Effect of dietary components on DNA repair

描述(由申请人提供)： 我们的长期目标是提供有关饮食中天然化合物对致癌影响的基础知识。这一知识将促进一种理性的方法，对饮食成分作为人类癌症化学预防药物的影响进行关键评估。吸烟是肺癌的主要决定因素。耐克(4-(Methylnitrosamino)-l-(3-pyridyl)-l-butanone)是一种烟草特有的亚硝胺，被怀疑是人类致癌物质。异硫氰酸苯乙酯(PEITC)和角鲨烯是有效抑制NNK诱导的肺肿瘤发生的饮食成分。该项目的总体目标是阐明：1)DNA修复途径，包括碱基切除修复(BER)、错配DNA修复(MMR)和甲基鸟嘌呤DNA-甲基转移酶(MGMT)在烷化剂诱导的DNA损伤反应中的作用；2)饮食成分对这些DNA修复途径的影响。有待检验的假设是，饮食成分通过调节DNA修复途径来抑制肺肿瘤的发生。我们将通过以下具体目标来验证我们的假设：1)确定饮食成分在体外对烷基化剂诱导的DNA损伤和修复的影响。在甲基亚硝脲或NNK存在和不存在PEITC、角鲨烯、杨梅素或α-生育酚的情况下，将对肝细胞和肺细胞进行甲基化DNA加合物水平、MGMT水平、MMR状态和BER状态的研究；2)确定饮食中PEITC和角鲨烯对NNK诱导的体内DNA损伤和修复的影响。研究将在NNK给药后的几个时间点，在有无PEITC或角鲨烯的情况下，对小鼠肺和肝样本进行氧化和甲基化DNA加合物水平、MGMT水平、MMR状态和BER状态的研究。 这项研究的结果将极大地加深我们对饮食成分在降低肺癌发生中的作用机制的理解。这些信息将对规划未来的流行病学研究和制定预防人类肺癌的战略非常有用。

DESCRIPTION (provided by applicant): Our long-term goal is to provide fundamental knowledge on the effects of naturally occurring compounds present in the diet on carcinogenesis. This knowledge will facilitate a rational approach for the critical evaluation of the effects of dietary components as cancer chemopreventive agents in humans. Smoking is a major determinant for lung cancer. 4-(Methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) is a tobacco-specific nitrosamine and suspected human carcinogen. Phenethyl isothiocyanate (PEITC) and squalene are dietary components that are effective inhibitors of NNK-induced lung tumorigenesis. The overall goal of this project is to elucidate: 1) the role of DNA repair pathways, including Base Excision Repair (BER), mismatch DNA repair (MMR), and methylguanine DNA-methyltransferase (MGMT), in the response to alkylating agent-induced DNA damage; and 2) the effect of dietary constituents on these DNA repair pathways. The hypothesis to be tested is that dietary constituents inhibit lung tumorigenesis by modulating DNA repair pathways. We will test our hypothesis with the following Specific Aims: 1) to determine the effect of dietary constituents on alkylating agent-induced DNA damage and repair in vitro. Studies examining methylated DNA adduct levels, MGMT levels, MMR status, and BER status will be conducted with hepatocytes and lung cells after methylnitrosourea or NNK administration in the presence and absence PEITC, squalene, myricetin or alpha-tocopherol; and 2) to determine the effect of dietary PEITC and squalene on NNK-induced DNA damage and repair in vivo. Studies examining oxidative and methylated DNA adduct levels, MGMT levels, MMR status, and BER status will be conducted with mouse lung and liver samples at several time points after NNK administration in the presence and absence of PEITC or squalene. The results from this study will greatly enhance our understanding of the mechanisms for the action of dietary constituents in decreasing lung carcinogenesis. This information will be very useful for planning future epidemiological studies and in the designing of strategies for the prevention of human lung cancer.