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

烟草相关化学致癌物和氧化自由基在人类癌症中的作用

• 批准号: 6289305
• 负责人: CURTIS HARRIS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289305
• 关键词: cancer risk; chemical carcinogen; chemical carcinogenesis; clinical research; colon neoplasms; enzyme activity; free radical oxygen; gene mutation; human tissue; neoplasm /cancer genetics; nitric oxide synthase; polymerase chain reaction; restriction fragment length polymorphism; tobacco abuse; tumor suppressor genes; ulcerative colitis

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.

高浓度的一氧化氮（NO）调节NO合酶（NOS）活性对于最小化细胞毒性和遗传毒性氮氧化物种类的影响是必不可少的。我们先前已经表明，NO诱导的p53蛋白积累，下调体外人细胞中基础和细胞因子调节的诱导型NOS（NOS 2）表达，并且p53缺失小鼠具有升高的NOS 2酶活性。我们对原发性结肠肿瘤的研究建立了肿瘤中NOS 2的存在与CpG二核苷酸处G：C到A：T转换的频率之间的强正相关关系。这些突变在淋巴癌、食管癌、头颈癌、胃癌、脑癌和乳腺癌中也很常见。在这些癌症中的四种中已经证明了NOS 2表达增加。肿瘤相关的NO产生可以直接修饰DNA，或者可以抑制DNA修复活性，例如最近描述的人胸腺嘧啶-DNA糖基化酶，其已被证明可以修复CpG二核苷酸处的G：T错配。由于NO的产生也诱导野生型p53的积累，因此产生的生长抑制可以为无功能的突变型p53提供额外的强选择压力。因此，NO在人结肠癌的发生中可能既是内源性的启动子又是促进子，而最近在动物肿瘤模型中证实的特异性NOS 2抑制剂可能在人结肠癌的发生中具有重要的化学预防潜力，这些研究结果表明NO在结肠癌的发生中具有病理生理作用。为了确定NO在肿瘤进展中的作用，我们产生了组成型产生NO的人癌细胞系。表达NOS 2的癌细胞具有野生型p53，在无胸腺裸鼠中具有减少的肿瘤生长，而具有突变的p53的那些具有与增加的血管内皮生长因子表达和新血管形成相关的加速的肿瘤生长。我们的数据表明，肿瘤相关的NO产生可能通过为具有突变型p53的肿瘤细胞提供选择性生长优势来促进癌症进展，并且NOS 2抑制剂可能在这些肿瘤中具有治疗活性。我们还在研究慢性炎症性疾病，例如，溃疡性结肠炎和遗传性氧自由基超负荷疾病，例如，血色素沉着症和威尔逊病，这些都是容易患癌症的疾病。p53突变负荷、乙醇-DNA加合物、微卫星不稳定性、NOS 2和COX 2的分析正在进行中。- 突变、一氧化氮、p、肿瘤抑制因子、血管生成、肿瘤进展、-人体组织、体液、细胞等。