New strategy for cancerous peritonitis : cyclosporin-A combination therapy

癌性腹膜炎新策略：环孢素A联合治疗

• 批准号: 11671253
• 负责人: KATANO Mitsuo
• 金额: $ 1.98万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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/grant/KAKENHI-PROJECT-11671253/
• 关键词: cancerous peritonitis; cyclosporin-A; interferon-gamma; carcineurin; apoptosis; JAK; STAT pathway; NF-AT; NF-κB; 胃癌細胞; インターフェロンーガンマ; FK506; カルシウム

The prognois of cancerous peritonitis originated from digestive organ cancer is very poor. This study was planned to develop new treatment for cancer patients with cancerous peritonitis. For this purpose, we used cyclosporin-A (CsA) which is a clinically important immunosuppressive drug widely used to prevent graft rejection following organ or bone marrow transplantation. Results obtained during this observation period are as follows. (1) Combination of CsA and interferon-gamma (IFN-γ) induces significant apoptosis in various types of human carcinoma cells. (2) Proposed mechamism : IFN-γ activates not only JAK/STAT pathway and caspase cascade (apotosis pathway) but also NF-AT and/or NF-κB through activastion the Ca^<2+>-/CaM-dependent carcineurin pathway (anti-apotosis pathway). Suppression of anti-apoptosis pathway by CsA induces predominance of apoptosis pathway. (3) Intraperitoneal injection of OK-432 for managenent of cancerous peritonitis induces a detectable IFN-γ production in ascitic fluids. A combination of CsA with IFN-γ-containing ascitic fluids after but not before OK-432 injection induced significant apoptosis in carcinoma cells existing in the fluids. These results indicate that a combination of CsA and the OK-432 therapy or IFN-γ may, in the near future, be a useful therapeutic strategy for gastrointestinal cancer patients with cancerous peritonitis.

由消化器官癌引起的癌性腹膜炎预后很差。这项研究计划为癌症患者的癌性腹膜炎开发新的治疗方法。为此，我们使用环孢素a (cyclosporin-A, CsA)，这是一种临床上重要的免疫抑制药物，广泛用于预防器官或骨髓移植后的移植排斥反应。在此观察期间获得的结果如下：(1) CsA与干扰素γ (IFN-γ)联用可显著诱导多种类型人癌细胞凋亡。(2)提出的机制：IFN-γ不仅激活JAK/STAT通路和caspase级联通路（凋亡通路），还通过激活Ca^<2+>-/ cam依赖性癌蛋白通路（抗凋亡通路）激活NF- at和/或NF-κ b。CsA抑制抗凋亡通路，诱导凋亡通路优势。(3)腹腔注射OK-432治疗癌性腹膜炎可诱导腹水产生可检测到的IFN-γ。注射OK-432后，CsA与含IFN-γ的腹水联合使用，可显著诱导腹水中存在的癌细胞凋亡。这些结果表明，在不久的将来，CsA与OK-432疗法或IFN-γ的联合治疗可能是胃肠道癌症合并癌性腹膜炎的有效治疗策略。

项目成果

Hao Z: "Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-β1 and MMPs."Clinical & Experimental Metastasis. (In press).

郝Z：“蛋白质结合多糖PSK通过下调TGF-β1和MMP来抑制肿瘤侵袭性。”临床与实验转移（正在出版）。

Sato N: "Establishment of a new human pancreatic cancer cell line, NOR-P1, with high angiogenic activity and metastatic potential."Cancer Letters. 155. 153-161 (2000)

Sato N：“建立了一种新的人类胰腺癌细胞系 NOR-P1，具有高血管生成活性和转移潜力。”《癌症快报》。

Hao Z: "Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-b1 and MMPs."Clinical & Experimental Metastasis. (In Press). (2001)

郝Z：“蛋白质结合多糖PSK通过下调TGF-b1和MMPs抑制肿瘤侵袭性。”临床

Beppu K: "Elevation of serum hepatocyte growth factor concentration in patients with gastric cancer is mediated by production from tumor tissue."Anticancer Research. 20. 1263-1268 (2000)

Beppu K：“胃癌患者血清肝细胞生长因子浓度的升高是由肿瘤组织的产生介导的。”抗癌研究。

片野光男: "癌性胸腹水に対するOK-432/G-CSF併用療法"Therapeutic Research. 21. 1935-1938 (2000)

Mitsuo Katano：“OK-432/G-CSF 联合疗法治疗癌性胸膜腹水”治疗研究 21. 1935-1938 (2000)。