Selective blockade of vascular endothelial growth factor receptor 2 with an antibody against tumor-derived vascular endothelial growth factor controls the growth of human pancreatic adenocarcinoma xenografts.
BACKGROUND
Vascular endothelial growth factor (VEGF), a key regulator of angiogenesis, is critical for growth of human pancreatic adenocarcinoma. Preclinical studies demonstrate that blockade of VEGF activity can control the growth of pancreatic tumors in mice. In this study, we evaluated the efficacy of 2C3, an antibody that inhibits VEGF receptor 2 activation by human VEGF, to inhibit the growth of human pancreatic adenocarcinoma in mice.


METHODS
Human pancreatic cancer cell lines (MiaPaca-2, Panc-1, and Capan-1) were used to establish xenografts in nu/nu mice. The expression of VEGF and its receptors was determined in each cell line. Proliferation of tumor cells in vitro and tumor growth in vivo in the presence of 2C3 or a control antibody was evaluated. The effect of 2C3 on tumor weight, total vessel density, number of pericyte-associated vessels, and tumor perfusion was determined, and the level of 2C3 in the serum of animals was measured by enzyme-linked immunosorbent assay.


RESULTS
2C3 did not affect the proliferation of cells in culture. 2C3 was present and active in the serum of tumor-bearing animals treated with 2C3, and these animals showed a decrease in tumor burden compared with control-treated mice. Therapy with 2C3 resulted in reduced vascular function, measured by a decrease in vessel density and in the percentage of vessels associated with pericytes. Furthermore, tumors derived from Capan-1 cells demonstrated decreased perfusion after treatment with 2C3.


CONCLUSIONS
Blockade of VEGF receptor 2 activation by tumor-derived VEGF decreases tumor vessel function and growth of some human pancreatic adenocarcinoma cell lines in mice.
Holloway
Shane E
SE
Department of Surgery, Division of Surgical Oncology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-8593, USA.
Beck
Adam W
AW
Shivakumar
Latha
L
Shih
Jessica
J
Fleming
Jason B
JB
Brekken
Rolf A
RA
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology*; D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D042442:Vascular Endothelial Growth Factors / Q000276:immunology*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2