title: Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.
abstract: Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.
authors.affiliation: Ottawa Regional Cancer Centre Research Laboratories, 501, Smyth Road, Ottawa, ON, Canada.
authors.forename: D F
authors.initials: DF
authors.lastname: Stojdl
authors.forename: B
authors.initials: B
authors.lastname: Lichty
authors.forename: S
authors.initials: S
authors.lastname: Knowles
authors.forename: R
authors.initials: R
authors.lastname: Marius
authors.forename: H
authors.initials: H
authors.lastname: Atkins
authors.forename: N
authors.initials: N
authors.lastname: Sonenberg
authors.forename: J C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000821:virology; D003588:Cytopathogenic Effect, Viral; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000821:virology; D008546:Melanoma, Experimental / Q000628:therapy / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy* / Q000821:virology*; D014407:Tumor Cells, Cultured / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000472:pathogenicity*