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

专门的是，胃癌，尤其是肠道型，通过嗜血杆菌（HP）感染继续慢性活动胃炎，通过萎缩性胃炎，肠道化生或腺瘤进行癌症。另外，像结肠一样，胃中发生COX-2参与肿瘤发生过程的可能性也很高。然后，使用i）HP感染的胃腺瘤患者和II）胃皮细胞系（MKN28）共同培养的HP感染，我们研究了HP感染对通过COX通过COX的胃皮细胞增殖和致癌作用的影响。此外，它旨在通过HP辐射治疗或NSMDS探索胃癌化学预防的可能性。对感染HP的胃腺瘤患者进行了放射治疗。 13个病例中有12例成功进行了放射。它平均观察到辐射后13.1个月。在12例（41.7％）中的5例中，腺瘤的大小降低了，尽管组织学...更多的异型阶段没有变化。在COX-2的免疫组织化学中，观察到阳性细胞的重点是灌输前的表面粘膜附近的肠细胞，并且主要是在启发后消失的。尽管看到MMP-7的阳性细胞集中在陶瓷之前的腺瘤上皮细胞上，但在启发后它变得更加先进。 Ki67标记指数估计辐射后的增殖减少了，与辐射前相比。在MKN28中，通过HP感染（Western blot）诱导COX-2蛋白。当MKN28与HP感染共培养时，培养基中的IL-8和VEGF以时间依赖的方式增加。此外，选择性COX-1抑制剂（SC560），选择性COX-2抑制剂（Celecoxib）或非选择性COX抑制剂（吲哚美辛）抑制了增加。 HP辐射可以抑制具有增殖和致癌作用的COX-2和MMP7表达以及VEGF和IL-8产生。另一方面，NSAID可以抑制受HP感染刺激的VEGF和IL-8产生，不仅是COX-2，而且还可以通过COX-1抑制。消除治疗和NSAID抑制了胃皮细胞的癌变和增殖，预计对胃癌的化学预防作用。较少的

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

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。

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

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)。

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。