MODELS OF TOBACCO-ALCOHOL RELATED CARCINOGENESIS

在美国大约有5000万吸烟者， 另外1000万无烟烟草使用者。 有一千二百万 酗酒者和另外4000万酗酒者。 问题和 酗酒者通常是烟瘾很大的人。 癌症风险加剧， 饮酒和吸烟的结合。 由于乙醇本身并不 一种致癌物质，癌症发病率的增加一定是由于乙醇 增强烟草中致癌物的作用。 根据我们的调查结果， 最近的研究，这项研究计划将开发一种动物模型， 研究这两个因素的相互作用。 因为我们的研究表明 乙醇只有在使用时才能增强化学诱导的食管肿瘤 作为肿瘤促进剂，这些实验中的乙醇将仅给予 在引发剂暴露完成之后。 两种有效的烟草特异性 亚硝胺、N-亚硝基去甲烟碱和2-（甲基亚硝胺基）-1-（3-吡啶基）- 1-丁酮将用于引发致癌作用。 该研究将重点 对口腔和食道的影响，因为烟草和 酒精在这些地方最明显。 动物模型将是 分两个阶段发展。 首先，将进行一项试点研究，以确定 第二阶段使用的致癌物的最佳剂量和持续时间 将研究乙醇作为促进剂的贡献。 研究 还将进行脱落的人口腔粘膜细胞以测试是否 DNA损伤和修复抑制的程度可用作 与烟草和乙醇相关的致癌风险增加。 包括的生化研究将调查分子机制 例如DNA链断裂，假定的 前致突变损伤06甲基鸟嘌呤和甲基转移酶修复水平 酵素 将对吸烟者、饮酒者和 吸烟者及其控制 DNA损伤的程度可能是 用于化学预防研究中间标记物，以筛选 可以逆转这种伤害。 上述研究的结果将是有益的 制定旨在减少烟草致癌风险的战略， 饮酒

There are about 50 million cigarette smokers in the U.S. and at least another 10 million users of smokeless tobacco. There are 12 million problem drinkers and additional 40 million heavy drinkers. Problem and heavy drinkers are generally heavy smokers. Cancer risk is exacerbated by a combination of drinking and tobacco use. Since ethanol by itself is not a carcinogen, the increase in cancer incidence must be due to ethanol enhancing the effect of carcinogens in tobacco. Based on findings of our recent studies, this research proposal will develop an animal model to study the interaction of the two factors. Since our studies show that ethanol enhances chemically-induced esophageal tumors only when it is used as a tumor promoter, ethanol in these experiments will be administered only after initiator exposure has been completed. Two potent tobacco specific nitrosamines, N-nitrosonornicotine and 2-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone will be used to initiate carcinogenesis. The study will focus on the oral cavity and esophagus since the combined effects of tobacco and alcohol are most apparent at these sites. The animal model will be developed in two phases. First a pilot study will be done to determine the optimal dose(s) and duration of carcinogen to be used in the second phase which will study the contribution of ethanol as a promoter. Studies on exfoliated human oral mucosal cells will also be performed to test whether the extent of DNA damages and repair inhibition can be used as a marker for increased carcinogenesis risk associated with tobacco and ethanol. Biochemical studies included will investigate the molecular mechanisms involved such as DNA strand breaks, persistence of the putative promutagenic lesion 06methylguanine and levels of methyltransferase repair enzyme. Comparisons will be made between tobacco users, drinkers and smokers and their controls. The extent of DNA damage could be potential intermediate marker for chemoprevention studies to screen for agents that may reverse such injury. The results of the above studies will be useful in designing strategies aimed at reducing cancer risk due to tobacco and alcohol use.