MODELS OF TOBACCO-ALCOHOL RELATED CARCINOGENESIS

在美国大约有5000万吸烟者，至少 另有1000万无烟烟草使用者。有1200万人 酗酒者和额外的4000万酗酒者。问题和 酗酒者通常都是烟瘾很大的人。癌症风险因以下原因而加剧 饮酒和吸烟的结合。因为乙醇本身并不是 作为一种致癌物质，癌症发病率的增加一定是由于乙醇 提高烟草中致癌物质的作用。根据我们的调查结果 最近的研究，这项研究提案将开发一种动物模型来 研究这两个因素之间的相互作用。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道肿瘤 作为肿瘤促进剂，这些实验中的乙醇将仅用于 在引发剂曝光完成后。两种有效的烟草特效药 亚硝胺，N-亚硝基烟碱和2-(甲基亚硝氨基)-1-(3-吡啶)- 1-丁酮将被用来启动致癌。这项研究将集中于 吸烟与食道联合作用对口腔和食道的影响 酒精在这些部位最为明显。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 第二阶段使用致癌物的最佳剂量(S)和持续时间 这将研究乙醇作为促进剂的贡献。研究：关于 剥离的人类口腔粘膜细胞也将被用于测试 DNA损伤和修复抑制的程度可以作为一种标志 与烟草和酒精相关的致癌风险增加。 包括生化研究在内的研究将探讨分子机制。 例如DNA链断裂，推定的 06甲基鸟嘌呤致突变与甲基转移酶修复水平 酵素。将在吸烟者、饮酒者和 吸烟者和他们的对照。DNA损伤的程度可能是潜在的 用于化学预防研究的中间标志物，用于筛选 可以扭转这种伤害。上述研究的结果将是有用的。 在设计旨在降低烟草和烟草引起的癌症风险的策略时 酗酒。

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.