Abstract
Cisplatin is a key agent in combination chemotherapy for various types of solid tumor. We now show that cisplatin activates signaling by the epidermal growth factor receptor (EGFR) by inducing cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF). Matuzumab, a monoclonal antibody to EGFR, inhibited cisplatin-induced EGFR signaling, likely through competition with the soluble form of HB-EGF for binding to EGFR. Matuzumab enhanced the antitumor effect of cisplatin in nude mice harboring human non-small cell lung cancer xenografts. Our findings shed light on the mechanism by which monoclonal antibodies to EGFR might augment the efficacy of cisplatin.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology*
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Cisplatin / pharmacology*
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ErbB Receptors / agonists
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / metabolism
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Female
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Heparin-binding EGF-like Growth Factor
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Lung Neoplasms / metabolism*
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Mice
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Mice, Nude
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Small Cell Lung Carcinoma / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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HBEGF protein, human
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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EGFR protein, human
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ErbB Receptors
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matuzumab
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Cisplatin