title: Therapeutic antitumor efficacy of anti-epidermal growth factor receptor             antibody, cetuximab, against malignant pleural mesothelioma.
abstract: Epidermal growth factor receptor (EGFR) is commonly overexpressed in malignant             pleural mesothelioma (MPM). Cetuximab is a chimeric mouse-human antibody targeted             against EGFR and induces potent antibody-dependent cellular cytotoxicity (ADCC).             The action of cetuximab against MPM cells has not been well studied. Therefore,             in this study, we investigated the antitumor activity of cetuximab against MPM             cell lines, particularly with respect to ADCC activity in vitro and in vivo. EGFR             expression of MPM cells was measured by a quantitative flow cytometric analysis             and immunohistochemistry. The effect of cetuximab on growth inhibition was assessed             using a modified MTT assay. The ADCC activity was measured by a 4-h 51Cr release             assay using fresh or IL-2-activated peripheral blood mononuclear cells. In vivo             antitumor activity of cetuximab was evaluated using an orthotopic implantation             mouse model. Cetuximab-mediated ADCC activity against MPM cells was observed at             low concentration (0.25 mg/ml) and was enhanced by IL-2, whereas no direct effect             on growth inhibition was detected. A logarithmic correlation was observed between             the number of EGFRs on MPM cells and ADCC activity. Low EGFR expression on the             MPM cells, which was weakly detectable by immunohistochemistry, was sufficient             for maximum ADCC activity. In the mouse model, cetuximab treatment with or without             IL-2 significantly inhibited intrathoracic tumor growth and prolonged their survival.             Our study shows that cetuximab has potent anti-MPM activity both in vitro and             in vivo, mainly through the immunologic mechanism of ADCC. Cetuximab has the potential             to be used as a novel therapy for MPM patients.
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Department                     of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University,                     Yonago-shi, Tottori-ken 683-8504, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kurai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Chikumi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Miyako
authors.initials: M
authors.lastname: Takata
authors.forename: Takanori
authors.initials: T
authors.lastname: Sako
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Masanari
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Touge
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Makino
authors.forename: Tadashi
authors.initials: T
authors.lastname: Igishi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hamada
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.forename: Eiji
authors.initials: E
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007376:Interleukin-2; D066246:ErbB Receptors; D000068818:Cetuximab