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Vesicular stomatitis virus has extensive oncolytic activity against human sarcomas: rare resistance is overcome by blocking interferon pathways.
- Source :
-
Journal of virology [J Virol] 2011 Sep; Vol. 85 (18), pp. 9346-58. Date of Electronic Publication: 2011 Jul 06. - Publication Year :
- 2011
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Abstract
- Oncolytic viruses have been tested against many carcinomas of ectodermal and endodermal origin; however, sarcomas, arising from mesoderm, have received relatively little attention. Using 13 human sarcomas representing seven tumor types, we assessed the efficiency of infection, cytolysis, and replication of green fluorescent protein (GFP)-expressing vesicular stomatitis virus (VSV) and its oncolytically enhanced mutant VSV-rp30a. Both viruses efficiently infected and killed 12 of 13 sarcomas. VSV-rp30a showed a faster rate of infection and replication. In vitro and in vivo, VSV was selective for sarcomas compared with normal mesoderm. A single intravenous injection of VSV-rp30a selectively infected all subcutaneous human sarcomas tested in mice and arrested the growth of tumors that otherwise grew 11-fold. In contrast to other sarcomas, synovial sarcoma SW982 demonstrated remarkable resistance, even to high titers of virus (multiplicity of infection [MOI] of 100). We found no dysfunction in VSV binding or internalization. SW982 also resisted infection by human cytomegalovirus and Sindbis virus, suggesting a virus resistance mechanism based on an altered antiviral state. Quantitative reverse transcriptase (qRT)-PCR analysis revealed a heightened basal expression of interferon-stimulated genes (ISGs). Pretreatment, but not cotreatment, with interferon attenuators valproate, Jak1 inhibitor, or vaccinia virus B18R protein rendered SW982 highly susceptible, and this correlated with downregulation of ISG expression. Jak1 inhibitor pretreatment also enhanced susceptibility in moderately VSV-resistant liposarcoma and bladder carcinoma. Overall, we find that the potential efficacy of VSV as an oncolytic agent extends to nonhematologic mesodermal tumors and that unusually strong resistance to VSV oncolysis can be overcome with interferon attenuators.
- Subjects :
- Animals
Biometry methods
Cell Line, Tumor
Disease Models, Animal
Humans
Interferons antagonists & inhibitors
Mice
Oncolytic Viruses immunology
Pathology methods
Rodent Diseases pathology
Rodent Diseases therapy
Sarcoma pathology
Severity of Illness Index
Treatment Outcome
Vesiculovirus immunology
Interferons immunology
Oncolytic Virotherapy methods
Oncolytic Viruses growth & development
Sarcoma therapy
Sarcoma virology
Vesiculovirus growth & development
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 85
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 21734048
- Full Text :
- https://doi.org/10.1128/JVI.00723-11