a rat surgical model and humans. Carcinogenesis 23:123-30
Chen, X; Mikhail, S S; Ding, Y W et al. (2000) Effects of vitamin E and selenium supplementation on esophageal adenocarcinogenesis in a surgical model with rats. Carcinogenesis 21:1531-6

Showing the most recent 10 out of 13 publications