Molecular targeting therapy for digestive carcinomas

消化道癌的分子靶向治疗

• 批准号: 11470131
• 负责人: KAWANO Sunao
• 金额: $ 9.02万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470131/
• 关键词: cyclooxygenase; tumor angiogenesis; prostaglandins; digestive carcinomas; chemoprevention; metastasis; apoptosis; cell proliferation; 消化器癌; COX-2; 分子標的療法

We investigated mechanisms for development, invasion and metastasis of digestive carcinomas, based on interactions between neoplastic cells and parenchymal cells. Mitogen-inducible cyclooxygenase (cox-2) is upregulated in most neoplastic tissues as well as most neoplastic cells, and enhances expression of angiogenic factors. COX-2 inhibitors suppress production of these angiogenic factors. On the other hand, cox-1 expressed in vascular endothelial cells participates in tumor angiogenesis. In vivo studies using mouse xenografts showed that non-steroidal anti-inflammatory drugs suppress angiogenesis, inhibit cell replication, induce programmed cell death, and block tumor growth. Furthermore, tumors do not grow in cox-2 knockout mice, possibly because cox-2 also has important roles in angiogenic factor-production in the perineoplastic stromal cells.Human studies and animal studies demonstrate that cox-2 is upregulated in gastrointestinal tract in response to various stimuli including tissue damage, growth factors, H.pylori infection and gastrin. In addition, a study shows that COX-2 upregulation is associated with lymphatic invasion and lymphatic metastasis in patients with gastric carcinomas.All of the studies clearly indicate that cox-2 plays pivotal roles in development, growth, invasion and metastasis in digestive tumors. Thus, cox-2 is an important molecular target in prevention and treatment in digestive cancers.

我们基于肿瘤细胞和实质细胞之间的相互作用来研究消化道癌的发生、侵袭和转移的机制。丝裂原诱导型环氧合酶（考克斯-2）在大多数肿瘤组织和大多数肿瘤细胞中上调，并增强血管生成因子的表达。考克斯-2抑制剂抑制这些血管生成因子的产生。另一方面，在血管内皮细胞中表达的考克斯-1参与肿瘤血管生成。使用小鼠异种移植物的体内研究表明，非甾体抗炎药抑制血管生成，抑制细胞复制，诱导程序性细胞死亡，并阻断肿瘤生长。此外，考克斯-2基因敲除小鼠的肿瘤不会生长，这可能是因为考克斯-2在外周基质细胞中的血管生成因子的产生中也具有重要作用。此外，有研究表明，考克斯-2的表达上调与胃癌的淋巴道浸润和淋巴道转移有关，这些研究清楚地表明COX-2在消化道肿瘤的发生、生长、浸润和转移中起着关键作用。因此，考克斯-2是预防和治疗消化道肿瘤的重要分子靶点。

项目成果

Sun WH, et al.: "Cyclooxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in rats."Journal of Gastroenterology and Hepatology. 15. 752-761 (2000)

Sun WH 等人：“Cyclooxygenase-2 抑制剂可抑制大鼠上皮细胞动力学并延迟胃伤口愈合。”胃肠病学和肝脏病学杂志。

Murata H, Kawano S, Tsuji S, Tsujii M, et al.: "Cydooxygenase-2 overexpression enhances lymphatic invasion and metastasis in human gastric carcinoma"American Journal of Gastroenterology. 94. 451-455 (1999)

Murata H、Kawano S、Tsuji S、Tsujii M 等人：“Cydooxygenase-2 过表达增强人胃癌的淋巴侵袭和转移”美国胃肠病学杂志。

Tsuji S, Sun WH, Tsujii M, Kawano S, Hori M.: "Asakura H (ed) Gastroenterology and Hepatology : Millenium 2000, Springer-Verlag Tokyo, Tokyo, (in press)"Does cyclooxygenase-2 down-regulate gastric inflammation ?.

Tsuji S、Sun WH、Tsujii M、Kawano S、Hori M.：“Asakura H (ed) Gastroenterology and Hepatology : Millenium 2000，Springer-Verlag Tokyo，东京，（正在印刷中）”环氧合酶 2 是否下调胃部炎症

Sun WH, Tsuji S, Tsujii M, Sawaoka H, Kawai N, Gunawan ES, Kimura A, Kakiuchi Y, Yasumaru S, Kawano S, Hori M.: "Cyclooxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in rats"J Gastroenterol Hepatol. 15. 752-761 (20

Sun WH、Tsuji S、Tsujii M、Sawaoka H、Kawai N、Gunawan ES、Kimura A、Kakiuchi Y、Yasumaru S、Kawano S、Hori M.：“Cyclooxygenase-2 抑制剂抑制上皮细胞动力学并延迟大鼠胃伤口愈合

Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Kawai N, Sasaki Y, Hori M, Kawano S.: "Involvement of cyclooxygenase-2 in proliferation and morphogenesis induced by transforming growth factor alpha in gastric epithelial cells."Prostagland Leukotr Ess Fatty Acid

Sawaoka H、Tsuji S、Tsujii M、Gunawan ES、Kawai N、Sasaki Y、Hori M、Kawano S.：“环氧合酶 2 参与胃上皮细胞中转化生长因子 α 诱导的增殖和形态发生。”Prostagland Leukotr Ess