New strategy for cancerous peritonitis : cyclosporin-A combination therapy

消化系统癌引起的癌性腹膜炎预后很差。这项研究计划为癌症患者合并癌性腹膜炎开发新的治疗方法。为此，我们使用了环孢素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物排斥反应。本次观测期间取得的成果如下。(1)CsA和干扰素-γ联合应用可诱导多种类型的人癌细胞发生明显的凋亡。(2)提出的机制：干扰素-γ不仅激活JAK/STAT通路和caspase级联通路(凋亡通路)，而且通过激活依赖于Ca~(2+)和Ca~(2+)/CaM的Carcineurin通路(抗凋亡通路)而激活NF-AT和/或NF-κB。CsA抑制抗细胞凋亡途径可诱导细胞凋亡途径占优势。(3)腹膜腔内注射OK-432治疗癌性腹膜炎，腹水中可检测到干扰素-γ的产生。在注射OK-432后而不是注射前，CsA与含有干扰素-γ的腹水联合应用，可诱导腹水中存在的癌细胞发生显著的凋亡。这些结果表明，在不久的将来，CsA联合OK-432或干扰素-γ治疗胃肠道癌合并癌性腹膜炎可能是一种有用的治疗策略。

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.