Cyclooxygenase-2 Inhibition, Angiogenesis, Breast Cancer

说明书(申请人提供)人们对非类固醇抗炎药(NSAIDs)，特别是环氧合酶(COX)-2抑制剂在预防和治疗癌症中的作用越来越感兴趣。最近的病例对照、前瞻性和动物研究表明，这些药物在降低乳腺癌风险方面有好处。非甾体抗炎药抑制环氧合酶，环氧合酶是将花生四烯酸转化为前列腺素(PG)的酶。COX-1形式是结构性的，而COX-2是可诱导的，并在人类乳腺肿瘤、乳腺癌细胞系和啮齿动物乳腺肿瘤中过表达。新近开发的环氧合酶-2抑制剂已被证明可以降低啮齿动物的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。虽然作用机制尚不清楚，但这些药物已被证明可以抑制COX酶，减少PG的产生，抑制血管生成因子，并抑制血管生成。阻断COX可减少自发性乳腺肿瘤小鼠的血管生成。特异性的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还没有被评估。本研究的目的是验证抑制COX-2抑制HER-2/neu高表达小鼠乳腺肿瘤生长的假设，该假说是通过调节血管生成因子：血管内皮生长因子、碱性成纤维细胞生长因子和血小板衍生生长因子来调节血管生成来实现的。我们之所以选择HER-2/neu小鼠模型，是因为HER-2在30%的乳腺癌中都有表达，并且HER-2的表达增加可以上调COX-2的表达。鉴于这一证据，本研究的具体目的是：1.评价COX-1和COX-2抑制对已建立的乳腺肿瘤生长的影响；2.检测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.通过检测乳腺中免疫细胞(巨噬细胞和淋巴细胞)的存在以及正常小鼠上皮细胞和小鼠肿瘤细胞产生Th-1和Th-2细胞因子和前列腺素来评价COX-1和COX-2抑制对乳腺免疫功能的影响。这项研究的结果将确定COX抑制剂作为一种重要的治疗策略在控制乳腺癌进展中的作用。

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.