Adenoviral Mediated Interferon-α 2b Gene Therapy Suppresses the Pro-Angiogenic Effect of Vascular Endothelial Growth Factor in Superficial Bladder Cancer

Liana Adam, Peter C. Black, Wassim Kassouf, Beryl Eve, David McConkey, Mark F. Munsell, William F. Benedict, Colin P.N. Dinney

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Intravesical adenovirus mediated interferon-α gene transfer has a potent therapeutic effect against superficial human bladder carcinoma xenografts growing in the bladder of athymic nude mice. We determined whether the inhibition of angiogenesis might contribute to the antitumor effect. Materials and Methods: We treated several human urothelial carcinoma cells with adenovirus mediated interferon-α 2b and monitored its effects on the production of angiogenic factors using real-time reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemical analysis and a gel shift based transcription factor array. To assess the role of adenovirus mediated interferon 2b in angiogenic activity we used in vitro invasion assays and evaluated the anti-angiogenic effects of adenovirus mediated interferon gene therapy in an orthotopic murine model of human superficial bladder cancer. Results: In adenovirus mediated interferon-α infected 253J B-V cells vascular endothelial growth factor was decreased and anti-angiogenic interferon-γ inducible protein 10 was up-regulated. In contrast, the addition of as much as 100,000 IU recombinant interferon had no apparent effect on vascular endothelial growth factor production. Conditioned medium derived from adenovirus mediated interferon 2b infected 253J B-V cells greatly decreased the invasive potential of human endothelial cells and down-regulated their matrix metalloproteinase 2 expression compared to controls. Furthermore, adenovirus mediated interferon 2b blocked pro-angiogenic nuclear signals, such as the transcription factors activating protein-1 and 2, stimulating protein-1, nuclear factor κB and c-myb. In vivo experiments revealed significant vascular endothelial growth factor down-regulation and decreased tumor vessel density in the adenovirus mediated interferon 2b treated group compared to controls. Conclusions: Treatment with adenovirus mediated interferon 2b increases the angiostatic activity of the bladder cancer microenvironment. This inhibition may prove beneficial for treating superficial bladder cancer with adenovirus mediated interferon-α and hopefully contribute to a decreased recurrence rate of this neoplasm.

Original languageEnglish (US)
Pages (from-to)1900-1906
Number of pages7
JournalJournal of Urology
Volume177
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

Keywords

  • Adenoviridae
  • angiogenesis inhibitors
  • bladder
  • bladder neoplasms
  • interferons

ASJC Scopus subject areas

  • Urology

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