12月15日出版的《國(guó)際癌癥雜志》上，一篇報(bào)道說(shuō)，一種白介素4(IL-4)結(jié)合的假單胞菌外毒素(IL-4 PE)可以有效治療人類膽管癌,。日本京都大學(xué)的Koji Kawakami博士說(shuō)：“針對(duì)IL-4受體(IL-4R)是治療膽管癌和胰腺癌的有希望的方法,，因?yàn)檫@些癌癥細(xì)胞表達(dá)高水平IL-4R。”
Kawakami博士及其同事在人類膽管癌細(xì)胞系和皮下接種人類膽管癌細(xì)胞的免疫缺陷小鼠體內(nèi)做了細(xì)胞毒素的抗腫瘤活性研究,。所有膽管癌組織都表達(dá)IL-4R,，而正常膽囊組織不表達(dá)。在早期和晚期膽管癌中,，IL-4R蛋白水平?jīng)]有明顯變化,。研究發(fā)現(xiàn)，培養(yǎng)的膽管癌細(xì)胞對(duì)IL-4 PE高度敏感,，50%的抑制濃度低于5納克/毫升,。在荷瘤小鼠中，瘤內(nèi)注射三次IL-4 PE可以使皮下腫瘤明顯縮小,，而整個(gè)研究過(guò)程中只瘤內(nèi)注射載體的小鼠腫瘤繼續(xù)生長(zhǎng),。在腹腔播散性膽管癌模型中，10只小鼠中6只使用IL-4 PE可以預(yù)防癥狀,，延長(zhǎng)生存期超過(guò)20周。而使用載體治療的小鼠在注射腫瘤四周以后都有惡病質(zhì)體征,，腫瘤廣泛腹腔擴(kuò)散,，出現(xiàn)血性腹水。
Kawakami博士說(shuō)：“在美國(guó)和德國(guó)進(jìn)行了多項(xiàng)IL-4 PE治療腦瘤和腎癌的臨床實(shí)驗(yàn),，因此膽管癌患者瘤內(nèi)直接使用這種藥物可能是可行的,，并且有效的。”
他還說(shuō)：“目前我們正在研制新一代針對(duì)IL-4R的肽類藥物,，比舊藥更加有效,，副作用更小，在臨床中易于使用,。我們希望盡快進(jìn)入臨床實(shí)驗(yàn),。”（生物谷Bioon.com）
生物谷推薦原始出處：
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.
