title: Insulin-like growth factor-I receptor signaling blockade combined with radiation.
abstract: Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials.
authors.affiliation: Department of Human Oncology, School of Medicine and Comprehensive Cancer Center, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Allen
authors.forename: Corey
authors.initials: C
authors.lastname: Saba
authors.forename: Eric A
authors.initials: EA
authors.lastname: Armstrong
authors.forename: Shyh-Min
authors.initials: SM
authors.lastname: Huang
authors.forename: Sergio
authors.initials: S
authors.lastname: Benavente
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000528:radiation effects; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D004273:DNA, Neoplasm; D017526:Receptor, IGF Type 1