Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel

Khalid A. Mohamedali, Ann T. Poblenz, Charles R. Sikes, Nora M. Navone, Philip E. Thorpe, Bryant G. Darnay, Michael G. Rosenblum

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27 Scopus citations


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. VEGF 121/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.

Original languageEnglish (US)
Pages (from-to)10919-10928
Number of pages10
JournalCancer research
Issue number22
StatePublished - Nov 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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