Cyclooxygenase-2 Inhibition, Angiogenesis, Breast Cancer

环氧合酶 2 抑制、血管生成、乳腺癌

• 批准号: 6613859
• 负责人: Susan Patricia Lanza-Jacoby
• 金额: $ 7.85万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-19 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613859
• 关键词: RNase protection assay; SDS polyacrylamide gel electrophoresis; angiogenesis; breast neoplasms; enzyme inhibitors; enzyme linked immunosorbent assay; enzyme mechanism; fibroblast growth factor; gene expression; genetically modified animals; growth inhibitors; helper T lymphocyte; immunocytochemistry; laboratory mouse; macrophage; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; platelet derived growth factor; prostaglandin endoperoxide synthase; prostaglandins; vascular endothelial growth factors; western blottings

DESCRIPTION (provided by applicant) There is a growing interest in the role of the nonsteroidal anti-inflammatory drugs (NSAIDs), in particular the cyclooxygenase (COX)-2 inhibitors, in the prevention and treatment of cancer. The benefit of these drugs in reducing the risk of breast cancer has been suggested by recent case control, prospective, and animal studies. The NSAIDs inhibit COX, the enzyme that converts arachidonic acid into prostaglandins (PG). The COX-1 form is constitutive while COX 2 is inducible and overexpressed in human breast tumors, breast cancer cell lines, and rodent mammary tumors. The newly developed COX-2 inhibitors have been shown to reduce the incidence of colon and mammary tumors in rodents and inhibit the growth of established mammary tumors. Although the mechanism of action is not clear, these drugs have been shown to inhibit the COX enzyme, reduce PG production, suppress angiogenic factors, and inhibit angiogenesis. Blocking COX reduced angiogenesis in mice with spontaneous mammary tumors. The ability of the specific COX-2 inhibitors to control the growth of mammary tumors by regulating angiogenesis has not been evaluated. The purpose of this study is to test the hypothesis that inhibition of COX-2 reduces the growth of mammary tumors in a mouse model with overexpression of HER-2/neu by regulating angiogenesis through modulation of the angiogenic factors: vascular endothelial growth factor, basic fibroblast growth factor, and platelet- derived growth factor. We have selected the HER-2/neu mouse model because HER-2 is expressed in 30% of all breast cancers and increased HER-2 expression has been shown to upregulate COX-2. In view of this evidence the specific aims are to: 1. evaluate the effect of COX-1 and COX-2 inhibition on the growth of established mammary tumors; 2. examine the effect of COX-1 and COX-2 suppression on the expression of angiogenic factors; 3. investigate the effect of COX-1 and COX-2 inhibition on angiogenesis; 4. evaluate the effect of COX-1 and COX-2 inhibition on immune function in the mammary gland by determining the presence of immune cells (macrophages and lymphocytes) in the mammary gland and the production of Th-1 and Th-2 cytokines and prostaglandins by normal mouse epithelial cells and mouse tumor cells. The results of this study will define the role of COX inhibitors as an important therapeutic strategy in controlling the progression of breast cancer.

描述（由申请人提供）对非甾体类抗炎药（NSAID）的作用越来越兴趣，尤其是环氧合酶（COX）-2抑制剂在预防和治疗癌症中的作用。最近的病例控制，前瞻性和动物研究表明，这些药物在降低乳腺癌风险方面的好处。 NSAID抑制Cox，Cox是将黄氨酸酸转化为前列腺素（PG）的酶。 COX-1形式是组成型的，而COX 2在人类乳腺肿瘤，乳腺癌细胞系和啮齿动物乳腺肿瘤中诱导且过表达。已显示新开发的COX-2抑制剂可降低啮齿动物中结肠和乳腺肿瘤的发生率并抑制已建立的乳腺肿瘤的生长。尽管作用机理尚不清楚，但这些药物已被证明可以抑制COX酶，减少PG产生，抑制血管生成因子并抑制血管生成。阻塞Cox可减少自发乳腺肿瘤小鼠的血管生成。尚未评估特定的COX-2抑制剂通过调节血管生成来控制乳腺肿瘤生长的能力。这项研究的目的是检验以下假设：抑制COX-2通过调节血管生成因子的调节血管生成通过调节血管生成，从而降低了小鼠模型中乳腺肿瘤的生长：血管内皮生长因子：碱性成纤维细胞生长因子和血小板生长因子。我们选择了HER-2/NEU小鼠模型，因为HER-2在所有乳腺癌的30％中表达，并且已经显示出HER-2表达的增加可以上调COX-2。鉴于此证据，具体的目的是：1。评估COX-1和COX-2抑制对已建立乳腺肿瘤生长的影响； 2。检查COX-1和COX-2抑制对血管生成因子表达的影响； 3。研究COX-1和COX-2抑制对血管生成的影响； 4。通过确定乳腺中免疫细胞（巨噬细胞和淋巴细胞）的存在，评估COX-1和COX-2抑制对乳腺中免疫功能的影响，并通过正常小鼠上皮细胞和小鼠肿瘤细胞的产生TH-1和TH-2细胞因子和Prostaglandins的TH-1和TH-2细胞因子和Prostaglandins。这项研究的结果将定义Cox抑制剂作为控制乳腺癌进展的重要治疗策略的作用。

项目成果

Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice.

抑制剂 SC236 与电离辐射联合使用时，对 HER-2/neu 小鼠乳腺肿瘤细胞产生环加氧酶 (COX)-2 依赖性作用。

• DOI: 10.4161/cbt.3.4.803
• 发表时间: 2004
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Lanza-Jacoby,Susan;Dicker,AdamP;Miller,Sheldon;Rosato,FrancisE;Flynn,JohnT;Lavorgna,StephanieN;Burd,Randy
• 通讯作者: Burd,Randy