Abstract
Previously we have developed a prototype for conditionally replicating oncolytic influenza A virus which is based on deletions in the non-structural (NS1) protein. Multi-cycle replication of influenza A virus in malignant tissue is critically dependent on a protease which cleaves the viral entry protein. Here we demonstrate that the malignant colon cancer cell lines Caco-2, HT-29 and SW-620 can endogenously provide a virus-activating protease, which allows lytic multi-cycle replication of NS1 deletion viruses in those cancer cells in vitro. The oncolytic potency of an influenza NS1 deletion virus (NS1-80) was further tested in SCID mice bearing HT-29 derived tumors. The intra-tumoral injection of live, but not of heat inactivated NS1-80 virus significantly inhibited progression of established tumors. We conclude that a selected set of human cancer expressing virus activating- proteases will be a preferred target for oncolytic tumor therapy using influenza A virus mutants.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Caco-2 Cells
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Cell Line, Tumor
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Chlorocebus aethiops
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Colonic Neoplasms / enzymology*
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Colonic Neoplasms / pathology
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Colonic Neoplasms / virology
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Female
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HCT116 Cells
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HT29 Cells
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Host-Pathogen Interactions
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Humans
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Influenza A virus / genetics
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Influenza A virus / metabolism*
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Influenza A virus / physiology
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Mice
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Mice, SCID
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Mutation
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Neoplasms, Experimental / enzymology
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Neoplasms, Experimental / pathology
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Neoplasms, Experimental / virology
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Oncolytic Viruses / genetics
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Oncolytic Viruses / metabolism*
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Oncolytic Viruses / physiology
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Orthomyxoviridae Infections / enzymology
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Orthomyxoviridae Infections / pathology
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Orthomyxoviridae Infections / virology
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Peptide Hydrolases / genetics
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Peptide Hydrolases / metabolism*
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Transplantation, Heterologous
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Vero Cells
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / metabolism*
Substances
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INS1 protein, influenza virus
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Viral Nonstructural Proteins
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Peptide Hydrolases