NITRIC OXIDE AND TUMOR PROMOTION

一氧化氮与肿瘤促进

• 批准号: 2837792
• 负责人: FREDIKA A ROBERTSON
• 金额: $ 26.61万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-24 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2837792
• 关键词: animal genetic material tag; apoptosis; arginine; benzanthracenes; chemical carcinogenesis; enzyme activity; enzyme induction /repression; gene mutation; inhibitor /antagonist; laboratory mouse; mixed tissue /cell culture; neoplasm /cancer genetics; nitric oxide; nitric oxide synthase; p53 gene /protein; peroxynitrites; phorbols; skin; skin neoplasms; vascular endothelium

DESCRIPTION: This is a proposal to investigate the role of reactive nitrogen species in skin tumor promotion in mice. Considerable recent evidence indicates that both reactive nitrogen and oxygen species are formed in skin treated with tumor promoter tetradecanoylphorbol acetate (TPA) in a multistage carcinogenesis (DMBA/TPA) model and in skin treated chronically with the complete carcinogen DMBA. The hypothesis to be investigated in this project is that reactive nitrogen intermediates produced by inflammatory leukocytes present in the dermis and the dermal/epidermal junction cause oxidative DNA damage that leads to mutations and affects clonal expansion of initiated cell populations through the selective induction of apoptosis. This hypothesis will be addressed through three specific aims. Studies in aim 1 will characterize changes in the expression of genes for inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) as well as the induction of apoptosis in epidermis of mice subjected to a DMBA/TPA protocol or multiple treatments with DMBA alone. Studies in Aim 2 will investigate the effects of modulation of NO production with the NOS inhibitor monomethyl-L-arginine monoacetate (L-NMMA) or the NO-releasing compound DETA/NO in the DMBA/TPA or DMBA-only protocols. Parameters to be investigated include NOS gene expression, vascular permeability, skin thickness, vascular endothelial growth factor and vascular permeability factor induction, NO and peroxynitrite production, leukocyte infiltration, apoptosis, and oxidative DNA damage. Studies in aim 3 will attempt to determine the nature of the reactive nitrogen species involved in mutagenesis and the mutations they produce in an in vitro co-culture system employing AS52 cells exposed to oxidants or incubated in co-culture with peripheral leukocytes isolated from DMBA/TPA or DMBA treated mice. Mutations in the gpt gene of the AS52 cells will be characterized.

描述：这是一项研究反应性 氮物种在小鼠皮肤肿瘤促进中的作用。 相当近期 有证据表明，活性氮和氧物种都是在 在用肿瘤促进剂十四烷酰佛波醇乙酸酯（TPA）处理的皮肤中， 多阶段致癌（DMBA/TPA）模型和长期治疗的皮肤 完全致癌的DMBA 要研究的假设 该项目是由活性氮中间体产生的， 真皮和真皮/表皮中存在炎性白细胞 连接导致氧化DNA损伤，导致突变和影响 通过选择性的克隆扩增起始的细胞群体， 诱导细胞凋亡。 这一假设将通过三个解决 具体目标。 目标1中的研究将描述表达的变化， 诱导型一氧化氮合酶（iNOS）和内皮型一氧化氮合酶（NOS）基因 （eNOS）以及诱导表皮细胞凋亡， DMBA/TPA方案或单独使用DMBA的多次治疗。 研究 目的2将研究NO产生的调制与 NOS抑制剂单甲基-L-精氨酸单乙酸酯（L-NMMA）或NO释放 化合物DETA/NO在DMBA/TPA或仅DMBA的方案中。 的参数 研究包括NOS基因表达、血管通透性、皮肤 厚度、血管内皮生长因子和血管通透性 因子诱导，NO和过氧亚硝酸盐产生，白细胞浸润， 凋亡和氧化性DNA损伤。 目标3中的研究将试图 确定所涉及的活性氮物质的性质， 诱变和它们在体外共培养系统中产生的突变 使用暴露于氧化剂或与以下物质共培养的AS 52细胞 从DMBA/TPA或DMBA处理的小鼠分离的外周白细胞。 将表征AS 52细胞gpt基因的突变。