Intravesical Ad-IFNα causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-α protein

William F. Benedict, Ziming Tao, Chang Soo Kim, Xinqiao Zhang, Jain Hua Zhou, Liana Adam, David J. McConkey, Angela Papageorgiou, Mark Munsell, Jennifer Philopena, Heidrun Engler, William Demers, Daniel C. Maneval, Colin P.N. Dinney, Robert J. Connor

Research output: Contribution to journalArticle

Abstract

We have produced prolonged, high local concentrations of interferon in vivo by intravesical instillation of adenoviruses encoding interferon-α (Ad-IFNα) together with the gene transfer-enhancing agent Syn3. We found sustained interferon protein levels for days, both in normal mouse urothelium and in human bladder cancer cells growing as superficial bladder tumors in nude mice using an orthotopic bladder model developed by us. Tumor burden in the bladder was determined utilizing cancer cells containing the green fluorescent protein. Marked tumor regression was observed following two 1-h exposures of Ad-IFNα/Syn3 and little or no cytotoxicity was detected in normal cells. Similar intravesical instillation of clinically relevant concentrations of IFN protein alone or Ad-IFNα without Syn3 was ineffective. Surprisingly, in vitro, Ad-IFNα also caused caspase-dependent death of bladder cancer cell lines that were resistant to high concentrations of IFN-α protein, including the cell line used in vivo. These findings demonstrate that Ad-IFNα can overcome resistance to IFN-α protein both in vitro and in vivo and support evaluation of intravesical Ad-IFNα/Syn3 for the treatment of superficial bladder cancer.

Original languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalMolecular Therapy
Volume10
Issue number3
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

Keywords

  • Enhanced adenoviral gene transfer
  • Gene therapy
  • Orthotopic bladder cancer model
  • Overcoming interferon protein resistance
  • Superficial human bladder cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Benedict, W. F., Tao, Z., Kim, C. S., Zhang, X., Zhou, J. H., Adam, L., McConkey, D. J., Papageorgiou, A., Munsell, M., Philopena, J., Engler, H., Demers, W., Maneval, D. C., Dinney, C. P. N., & Connor, R. J. (2004). Intravesical Ad-IFNα causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-α protein. Molecular Therapy, 10(3), 525-532. https://doi.org/10.1016/j.ymthe.2004.05.027