Abstract
Overexpression of colony-stimulating factor-1 (CSF-1) and its receptor in breast cancer is correlated with poor prognosis. Based on the hypothesis that blockade of CSF-1 would be beneficial in breast cancer treatment, we developed a murinized, polyethylene glycol-linked antigen-binding fragment (Fab) against mouse (host) CSF-1 (anti-CSF-1 Fab). Mice bearing human, chemoresistant MCF-7 breast cancer xenografts were treated with combination chemotherapy (CMF: cyclophosphamide, methotrexate, 5-fluorouracil; cycled twice i.p.), anti-CSF-1 Fab (i.p., cycled every 3 days for 14 days), combined CMF and anti-CSF-1 Fab, or with Ringer's solution as a control. Anti-CSF-1 Fab alone suppressed tissue CSF-1 and retarded tumor growth by 40%. Importantly, in combination with CMF, anti-CSF-1 Fab reversed chemoresistance of MCF-7 xenografts, suppressing tumor development by 56%, down-regulating expression of the chemoresistance genes breast cancer-related protein, multidrug resistance gene 1, and glucosylceramide synthase, and prolonging survival significantly. Combined treatment also reduced angiogenesis and macrophage recruitment and down-regulated tumor matrix metalloproteinase-2 (MMP-2) and MMP-12 expression. These studies support the paradigm of CSF-1 blockade in the treatment of solid tumors and show that anti-CSF-1 antibodies are potential therapeutic agents for the treatment of mammary cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Breast Neoplasms / immunology
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Breast Neoplasms / pathology
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Cell Growth Processes / drug effects
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cyclophosphamide / administration & dosage
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DNA Primers
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Down-Regulation / drug effects
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Fluorouracil / administration & dosage
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Humans
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Immunoglobulin Fragments / chemistry
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Immunoglobulin Fragments / immunology
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Immunoglobulin Fragments / pharmacology*
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Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Macrophage Colony-Stimulating Factor / biosynthesis
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Macrophage Colony-Stimulating Factor / genetics
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Macrophage Colony-Stimulating Factor / immunology
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Matrix Metalloproteinases / biosynthesis
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Matrix Metalloproteinases / genetics
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Methotrexate / administration & dosage
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Mice
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RNA, Messenger / genetics
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Receptor, Macrophage Colony-Stimulating Factor / genetics
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor Receptor-1 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Xenograft Model Antitumor Assays
Substances
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DNA Primers
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Immunoglobulin Fragments
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RNA, Messenger
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Vascular Endothelial Growth Factor A
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Macrophage Colony-Stimulating Factor
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Cyclophosphamide
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FLT1 protein, human
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Receptor, Macrophage Colony-Stimulating Factor
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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Matrix Metalloproteinases
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Fluorouracil
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Methotrexate