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RISS 인기검색어
- 검색키워드
- 저자 : Rancourt, Derrick E (검색결과 2 건)
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Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo.
Kim, Manbok,Hansen, Kristina K,Davis, Lesley,van Marle, Guido,Gill, Michael John,Fox, Julie D,Hollenberg, Morley D,Rancourt, Derrick E,Lee, Patrick W K,Yun, Chae-Ok,Johnston, Randal N International Medical Press 2010 ANTIVIRAL THERAPY Vol.15 No.6
<P>BACKGROUND: Respiratory enteric orphan (reo)virus is a promising oncolytic viral candidate. Reoviral anticancer therapy is currently undergoing multiple clinical trials targeting various human cancers; however, there is no effective reoviral inhibitor that can be used to block unwanted reovirus replication during reoviral anticancer therapy. METHODS: Studies were conducted with transformed or normal cells in vitro and in vivo to characterize viral replication in the presence or absence of chemical inhibitors. RESULTS: We have identified a protease inhibitor that is very effective in the inhibition of viral replication. The dipeptide benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (Z-FA-FMK) effectively inhibited reovirus replication in a susceptible host and cured cells of a persistent infection with reovirus in vitro. Electron microscopic analysis of Z-FA-FMK-treated cells revealed that internalized reovirus virions, retained in a perinuclear localization, no longer undergo further processing into viral factories following Z-FA-FMK treatment, suggesting that Z-FA-FMK specifically affects a reovirus virion maturation step. Animal studies showed that reovirus infection of Ras oncogenic tumours and host heart tissues is completely blocked by Z-FA-FMK treatment in severe combined immunodeficiency mice. CONCLUSIONS: Z-FA-FMK is a very effective viral inhibitor that can prevent reovirus replication in vitro and reovirus-mediated myocarditis, as well as reovirus-mediated oncolysis, in vivo. A potential application of this drug for inhibition of reovirus infection is suggested.</P>
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Attenuated reovirus displays oncolysis with reduced host toxicity
Kim, M,Garant, K A,zur Nieden, N I,Alain, T,Loken, S D,Urbanski, S J,Forsyth, P A,Rancourt, D E,Lee, P W K,Johnston, R N Nature Publishing Group 2011 The British journal of cancer Vol.104 No.2
<P><B>Background:</B></P><P>Although the naturally occurring reovirus causes only mild symptoms in humans, it shows considerable potential as an oncolytic agent because of its innate ability to target cancer cells. In immunocompromised hosts, however, wild-type reovirus can target healthy tissues, including heart, liver, pancreas and neural structures.</P><P><B>Methods:</B></P><P>We characterized an attenuated form of reovirus (AV) derived from a persistently infected cell line through sequence analysis, as well as western blot and <I>in vitro</I> transcription and translation techniques. To examine its pathogenesis and oncolytic potential, AV reovirus was tested on healthy embryonic stem cells, various non-transformed and transformed cell lines, and in severe combined immunodeficiency (SCID) mice with tumour xenografts.</P><P><B>Results:</B></P><P>Sequence analysis of AV reovirus revealed a premature STOP codon in its sigma 1 attachment protein. Western blot and <I>in vitro</I> translation confirmed the presence of a truncated <I>σ</I>1. In comparison to wild-type reovirus, AV reovirus did not kill healthy stem cells or induce black tail formation in SCID mice. However, it did retain its ability to target cancer cells and reduce tumour size.</P><P><B>Conclusion:</B></P><P>Despite containing a truncated attachment protein, AV reovirus still preferentially targets cancer cells, and compared with wild-type reovirus it shows reduced toxicity when administered to immunodeficient hosts, suggesting the potential use of AV reovirus in combination cancer therapy.</P>
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