title: Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts.
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.
authors.affiliation: Laboratory for Cardiovascular Research, Department of Anatomy and Cell Biology, Vienna Medical University, Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Paulus
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
authors.forename: Romana
authors.initials: R
authors.lastname: Schäfer
authors.forename: Dietmar
authors.initials: D
authors.lastname: Abraham
authors.forename: Seyedhossein
authors.initials: S
authors.lastname: Aharinejad
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D008727:Methotrexate / Q000008:administration & dosage; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D017931:DNA Primers; D007128:Immunoglobulin Fragments; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016173:Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; C501162:FLT1 protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020782:Matrix Metalloproteinases; D005472:Fluorouracil; D008727:Methotrexate