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.
NIH ExPorter
NIH ExPorter