NITRIC OXIDE AND TUMOR PROMOTION

一氧化氮与肿瘤促进

• 批准号: 6124460
• 负责人: FREDIKA A ROBERTSON
• 金额: $ 27.41万
• 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 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124460
• 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：这是一项研究活性物作用的提案

项目成果

Comparative expression of novel vascular endothelial growth factor/vascular permeability factor transcripts in skin, papillomas, and carcinomas of v-Ha-ras Tg.AC transgenic mice and FVB/N mice.

v-Ha-ras Tg.AC 转基因小鼠和 FVB/N 小鼠的皮肤、乳头状瘤和癌中新型血管内皮生长因子/血管通透性因子转录物的比较表达。

• DOI: 10.1006/bbrc.1998.8787
• 发表时间: 1998
• 期刊: Biochemical and biophysical research communications.
• 作者: Tober,KL;Cannon,RE;Spalding,JW;Oberyszyn,TM;Parrett,ML;Rackoff,AI;Oberyszyn,AS;Tennant,RW;Robertson,FM
• 通讯作者: Robertson,FM