Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo.

Abstract

The endothelial cell receptor-tyrosine kinases, VEGF receptor 2 (VEGF-R2) and Tie-2, and their ligands, vascular endothelial growth factor (VEGF) and angiopoietins 1 and 2, respectively, play key roles in tumor angiogenesis. Several studies suggest that the VEGF receptor pathway and the Tie-2 pathway are independent and essential mediators of angiogenesis, leading to the hypothesis that simultaneous interference with both pathways should result in additive effects on tumor growth. In this study, a human melanoma xenograft model (M21) was used to analyze the effects of simultaneous intradiabody depletion of vascular endothelial growth receptor-R2 and Tie-2 on tumor angiogenesis and tumor xenograft growth. The intradiabodies were expressed from recombinant adenovirus delivered through subtumoral injection. Blockade of both VEGF-R2 and Tie-2 pathways simultaneously or the VEGF receptor pathway alone resulted in a significant inhibition of tumor growth and tumor angiogenesis (92.2% and 74.4%, respectively). In addition, immunohistochemical staining of intradiabody-treated tumors demonstrated a decreased number of tumor-associated blood vessels versus control treatment. Previous studies with intrabodies had demonstrated that the Tie-2 receptor pathway was essential for tumor growth. The simultaneous blockade of the VEGF and Tie-2 pathways resulted in effective inhibition of tumor growth and demonstrated the potential of simultaneous targeting of multiple pathways as a therapeutic strategy.

• Authors: Nina Jendreyko, Mikhail Popkov, Christoph Rader, Carlos F Barbas 3rd
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 23 Pg. 8293-8 (Jun 07 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15928093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Immunoglobulin Fab Fragments
• Receptor, TIE-2
• Receptors, Vascular Endothelial Growth Factor

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Humans
• Immunoglobulin Fab Fragments (genetics, immunology, pharmacology)
• Melanoma (blood supply, immunology, pathology, therapy)
• Mice
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Phenotype
• Rabbits
• Receptor, TIE-2 (deficiency, immunology, metabolism)
• Receptors, Vascular Endothelial Growth Factor (deficiency, immunology, metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays