Nature Medicine
6, 821 - 825 (2000)
doi:10.1038/77558
Exploiting tumor-specific defects in the interferon pathway with a previously
unknown oncolytic virusDavid F. Stojdl1, 2, 4, Brian Lichty1, 4, Shane Knowles1, Ricardo Marius1, Harold Atkins1, Nahum Sonenberg3
& John C. Bell1, 21
Ottawa Regional Cancer Centre Research Laboratories
, 501, Smyth Road, Ottawa, ON,
Canada K1H 8L6
2
Department of Biochemistry, Microbiology and Immunology,
University of Ottawa, 451, Smyth Road, Ottawa
, ON, Canada K1H 8M5
3
Department of Biochemistry, McGill University,
3655, Drummond Street, Montreal, PQ, Canada
, H3G 1Y6
4
D.F.S and B.L. contributed equally to this article.
Correspondence should be addressed to John C. Bell jbell@med.uottawa.caInterferons 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 cells1. Attempts to exploit the ability of interferons
to limit the growth of tumors in patients has met with limited results2 because of cancer-specific mutations of gene products in the interferon
pathway3,
4,
5,
6,
7. 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 virus8 exquisitely sensitive to treatment with interferon9. 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.
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