Mechanisms of preventive effects of nonsteroidal anti- inflammatory drugs on colon carcinogenesis

非甾体类抗炎药预防结肠癌的机制

• 批准号: 10670499
• 负责人: OTA Shinichi
• 金额: $ 1.98万
• 依托单位: Saitama Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670499/
• 关键词: NSAIDs; PROSTAGLANDIN; COX-2; COLON CARCINOGENESIS; COLON ADENOMA; VEGF; PROSTAGLANDIN RECEPTORS; MACROPHAGE; PPArγ; NSAID; COX

We investigated the localization of cyclooxygenase (COX)-2, a possible target of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of colon carcinogenesis. Then effects of prostaglandins on vascular endothelial growth factor (VEGF), an essential factor in tumor angiogenesis, production was studied. Results are as follows;a. High expression of COX-2 was detected in sub-epithelial interstitial cells, possibly macrophages, broadly present in the surface area of human adenomas.b. Coz-2 was only partly and weekly expressed in human advanced colon cancer.c. Prostaglandin (PG) E dramatically increased the production of VEGF by human macrophages but not by human colonic adenoma cells or cancer cells.d. This action was mediated by the increase of cAMP through EPィイD22ィエD2 and EPィイD24ィエD2 PGE receptorse. PGJ2, an agonist of nuclear receptor PPAR γ, also dramatically increased VEGF production by human macrophages.These results suggest that PGs produced by macrophaged of human colonic adenomas may play important roles in human colon carcinogenesis through the induction of VEGF. NSAIDs possibly prevent human coloncarcinogenesis by the suppression of this step.

我们研究了环加氧酶 (COX)-2 的定位，这是非甾体抗炎药 (NSAID) 预防结肠癌发生的可能靶标，然后研究了前列腺素对血管内皮生长因子 (VEGF) 的影响，血管内皮生长因子 (VEGF) 是肿瘤血管生成的重要因素。研究结果如下：a.在上皮下间质细胞（可能是巨噬细胞）中检测到COX-2的高表达。 b. Coz-2 在人类晚期结肠癌中仅部分且每周表达。 c. 前列腺素 (PG) E 显着增加人类巨噬细胞的 VEGF 产生，但人类结肠腺瘤细胞或癌症则不然。 d. 该作用是通过 EP-D22-D2 和 EP-D24-D2 PGE2（核受体激动剂）的增加来介导的。 PPAR γ 也显着增加人巨噬细胞产生 VEGF。这些结果表明，人结肠腺瘤巨噬细胞产生的 PG 可能通过诱导 VEGF 在人结肠癌发生中发挥重要作用，NSAID 可能通过抑制这一步骤来预防人结肠癌发生。 。

项目成果

Hiromi Bamba, Shinichi Ota, Akira Kato, Fukashi Matsuzaki.: "Effect of prostaglandin E1 on vascular endothelial growth factor production by human macrophages and colon cancer cells."Journal of Experimental & Clinical Cancer Research. (in press).

Hiromi Bamba、Shinichi Ota、Akira Kato、Fukashi Matsuzaki.：“前列腺素 E1 对人类巨噬细胞和结肠癌细胞产生血管内皮生长因子的影响。”实验杂志

S.Ota, Y.Tanaka, H.Banaba, A.Kato, F.Matsuzaki: "Nonsteroidal anti-inllammatory druugs may prevent color cancer through suppression of hepatocyte growth factor" European Journal of Pharmacology. 367. 131-138 (1999)

S.Ota、Y.Tanaka、H.Banaba、A.Kato、F.Matsuzaki：“非甾体类抗炎药物可以通过抑制肝细胞生长因子来预防彩色癌”《欧洲药理学杂志》。