Chemopreventive action to gastric cancer by selective cox-2 inhibitor coutribution of cox-1 inhibitor

选择性cox-2抑制剂与cox-1抑制剂联合对胃癌的化学预防作用

• 批准号: 14570519
• 负责人: MIYAKE Kazumasa
• 金额: $ 1.73万
• 依托单位: Nippon 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: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570519/
• 关键词: Helicobacter pylori; Gastric adenoma; eradication; cyclooxygenase; NSAID; VEGF; IL8; chemoprevention; COX(シクロオキシゲナーゼ)

It is speculated that gastric cancer, especially intestinal type, cancerates through atrophic gastritis, intestinal metaplasia, or adenoma by continuation of the chronic activity gastritis by H.pylori (HP) infection. In addition, a possibility that COX-2 is involving in the tumorigenesis process is high also in the stomach, as in the colon. Then, using i) the gastric adenoma patient with HP Infection and ii) gastric epithelium cell line (MKN28) co-cultured HP infection, we investigated the influence which HP infection has on proliferation and carcinogenesis of gastric epithelium through COX. Furthermore, it aimed at exploring the possibility as chemoprevention of the gastric cancer by HP eradication treatment or NSMDs. The eradication treatment was performed to gastric adenoma patients infected with HP. 12 of 13 cases succeeded in eradication. It observes for an average of 13.1 months after eradication. In five of 12 cases (41.7%), size of the adenoma reduced, although the histological … More grade of atypia did not change. In immunohistochemistry of COX-2, the positive cells were seen focusing on the intestinal cells near the surface mucosa before eradication, and disappeared mostly after eradication. Although the positive cells of MMP-7 were seen focusing on epithelial cells of the adenoma before eradication, it decreased after eradication. Ki67 Labeling index which estimates the proliferation decreased after eradication compared with that before eradication. In MKN28, COX-2 protein was induced by HP infection (Western blot). When MKN28 was co-cultured with HP infection, IL-8 and VEGF in culture medium increased in a time-dependent manner. Furthermore, the increase was suppressed by the selective COX-1 inhibitor (SC560), the selective COX-2 inhibitor (celecoxib), or the non-selective COX inhibitor (indomethacin), respectively. HP eradication may inhibit COX-2 and MMP7 expression and VEGF and IL-8 production which have actions of proliferation and carcinogenesis. On the other hand, NSAIDs may suppress VEGF and IL-8 production who were stimulated with HP infection, through not only COX-2 but COX-1 inhibition. Eradication treatment and NSAIDs suppress carcinogenesis and proliferation of gastric epithelium, and the chemopreventive action to gastric cancer is expected. Less

据推测，胃癌，特别是肠型胃癌，通过幽门螺杆菌（HP）感染引起的慢性活动性胃炎的延续，通过萎缩性胃炎、肠上皮化生或腺瘤癌变。另外，考克斯-2参与肿瘤发生过程的可能性在胃中也很高，如在结肠中。然后，我们利用HP感染的胃腺瘤患者和HP感染的胃上皮细胞系（MKN 28），研究HP感染通过考克斯对胃上皮细胞增殖和癌变的影响。本研究旨在探讨HP根除治疗或NSMDs作为胃癌化学预防的可能性。对HP感染的胃腺瘤患者进行根除治疗。13例中12例根除成功。根除后平均观察13.1个月。12例中有5例（41.7%）腺瘤缩小，尽管组织学检查显示腺瘤缩小， ...更多信息 肾功能分级无变化。考克斯-2免疫组化显示，根除前阳性细胞主要集中于肠黏膜表面的肠上皮细胞，根除后大部分细胞消失。MMP-7阳性细胞在根治术前主要集中于腺瘤上皮细胞，根治术后减少。Ki 67标记指数用于评价细胞增殖，根除后较根除前减少。在MKN 28中，考克斯-2蛋白被HP感染诱导（Western印迹）。当MKN 28与HP感染共培养时，培养液中IL-8和VEGF呈时间依赖性增加。此外，选择性考克斯-1抑制剂（SC 560）、选择性考克斯-2抑制剂（塞来昔布）或非选择性考克斯抑制剂（吲哚美辛）分别抑制了这种增加。根除HP可抑制具有增殖和致癌作用的考克斯-2和MMP 7的表达及VEGF和IL-8的产生。另一方面，NSAID可能通过抑制考克斯-2和考克斯-1而抑制HP感染刺激的VEGF和IL-8的产生。根除治疗和非甾体类抗炎药可抑制胃上皮的癌变和增殖，有望对胃癌起到化学预防作用。少

项目成果

Miyake K, Tsukui T, Wada K, Tatsuguchi A, Futagami S, Hiratsuka T, Shinoki K, Iizumi T, Akamatsu T, Sakamoto C, Kabayashi M: "Irritant-induced cyclooxygenase-2 is involved in the defence mechanism of the gastric mucosa in mice."J Gastroenterol. 37(3). 164

Miyake K、Tsukui T、Wada K、Tatsuguchi A、Futagami S、Hiratsuka T、Shinoki K、Iizumi T、Akamatsu T、Sakamoto C、Kabayashi M：“刺激物诱导的环氧合酶-2 参与胃粘膜的防御机制

三宅一昌, 坂本長逸: "Annual Review 消化器2002 新しい消化管治療薬"中外医学社. 6 (2002)

Kazumasa Miyake、Choitsu Sakamoto：“年度回顾胃肠病学 2002 年新胃肠治疗药物”中外医学社 6 (2002)。

Futagami S, Hiratsuka T, Wada K, Tatsuguchi A, Tsukui T, Miyake K, Akamatsu T, Hosone M, Sakamoto C, Kobayashi M: "Inhibition of Helicobacter pylori-induced cyclo-oxygenase-2 aggravates NSAID-caused gastric damage in Mongolian gerbils."Aliment Pharmacol T

Futagami S、Hiratsuka T、Wada K、Tatsuguchi A、Tsukui T、Miyake K、Akamatsu T、Hosone M、Sakamoto C、Kobayashi M：“抑制幽门螺杆菌诱导的环加氧酶 2 会加重蒙古人非甾体抗炎药引起的胃损伤

Miyake K, Sakamoto C: "Prophylaxis against non-steroidal anti-inflammatory drug-associated ulcers and erosions"Nippon Rinsho. 60 Suppl 2. 577-582 (2002)

Miyake K，Sakamoto C：“预防非甾体抗炎药相关的溃疡和糜烂”Nippon Rinsho。

Takeyama H, Miyake K et al.: "NSAIDs are not involved in ICAM-1 expression of endothelial cells but in that of gastric fibroblasts in vitro."J Tokyo Med University. 61(2). 166-176 (2003)

Takeyama H、Miyake K 等人：“NSAID 不参与内皮细胞的 ICAM-1 表达，但参与体外胃成纤维细胞的 ICAM-1 表达。”J 东京医科大学。