title: Potent in vitro and in vivo antitumor activity of interleukin-4-conjugated Pseudomonas exotoxin against human biliary tract carcinoma.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba-Shi, Ibaraki, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ishige
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.forename: Toru
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Matsuda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ueda
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohkohchi
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000188:drug therapy; D001661:Biliary Tract Neoplasms / Q000188:drug therapy*; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy; D005098:Exotoxins / Q000494:pharmacology*; D005260:Female; D005706:Gallbladder Neoplasms / Q000188:drug therapy; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D019948:Receptors, Interleukin-4 / Q000032:analysis*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D037521:Virulence Factors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D014408:Biomarkers, Tumor; D005098:Exotoxins; D015847:Interleukin-4; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C479467:interleukin-4-Pseudomonas exotoxin