Potent in vitro and in vivo antitumor activity of interleukin‐4‐conjugated Pseudomonas exotoxin against human biliary tract carcinoma
Potent in vitro and in vivo antitumor activity of interleukin‐4‐conjugated Pseudomonas exotoxin against human biliary tract carcinoma
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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
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发表时间：
2008
影响因子：
6.4
通讯作者：
K. Kawakami
中科院分区：
文献类型：
--
作者：
K. Ishige;J. Shoda;T. Kawamoto;S. Matsuda;T. Ueda;I. Hyodo;N. Ohkohchi;R. Puri;K. Kawakami
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。我们测试了由白细胞介素-4（IL-4）靶向部分和截短形式的假单胞菌外毒素A组成的细胞毒素（IL-4-PE）对人胆道癌（BTC）的抗肿瘤活性。免疫组织化学分析显示培养的BTC细胞系和BTC组织中的癌上皮（例如，胆囊癌、肝外胆管癌和肝内胆管癌）以高密度原位表达IL-4受体。然而，胆囊和胆管组织中的正常上皮细胞不表达这些IL-4受体。通过放射性标记配体结合试验测定，8种BTC细胞系在细胞表面表达IL-4 R。当这些细胞用IL-4-PE处理时，通过蛋白质合成的抑制来确定，观察到显着的细胞毒性。在所研究的8种BTC细胞系中，发现引起蛋白质合成50%抑制的药剂浓度（IC 50）小于10 ng/mL。针对皮下植入免疫缺陷小鼠中的人BTC细胞评估IL-4-PE的抗肿瘤活性。通过瘤内注射IL-4-PE，在40%的动物中观察到已建立的肿瘤完全消失。与未处理的动物相比，以耐受剂量向具有腹膜播散BTC的动物腹膜内施用IL-4-PE表现出显著延长的存活（在处理和未处理的小鼠中分别为>14周对5周）。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。© 2008 Wiley利斯公司
Targeting cytotoxins or immunotoxins to tumor cell surface receptors represents a new approach for the treatment of cancers. We tested the antitumor activity of a cytotoxin (IL‐4‐PE) composed of an interleukin‐4 (IL‐4) targeting moiety and a truncated form of Pseudomonas exotoxin A against human biliary tract carcinoma (BTC). Immunohistochemical analysis showed that cultured BTC cell lines and cancerous epithelia in BTC tissue (e.g., gallbladder carcinoma, extraheaptic cholangiocarcinoma, and intrahepatic cholangiocarcinoma) expressed receptors for IL‐4 in situ at high densities. However, normal epithelial cells in gallbladder and bile duct tissues did not express these IL‐4 receptors. 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 antitumor 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 (>14 weeks vs. 5 weeks in treated and untreated mice, respectively). These results indicate that IL‐4 receptor‐targeted cytotoxin is a potent agent that may provide a new therapeutic option for BTC. © 2008 Wiley‐Liss, Inc.
白细胞介素4受体的表达及白细胞介素4对胃癌细胞生长的抑制作用。
影响因子：
11.2
作者：
Morisaki,T;Yuzuki,DH;Lin,RT;Foshag,LJ;Morton,DL;Hoon,DS
通讯作者：
Hoon,DS
蛋白质合成的蛋白质毒素抑制剂。
DOI：
--
发表时间：
1992
期刊：
BioFactors (Oxford, England)
影响因子：
--
作者：
Perentesis,JP;Miller,SP;Bodley,JW
通讯作者：
Bodley,JW