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Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

¹ Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; ² Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; ³ Washington University, School of Medicine, St. Louis, Missouri; ⁴ Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; ⁵ OXiGENE, Inc., Waltham, Massachusetts; ⁶ Cancer Research UK Molecular Oncology Laboratories, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; ⁷ Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, United Kingdom; ⁸ Department of Medical Oncology, Royal Marsden Hospital, Sutton, Surrey, United Kingdom; and ⁹ Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy

Requests for reprints: Robert S. Kerbel, Molecular and Cellular Biology Research, Room S-217, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Phone: 416-480-5711; Fax: 416-480-5884; E-mail: Robert.Kerbel{at}sri.utoronto.ca and Yuval Shaked, Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 31096 Haifa, Israel. Phone: 972-4-829-5215; Fax: 972-4-829-5271; E-mail: yshaked{at}tx.technion.ac.il.

Key Words: angiogenesis • endothelial precursor cells • G-CSF

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow–derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R^–/– mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R^–/– mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target. [Cancer Res 2009;69(19):7524–8]

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