12月15日出版的《国际癌症杂志》上，一篇报道说，一种白介素4(IL-4)结合的假单胞菌外毒素(IL-4 PE)可以有效治疗人类胆管癌。日本京都大学的Koji Kawakami博士说：“针对IL-4受体(IL-4R)是治疗胆管癌和胰腺癌的有希望的方法，因为这些癌症细胞表达高水平IL-4R。”
Kawakami博士及其同事在人类胆管癌细胞系和皮下接种人类胆管癌细胞的免疫缺陷小鼠体内做了细胞毒素的抗肿瘤活性研究。所有胆管癌组织都表达IL-4R，而正常胆囊组织不表达。在早期和晚期胆管癌中，IL-4R蛋白水平没有明显变化。研究发现，培养的胆管癌细胞对IL-4 PE高度敏感，50%的抑制浓度低于5纳克/毫升。在荷瘤小鼠中，瘤内注射三次IL-4 PE可以使皮下肿瘤明显缩小，而整个研究过程中只瘤内注射载体的小鼠肿瘤继续生长。在腹腔播散性胆管癌模型中，10只小鼠中6只使用IL-4 PE可以预防症状，延长生存期超过20周。而使用载体治疗的小鼠在注射肿瘤四周以后都有恶病质体征，肿瘤广泛腹腔扩散，出现血性腹水。
Kawakami博士说：“在美国和德国进行了多项IL-4 PE治疗脑瘤和肾癌的临床实验，因此胆管癌患者瘤内直接使用这种药物可能是可行的，并且有效的。”
他还说：“目前我们正在研制新一代针对IL-4R的肽类药物，比旧药更加有效，副作用更小，在临床中易于使用。我们希望尽快进入临床实验。”（生物谷Bioon.com）
生物谷推荐原始出处：
International Journal of Cancer Volume 123 Issue 12, Pages 2915 - 2922
Potent in vitro and in vivo antitumor activity of interleukin-4-conjugated Pseudomonas exotoxin against human biliary tract carcinoma
Kazunori Ishige 1 2, Junichi Shoda 1, Toru Kawamoto 3, Sachiko Matsuda 2, Tetsuya Ueda 4, Ichinosuke Hyodo 1, Nobuhiro Ohkohchi 5, Raj K. Puri 6, Koji Kawakami 2 7 *
1 Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba-Shi, Ibaraki, Japan
2 Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan
3 Department of Medical Oncology, M.D. Anderson Cancer Center, University of Texas, Houston, TX
4 Drug Development Service Division, Pharmacodynamics Group, Medi-Chem Business Segment, Mitsubishi Chemical Medience Corporation, Itabashi-Ku, Tokyo, Japan
5 Department of Surgery, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba-Shi, Ibaraki, Japan
6 Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Tumor Vaccines and Biotechnology Branch, Food and Drug Administration, Bethesda, MD
7 Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
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.
