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: Patrick Paulus, E Richard Stanley, Romana Schäfer, Dietmar Abraham, Seyedhossein Aharinejad
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 8 Pg. 4349-56 (Apr 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16618760 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Immunoglobulin Fragments
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Macrophage Colony-Stimulating Factor
• Cyclophosphamide
• FLT1 protein, human
• Receptor, Macrophage Colony-Stimulating Factor
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2
• Matrix Metalloproteinases
• Fluorouracil
• Methotrexate

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Breast Neoplasms (drug therapy, enzymology, immunology, pathology)
• Cell Growth Processes (drug effects, physiology)
• Cell Line, Tumor
• Cyclophosphamide (administration & dosage)
• DNA Primers
• Down-Regulation (drug effects)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Fluorouracil (administration & dosage)
• Humans
• Immunoglobulin Fragments (chemistry, immunology, pharmacology)
• Macrophage Colony-Stimulating Factor (antagonists & inhibitors, biosynthesis, genetics, immunology)
• Matrix Metalloproteinases (biosynthesis, genetics)
• Methotrexate (administration & dosage)
• Mice
• RNA, Messenger (genetics)
• Receptor, Macrophage Colony-Stimulating Factor (genetics)
• Vascular Endothelial Growth Factor A (genetics)
• Vascular Endothelial Growth Factor Receptor-1 (genetics)
• Vascular Endothelial Growth Factor Receptor-2 (genetics)
• Xenograft Model Antitumor Assays