权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cyclooxygenase-2 inhibitor is a possible new drug for treatment of gastrointestinal cancers

环加氧酶2抑制剂是治疗胃肠道癌症的可能新药

基本信息

批准号：
16390374
负责人：
SUGIHARA Kenichi
金额：
$ 9.62万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

项目摘要

COX-2 expression of gastrointestinal cancers: <Study1> We investigate COX-2 and Loxs of colorectal cancer. Of 91 primary colorectal cancers, Loxs mRNA was found in 72.5%. High expression of Loxs and COX-2 protein were found by immunohistochemical staining in 68.7% and 79.1%, respectively. The high expression of Loxs protein was correlated with that of COX-2 protein. Arachdonic acid is metabolized either by Loxs or COX. This study showed Loxs is up-regulated in colorectal cancer, and inhibition of Loxs as well as COX-2 may prevent development of colorectal cancer. <Study2> Expression of VEGF, COX-2 and CD34 for microvessel density was investigated in 169 gastric cancers. COX-2 and VEGF were highly expressed in 36.7% and 50.3%, respectively. Positive relation was found between VEGF and COX-2 expression and between VEGF and CD34 expression. VEGF expression was correlated with depth of invasion, metastatic lymph nodes, lymphatic and venous invasion and TNM stage. Patients with positive VEG … More F staining showed lower disease free survival and overall survival than those with negative VGEF staining. In multivariate analysis, tumor location, depth of invasion and lymph node metastasis were shown to be independent prognostic factor. VEGF expression may be a valuable prognostic factor in gastric cancer.COX-2 inhibitors and suppression of tumor growth: <Study1> We investigate the microvascular structure of small lung metastases and the effect of JTE-522, a selective COX-2 inhibitor, on the angiogenesis of pulmonary metastases from colorectal cancer in rats. The tail veins of 20 rats were injected with a tumor suspension of a rat colon cancer cell line. Three weeks later, pulmonary vascular resin corrosion casts were taken and the vascularity of metastases was studied with using stereo and scanning electron microscopes. In addition, we investigated the effect of 0, 10 and 30 mg/kg/day of JTE-522 on the angiogenesis of pulmonary metastases in 3 groups of 5 rats. The diameter of tumor vessels and the size of lung metastases significantly and positively correlated with neovascularization in 35 metastatic tumors. JTE-522 reduced the size of metastatic tumors and the diameter of tumor vessels. Selective COX-2 inhibitors may interfere the growth of hematogenous metastatic tumors by disrupting neovascularization. <Study2> We investigated the tumor vessel of metastatic liver tumors and the effect of Meloxicam, a selective COX-2 inhibitor, on growth and microvasculature of small metastatic liver tumors in rats. Metastatic liver tumors were produced by intraportal inoculation of RCN-H4 cells in 40 rats. Microvasculature of liver metastasis was studied by scanning electron microscopy and stereomicroscopy. Microvascular casts were produced by perfusion via the abdominal aorta 14 days after tumor inoculation. Meloxicam was administered in four groups with a dose of 0, 0.6, 1.0, 3.0 mg/kg/day orally 5 days per week from the day of inoculation of RCN-H4 cells for 2 weeks. The number of metastatic tumors and was less in the Meloxicam-treated groups in comparison with dose dependent fashion. From these observations, Meloxicam interfered growth of metastatic liver tumors through anti-angiogenic activity. Meloxicam may have therapeutic potential for liver tumors of colorectal carcinoma. Less

COX-2在胃肠道肿瘤中的表达：&lt；Study1&gt；我们研究了COX-2和LOXS在结直肠癌中的表达。91例原发结直肠癌中，Loxs基因表达阳性率为72.5%。免疫组织化学染色显示LOXS和COX-2蛋白高表达分别为68.7%和79.1%。Loxs蛋白的高表达与COX-2蛋白的高表达相关。花生四烯酸由低氧代谢或环氧合酶代谢。这项研究表明，LOXS在结直肠癌中表达上调，抑制LOXS和COX-2可能阻止结直肠癌的发展。研究169例胃癌组织中血管内皮生长因子(VEGF)、环氧合酶-2(COX-2)和CD34的表达及微血管密度。COX-2和VEGF的高表达分别为36.7%和50.3%。血管内皮生长因子与COX-2、CD34表达呈正相关。血管内皮生长因子的表达与肿瘤侵袭深度、淋巴结转移、淋巴和静脉侵犯及TNM分期有关。VEG…阳性的患者F染色越多，无病生存期和总生存期越低。多因素分析显示，肿瘤部位、侵犯深度和有无淋巴结转移是影响预后的独立因素。COX-2抑制剂与肿瘤生长抑制：&lt；Study1&gt；我们研究了小鼠肺转移瘤的微血管结构，以及选择性COX-2抑制剂JTE-522对大鼠结直肠癌肺转移瘤血管生成的影响。给20只大鼠尾静脉注射大鼠结肠癌细胞系的肿瘤悬液。3周后取肺血管铸型，用体视显微镜和扫描电子显微镜观察转移灶的血供。此外，我们还观察了JTE-522 0、10和30 mg/kg/d对3组5只大鼠肺转移瘤血管生成的影响。在35例转移性肿瘤中，肿瘤血管直径和肺转移灶大小与血管生成呈显著正相关。JTE-522缩小了转移瘤的大小和肿瘤血管的直径。选择性COX-2抑制剂可能通过破坏新生血管来干预血行转移肿瘤的生长。我们研究了转移性肝肿瘤的肿瘤血管，以及选择性COX-2抑制剂美洛昔康对小转移性肝肿瘤生长和微血管形成的影响。40只大鼠经门静脉接种RCN-H4细胞建立转移性肝肿瘤模型。应用扫描电子显微镜和体视显微镜对肝转移瘤的微血管进行了研究。接种肿瘤后14天，经腹主动脉灌流形成微血管铸型。美洛昔康0、0.6、1.0、3.0 mg/kg/d，自RCN-H4细胞接种之日起每周5天口服，共2周。与剂量依赖方式相比，美洛昔康治疗组转移瘤的数量和数量较少。根据这些观察，美洛昔康通过抗血管生成活性干预转移性肝肿瘤的生长。美洛昔康可能对结直肠癌肝肿瘤有治疗潜力。较少