CSF-1 antibody chemosensitizes human breast cancer in nude mice

Abstract

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Breast cancer remains a serious health care concern with an incidence that has continued to increase over the last two decades. Overexpression of colony-stimulating factor (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 murinized, antigen binding fragments (Fab) linked to polyethylene glycol (PEG) against mouse (host) CSF-1. Mice bearing human MCF-7 breast cancer xenografts were treated with combination chemotherapy (CMF; cyclophosphamide 100 mg/kg, methotrexate 50 mg/kg, 5-fluoro-uracil 100 mg/kg) cycled twice i.p., anti-CSF-1 Fab (4 mg/kg i.p.) cycled every three days for 14 days, combined CMF and anti-CSF-1 Fab, or with Ringer’s solution. CSF-1 Fab alone suppressed tissue CSF-1 and retarded tumor growth by 40% compared to controls or CMF treated mice (P < 0.0001). Importantly, in combination with CMF, CSF-1 Fab chemosensitized MCF-7 xenografts, suppressing tumor development by 56% (P < 0.0001) and prolonging survival significantly (P < 0.0001) when compared to controls or CMF treated mice. The body weight of animals in the CSF-1 Fab and the CSF-1 Fab/CMF groups was significantly higher at the end of the survival studies compared to controls and CMF-treated animals (P < 0.0001). CSF-1 protein expression was abrogated in CSF-1 Fab-treated mice and significantly reduced in mice receiving combined CMF and anti-CSF-1 Fab treatment (P < 0.0001). CMF/Fab and Fab-treated mice had significantly reduced c-fms mRNA levels when compared to controls or CMF-treated mice (P < 0.0001). Combined treatment also reduced angiogenesis (P < 0.0001), decreased macrophage recruitment (P < 0.0001) and downregulated tumor matrix metalloprotease (MMP)-2, -9 and -12 expression (P < 0.0001). These studies support the paradigm of CSF-1 blockade in treatment of solid tumors and indicate that anti-CSF-1 antibodies are potent tools in breast cancer treatment. This study was supported by grant No. S9412-B11 from the Austrian Research Foundation to S. Aharinejad.