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

Abstract

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 VEGF(121)/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 VEGF(121)/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 VEGF(121)/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 VEGF(121)/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, VEGF(121)/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.

• Authors: Khalid A Mohamedali, Ann T Poblenz, Charles R Sikes, Nora M Navone, Philip E Thorpe, Bryant G Darnay, Michael G Rosenblum
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 22 Pg. 10919-28 (Nov 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 17108129 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Plant Proteins
• Recombinant Fusion Proteins
• Ribosome Inactivating Proteins, Type 1
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• GEL protein, Gelonium multiflorum
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Bone Marrow Cells (metabolism)
• Bone Remodeling (drug effects)
• Cell Death (drug effects)
• Cell Differentiation (drug effects)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Humans
• Macrophages (cytology, drug effects, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Osteoclasts (drug effects, pathology)
• Plant Proteins (metabolism, pharmacokinetics, pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Recombinant Fusion Proteins (metabolism, pharmacokinetics, pharmacology)
• Ribosome Inactivating Proteins, Type 1
• Swine
• Vascular Endothelial Growth Factor A (metabolism, pharmacokinetics, pharmacology)
• Vascular Endothelial Growth Factor Receptor-1 (biosynthesis, genetics, metabolism)