Abstract
The effects of AVE1642, a human monoclonal antibody against IGF-IR, were examined in NSCLC cell lines in order to characterize its anti-proliferative and anti-angiogenic activity as a single agent and in combination with chemotherapy. AVE1642 inhibited IGF-IR signaling and suppressed IGF-I-induced, serum-stimulated or autocrine-mediated proliferation of NSCLC cells in vitro. Furthermore, the combination of paclitaxel and AVE1642 resulted in a sequence-dependent increase in the inhibition of cell proliferation, compared to each agent alone, which was associated with a dose-dependent increase in phosphorylated IGF-IR and Akt. Moreover, inhibition of IGF-IR signaling by AVE1642 reduced IGF-I-induced VEGF production by NSCLC cells as well as the migratory capacity of HUVEC cells challenged with conditioned media from lung cancer cells previously exposed to IGF-I. The above results suggest that inhibition of IGF-IR signaling by AVE1642 enhances the efficacy of chemotherapy and modulates VEGF and angiogenesis in NSCLC. These effects may have important clinical implications in the treatment of NSCLC.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / administration & dosage
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Angiogenesis Inhibitors / pharmacology
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Antibodies, Monoclonal, Humanized / administration & dosage
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Antibodies, Monoclonal, Humanized / pharmacology
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Carcinoma, Non-Small-Cell Lung
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Cell Line, Tumor / drug effects
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Cell Movement
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Cell Proliferation / drug effects*
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Culture Media, Conditioned
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Drug Interactions
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Endothelial Cells / drug effects
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Endothelial Cells / physiology
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Humans
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Insulin-Like Growth Factor I / pharmacology
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Lung Neoplasms
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Mitogen-Activated Protein Kinases / metabolism
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Paclitaxel / administration & dosage
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Paclitaxel / pharmacology
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Phosphorylation
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Receptor, IGF Type 1 / antagonists & inhibitors*
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Receptor, IGF Type 1 / metabolism
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Vascular Endothelial Growth Factor A / metabolism*
Substances
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Angiogenesis Inhibitors
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Culture Media, Conditioned
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Insulin-Like Growth Factor I
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Receptor, IGF Type 1
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Mitogen-Activated Protein Kinases
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Paclitaxel
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AVE1642