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

We have produced prolonged, high local concentrations of interferon in vivo by intravesical instillation of adenoviruses encoding interferon-alpha (Ad-IFNalpha) together with the gene transfer-enhancing agent Syn3. We found sustained interferon protein levels for days, both in normal mouse urotheliu...

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Bibliographic Details
Published in:Molecular therapy 2004-09, Vol.10 (3), p.525-532
Main Authors: Benedict, William F, Tao, Ziming, Kim, Chang-Soo, Zhang, Xinqiao, Zhou, Jain-Hua, Adam, Liana, McConkey, David J, Papageorgiou, Angela, Munsell, Mark, Philopena, Jennifer, Engler, Heidrun, Demers, William, Maneval, Daniel C, Dinney, Colin P N, Connor, Robert J
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Administration, Intravesical
Animals
Caspases - metabolism
Cell Death
Drug Resistance
Genetic Therapy
Green Fluorescent Proteins - genetics
Humans
Immunochemistry
Interferon-alpha - genetics
Interferon-alpha - therapeutic use
Mice
Mice, Nude
Neoplasm Transplantation
Nylons - pharmacology
Recombinant Proteins
Transplantation, Heterologous
Tumor Cells, Cultured
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - pathology
Urinary Bladder Neoplasms - therapy
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Summary:We have produced prolonged, high local concentrations of interferon in vivo by intravesical instillation of adenoviruses encoding interferon-alpha (Ad-IFNalpha) 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-IFNalpha/Syn3 and little or no cytotoxicity was detected in normal cells. Similar intravesical instillation of clinically relevant concentrations of IFN protein alone or Ad-IFNalpha without Syn3 was ineffective. Surprisingly, in vitro, Ad-IFNalpha also caused caspase-dependent death of bladder cancer cell lines that were resistant to high concentrations of IFN-alpha protein, including the cell line used in vivo. These findings demonstrate that Ad-IFNalpha can overcome resistance to IFN-alpha protein both in vitro and in vivo and support evaluation of intravesical Ad-IFNalpha/Syn3 for the treatment of superficial bladder cancer.
ISSN:1525-0016
1525-0024