THE ROLE OF TOBACCO-RELATED CHEMICAL CARCINOGENS AND OXYRADICALS IN HUMAN CANCER

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High concentrations of nitric oxide (NO) regulation of NO synthase (NOS) activity is essential for minimizing effects of cytotoxic and genotoxic nitrogen oxide species. We have shown previously, that NO- induced p53 protein accumulation, down-regulates basal and cytokine- modulated inducible NOS (NOS2) expression in human cells in vitro, and that p53-null mice have elevated NOS2 enzymatic activity. Our investigation of primary colon tumors establishes a strong positive relationship between the presence of NOS2 in tumors and the frequency of G:C to A:T transitions at CpG dinucleotides. These mutations also are common in lymphoid, esophageal, head and neck, stomach, brain and breast cancers. Increased NOS2 expression has been demonstrated in four of these cancers. Tumor-associated NO production may modify DNA directly, or may inhibit DNA repair activities, such as the recently described human thymine-DNA glycosylase, which has been shown to repair G:T mismatches at CpG dinucleotides. Because NO production also induces the accumulation of wild-type p53, the resulting growth inhibition can provide an additional strong selection pressure for nonfunctional, mutant p53. NO may, therefore, act as both an endogenous initiator and promoter in human colon carcinogenesis, and specific inhibitors of NOS2, as demonstrated recently in an animal tumor model, may have important chemopreventive potential in human colorectal cancer.These and other findings indicate that NO has a pathophysiological role in carcinogenesis. To determine the role of NO in tumor progression, we generated human carcinoma cell lines that produced NO constitutively. Cancer cells expressing NOS2 that had wild-type p53, had reduced tumor growth in athymic nude mice, whereas those with mutated p53 had accelerated tumor growth associated with increased vascular endothelial growth factor expression and neovascularization. Our data indicate that tumor-associated NO production may promote cancer progression by providing a selective growth advantage to tumor cells with mutant p53, and that inhibitors of NOS2 may have therapeutic activity in these tumors. We are also investigating chronic inflammatory diseases, e.g., ulcerative colitis, and genetic oxyradical overload diseases, e.g., hemochromatosis and Wilson Disease, that are cancer prone. Analyses of p53 mutation load, ethano-DNA adducts, microsatellite instability, NOS2 and COX2 are in progress. - Mutagenesis, Nitric oxide, p, Tumor Suppressor, Angiogenesis, Tumor Progression, - Human Tissues, Fluids, Cells, etc.