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The Vascular-Targeting Fusion Toxin VEGF 121/rGel Inhibits the Growth of Orthotopic Human Bladder Carcinoma Tumors 1

By Khalid A. Mohamedali, Daniel Kedar Y, Paul Sweeney Y, Ashish Kamat Y, Darren W. Davis Y, Beryl Y. Eve Y, Samuel Huang Y, Philip E. Thorpe Z, Colin P. Dinney Y and Michael G. Rosenblum

Abstract

Vascular endothelial growth factor (VEGF) and its receptors (FLT-1 and KDR) are overexpressed by human bladder cancer cells and tumor endothelial cells, respectively. Strategies that target VEGF receptors hold promise as antiangiogenic therapeutic approaches to bladder cancer. A fusion protein of VEGF121 and the plant toxin gelonin (rGel) was constructed, expressed in bacteria, and purified to homogeneity. Cytotoxicity experiments of VEGF 121/rGel on the highly metastatic 253J B-V human bladder cancer cell line demonstrated that the VEGF121/rGel does not specifically target these cells, whereas Western blot analysis showed no detectable expression of KDR. Treatment with VEGF121/rGel against orthotopically implanted 253J B-V xenografts in nude mice resulted in a significant suppression of bladder tumor growth (f60 % inhibition; P <.05) compared to controls. Immunohistochemistry studies of orthotopic 253J B-V tumors demonstrated that KDR is highly overexpressed in tumor vasculature. Immunofluorescence staining with antibodies to CD-31 (blood vessel endothelium) and rGel demonstrated a dramatic colocalization of the construct on tumor neovasculature. Treated tumors also displayed an increase in terminal deoxynucleotidyl transferase–mediated dUTPbiotin end labeling staining compared to controls. Thus, VEGF 121/rGel inhibits the growth of human bladder cancer by cytotoxic effects directed against the tumor vascular supply and has significant potential as a novel antiangiogenic therapeutic against human bladder cancer

Topics: Fusion toxin, VEGF, gelonin, vascular targeting, bladder
Year: 2013
OAI identifier: oai:CiteSeerX.psu:10.1.1.318.8624
Provided by: CiteSeerX
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