Effects Of Deficiency Of COX-1 or COX-2 On Chemically-In

COX-1 或 COX-2 缺乏对化学输入的影响

• 批准号: 6546704
• 负责人: Robert Langenbach
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/6546704
• 关键词: adenocarcinoma; azo compounds; cancer prevention; chemical carcinogen; chemical carcinogenesis; chemoprevention; colon polyp; colorectal neoplasms; enzyme deficiency; enzyme inhibitors; gastrointestinal neoplasms; laboratory mouse; methane; nonsteroidal antiinflammatory agent; preneoplastic state; prostaglandin endoperoxide synthase; protein isoforms

Epidemiology data indicate that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the incidence of colorectal cancer by approximately 50% in humans. Rodent models of colon cancer also show reductions in tumor formation following NSAID treatment. NSAIDs are believed to act by inhibition of cyclooxygenase (COX-1 and COX-2). Our previous studies have shown a reduction in precancerous lesions in COX deficient Min mice. In the present study azoxymethane is being used to induce colon cancer in isogenic wild type and COX deficient mice. Azoxymethane initially induces precancerous aberrant crypt foci followed by adenocarcinomas. Azoxymethane treatment of mice genetically deficient in either COX-1 or COX-2, heterozygous for COX-1 or COX-2, or heterozygous for both isoforms, provides a method of studying COX dependent development of premalignant and malignant lesions. Our studies with the COX deficient mice should provide valuable information about the advantages of selectively inhibiting COX-1 or COX-2 vs the use of dual COX inhibitors.

流行病学数据表明，定期使用非甾体抗炎药（NSAIDs）可使人类结直肠癌的发病率降低约50%。啮齿类动物结肠癌模型也显示非甾体抗炎药治疗后肿瘤形成减少。非甾体抗炎药被认为是通过抑制环氧化酶（COX-1和COX-2）起作用的。我们之前的研究表明，在COX缺乏的Min小鼠中，癌前病变减少。在目前的研究中，偶氮甲烷被用于诱导等基因野生型和COX缺乏小鼠结肠癌。偶氮甲烷最初诱导癌前异常隐窝灶，随后诱发腺癌。偶氮甲烷治疗COX-1或COX-2基因缺失、COX-1或COX-2基因杂合、或两种亚型基因杂合的小鼠，为研究COX依赖于癌前病变和恶性病变的发展提供了一种方法。我们对COX缺陷小鼠的研究应该提供有价值的信息，说明选择性抑制COX-1或COX-2与使用双重COX抑制剂的优势。