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Inhibition of Prostate Tumor Growth and Bone Remodeling by the Vascular Targeting Agent VEGF₁₂₁/rGel

Departments of ¹ Experimental Therapeutics and ² Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas and ³ Department of Pharmacology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: M.G. Rosenblum, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030. Phone: 713-792-3554; Fax: 713-794-4261 or 713-745-3916; E-mail: mrosenbl{at}mdanderson.org.

The pathophysiology of tumor growth following skeletal metastases and the poor response of this type of lesion to therapeutic intervention remains incompletely understood. Vascular endothelial growth factor (VEGF)-A and its receptors play a role in both osteoclastogenesis and tumor growth. Systemic (i.v.) treatment of nude mice bearing intrafemoral prostate (PC-3) tumors with the vascular ablative agent VEGF₁₂₁/recombinant gelonin (rGel) strongly inhibited tumor growth. Fifty percent of treated animals had complete regression of bone tumors with no development of lytic bone lesions. Immunohistochemical analysis showed that VEGF₁₂₁/rGel treatment suppressed tumor-mediated osteoclastogenesis in vivo. In vitro treatment of murine osteoclast precursors, both cell line (RAW264.7) and bone marrow–derived monocytes (BMM), revealed that VEGF₁₂₁/rGel was selectively cytotoxic to osteoclast precursor cells rather than mature osteoclasts. VEGF₁₂₁/rGel cytotoxicity was mediated by Flt-1, which was down-regulated during osteoclast differentiation. Analysis by flow cytometry and reverse transcription-PCR showed that both BMM and RAW264.7 cells display high levels of Flt-1 but low levels of Flk-1. Internalization of VEGF₁₂₁/rGel into osteoclast precursor cells was suppressed by pretreatment with an Flt-1 neutralizing antibody or by placenta growth factor but not with an Flk-1 neutralizing antibody. Thus, VEGF₁₂₁/rGel inhibits osteoclast maturation in vivo and it seems that this process is important in the resulting suppression of skeletal osteolytic lesions. This is a novel and unique mechanism of action for this class of agents and suggests a potentially new approach for treatment or prevention of tumor growth in bone. (Cancer Res 2006; 66(22): 10919-28)

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