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.
