Numerous reports relate an excess of site specific cancers to chronic alcohol (i.e. ethanol) consumption. Two tissues that develop excess cancers in humans are the liver and the esophagus. However, the mechanism(s) by which alcohol produces excess cancers in these tissues (as well as others) is unknown. In fact, animal models to relate alcohol effects on mechanistic events to enhanced alcohol associated carcinogenesis are sorely lacking. This study proposes to first develop appropriate animal models and then to study certain molecular events. It is unlikely that alcohol is carcinogenic per se. There is an abundance of data that suggests it is not. Therefore, it is generally assumed that alcohol modulates the carcinogenic response to other chemicals. If this is the case, then alcohol may modify the initiation stages of chemical carcinogenesis or act as a promoter. This study proposes to determine if alcohol enhances the initiation of hepatocytes by dimethylnitrosamine and of the esophageal cells by methylbenzylnitrosamine. Alternatively, it will also investigate if alcohol acts as a promoter when administered after these two initiating agents. Ethanol will be administered to rats as part of an isocaloric diet for various lengths of time before and during, or after initiation. Studies will focus on the development of animal models which will permit assessment of the carcinogenic process (i.e. formation of carcinogen altered foci and nodules as well as tumors) in both tissues. In addition the effects of alcohol on selected events associated with the initiation and promotion stages of carcinogenesis will be determined. These include the formation and removal of methylated bases from DNA (ex: 60-methylguanine) and the production of single strand breaks in DNA. These animal models and accompanying mechanistic studies will help resolve many of the conflicting reports concerning the effect of chronic alcohol consumption on the carcinogenic process. They should also provide a data base which will contribute to the development of medical strategies to reduce the risk of alcohol-carcinogen interactions at the clinical level.
