The vascular-targeting fusion toxin VEGF121/rGel inhibits the growth of orthotopic human bladder carcinoma tumors

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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 (∼60% 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 dUTP-biotin 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.

Original languageEnglish (US)
Pages (from-to)912-920
Number of pages9
JournalNeoplasia
Volume7
Issue number10
DOIs
StatePublished - Oct 2005

Keywords

  • Bladder cancer
  • Fusion toxin
  • Gelonin
  • VEGF
  • Vascular targeting

ASJC Scopus subject areas

  • Cancer Research

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