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

Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba-Shi, Ibaraki, Japan.
International Journal of Cancer (Impact Factor: 5.09). 12/2008; 123(12):2915-22. DOI: 10.1002/ijc.23865
Source: PubMed


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, extrahepatic 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 (IC(50)) 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.


Available from: Ichinosuke Hyodo, Sep 27, 2014

  • Emerging Cancer Therapy, 08/2010: pages 269 - 288; , ISBN: 9780470626528
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although macrophages were originally recognized as major immune effector cells, it is now appreciated that they also play many important roles in the maintenance of tissue homeostasis, and are involved in a variety of pathological conditions including cancer. Several studies have demonstrated the contributions of tumor-associated macrophages (TAMs) to tumor initiation, progression, and metastasis. However, the detailed mechanisms underlying how TAMs differ molecularly from their normal counterparts and how the conversion to TAMs occurs have only just begun to be understood. TAMs have been proposed to exhibit phenotypes of 'alternatively activated' macrophages, though there has been limited evidence directly linking the phenotypes of TAMs to the alternative activation of macrophages. This review will focus on IL-4, the prototypic cytokine that induces the alternative activation of macrophages, and review current knowledge regarding the contributions of IL-4 to the phenotypes of TAMs and its effects on tumorigenesis.
    Cell cycle (Georgetown, Tex.) 12/2010; 9(24):4824-35. DOI:10.4161/cc.9.24.14322 · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is rising in clinical importance due to the increasing incidence worldwide, poor prognosis, and suboptimal response to therapies. New effective therapeutic approaches are needed for improvement of treatment outcome. A recent study showed that sorafenib, a multikinase inhibitor that acts predominantly through inhibition of Raf kinase and vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, exhibited potent antitumor activity in a preclinical model of cholangiocarcinoma cells. We tested the in vitro and in vivo antitumor activity of sorafenib against human ICC cell lines. Treatment of ICC cells with sorafenib resulted in inhibition of proliferation and induction of apoptosis in the cell lines. In the cells treated with sorafenib, phosphorylation of mitogen-activated protein kinase kinase (MEK) and mitogen-activated protein kinase (MAPK) and also interleukin-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) were inhibited in a dose-dependent manner. Down-regulation of the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) paralleled the reduced phosphorylation of STAT3. However, sorafenib induced no significant change in the cell cycle distribution and the expression levels of cyclin D1 and p27(Kip1) in the cells. For the in vivo antitumor activity, oral administration of sorafenib significantly inhibited the growth of subcutaneous tumors established in immunodeficient mice at doses of 10, 30, and 100 mg/kg. Moreover, administration of sorafenib (30 mg/kg) to animals with peritoneally disseminated ICC resulted in significantly prolonged survival compared with that of untreated animals (76 vs. 43 days in treated and vehicle-treated mice, respectively). These results indicate that sorafenib is a potent agent that may provide a new therapeutic option for human ICC.
    Journal of Gastroenterology 02/2011; 46(6):779-89. DOI:10.1007/s00535-011-0380-3 · 4.52 Impact Factor
Show more