Development of novel cytotoxin therapy that targets tumor-associated surface molecules of biliary tract carcinoma

开发针对胆道癌肿瘤相关表面分子的新型细胞毒素疗法

• 批准号: 20390339
• 负责人: SHODA Junichi
• 金额: $ 12.48万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390339/
• 关键词: 胆道系悪性腫瘍; サイトトキシン; インターロイキン-4; 緑膿菌毒素; 分子標的治療; 肝内胆管癌; 胆道癌; 陽イオン抗菌ペプチド; ハイブリッドペプチド

Immunohistochemical analysis has shown that cancerous epithelia in biliary tract carcinoma (BTC) tissue (e.g., gallbladder carcinoma, extraheaptic cholangiocarcinoma, and intrahepatic cholangiocarcinoma) expressed receptors for IL-4 in situ at high densities. The expression rate is more than 50%. Also, cultured BTC cell lines have been shown to express the receptor. On the other hand, normal gallbladder tissues and bile duct tissues do not express the receptor. Therefore, the receptor can be a novel target for molecular target therapy in future. Targeting cytotoxins or immunotoxins to tumor cell surface receptors represents a new approach for the treatment of carcinomas. In this research project, the antitumor activity of a cytotoxin (IL-4-PE), that is composed of an interleukin-4 (IL-4) targeting moiety and a truncated form of Pseudomonas exotoxin A, was tested against human biliary tract carcinoma (BTC) cells. Eight BTC cell lines expressed IL-4R on the cell surface as determined by radiolabeled ligand binding assays. When these cells were treated with IL-4-PE, significant cytotoxicity was observed as determined by the inhibition of protein synthesis. The concentration of agent causing 50% inhibition of protein synthesis (IC50) was found to be less than 10 ng/mL in 4 of the 8 BTC cell lines studied. The anti-tumor activity of IL-4-PE was assessed for human BTC cells implanted subcutaneously in immunodeficient mice. By intratumoral injection of IL-4-PE, complete disappearance of the established tumors was observed in 40% of animals. Intraperitoneal administration of IL-4-PE at tolerated doses to animals with peritoneally disseminated BTC exhibited significantly prolonged survival compared to untreated animals. Taken together, these results indicate that IL-4 receptor-targeted cytotoxin is a potent agent that may provide a new therapeutic option for BTC.

免疫组织化学分析表明，胆道癌 (BTC) 组织（例如胆囊癌、肝外胆管癌和肝内胆管癌）中的癌性上皮原位高密度表达 IL-4 受体。表达率达50%以上。此外，培养的 BTC 细胞系已被证明表达该受体。另一方面，正常的胆囊组织和胆管组织不表达该受体。因此，该受体可以成为未来分子靶向治疗的新靶点。将细胞毒素或免疫毒素靶向肿瘤细胞表面受体代表了治疗癌症的新方法。在该研究项目中，测试了由白细胞介素 4 (IL-4) 靶向部分和假单胞菌外毒素 A 的截短形式组成的细胞毒素 (IL-4-PE) 对人胆道癌 (BTC) 细胞的抗肿瘤活性。通过放射性标记配体结合测定确定，八个 BTC 细胞系在细胞表面表达 IL-4R。当用 IL-4-PE 处理这些细胞时，通过抑制蛋白质合成来确定观察到显着的细胞毒性。在所研究的 8 种 BTC 细胞系中，有 4 种发现对蛋白质合成产生 50% 抑制 (IC50) 的试剂浓度低于 10 ng/mL。对皮下植入免疫缺陷小鼠体内的人 BTC 细胞评估了 IL-4-PE 的抗肿瘤活性。通过瘤内注射 IL-4-PE，40% 的动物体内已形成的肿瘤完全消失。与未治疗的动物相比，腹膜内给予腹膜播散 BTC 的动物以耐受剂量的 IL-4-PE 表现出显着延长的生存期。总而言之，这些结果表明 IL-4 受体靶向细胞毒素是一种有效的药物，可能为 BTC 提供新的治疗选择。

项目成果

Potent In Vitro and In Vivo Antitumor Activity of Sorafenib Against

索拉非尼的有效体外和体内抗肿瘤活性

• 发表时间: 2011
• 期刊: J Gastroenterol
• 影响因子: 6.3
• 作者: Sugiyama;H.;et al.
• 通讯作者: et al.

レクチンマイクロアレイシステムを用いた胆管癌新規糖タンパク質腫瘍マーカー開発

利用凝集素微阵列系统开发新型胆管癌糖蛋白肿瘤标志物

• 发表时间: 2009
• 作者: 松田厚志;久野敦;川本徹;松崎英樹;入村達郎;池原譲;成松久;中沼安二;山本雅一;大河内信弘;正田純一;平林淳
• 通讯作者: 平林淳

ウルソデオキシコール酸は転写因子Nrf2を活性化し,肝細胞の輸送,解毒代謝,抗酸化ストレス応答を賦活する

熊去氧胆酸激活转录因子Nrf2并激活肝细胞转运、解毒代谢和抗氧化应激反应。

• 发表时间: 2008
• 作者: 岡田浩介;正田純一;田口恵子;蕨栄治;宇都宮洋才;小田高司;後藤信治;石井哲郎;山本雅之;兵頭一之介
• 通讯作者: 兵頭一之介

Potent in vitro and in vivo antitumor activity of interleukin‐4‐conjugated Pseudomonas exotoxin against human biliary tract carcinoma

白细胞介素-4 结合的假单胞菌外毒素对人胆道癌具有有效的体外和体内抗肿瘤活性

• DOI: 10.1002/ijc.23865
• 发表时间: 2008
• 期刊: International Journal of Cancer
• 影响因子: 6.4
• 作者: K. Ishige;J. Shoda;T. Kawamoto;S. Matsuda;T. Ueda;I. Hyodo;N. Ohkohchi;R. Puri;K. Kawakami
• 通讯作者: K. Kawakami

転写因子Nrf2はコリンメチオニン欠乏食誘発脂肪性肝炎の発症を抑止する

转录因子 Nrf2 抑制胆碱甲硫氨酸缺乏饮食诱发的脂肪性肝炎的发展

• 发表时间: 2010
• 作者: 岡田浩介;正田純一;蕨栄治
• 通讯作者: 蕨栄治