Enhanced In vitro and In vivo Cytotoxicity of Combined Reovirus and Radiotherapy
Purpose: To test combination treatment schedules of reovirus and radiation in human and murine tumor cells in vitro and in vivo . Experimental Design: In vitro cytotoxicity and cell cycle effects of reovirus given alone and combined with radiotherapy were assessed by colorimetric, tissue culture inf...
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Published in | Clinical cancer research Vol. 14; no. 3; pp. 912 - 923 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.02.2008
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Subjects | |
Online Access | Get full text |
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Summary: | Purpose: To test combination treatment schedules of reovirus and radiation in human and murine tumor cells in vitro and in vivo .
Experimental Design: In vitro cytotoxicity and cell cycle effects of reovirus given alone and combined with radiotherapy were assessed by colorimetric,
tissue culture infectious dose 50, and fluorescence-activated cell sorting–based assays. Interactions between the agents were
evaluated using combination index analysis. The effect of different schedules of reovirus and radiotherapy on viral replication
and cytotoxicity was tested in vitro and the combination was assessed in three tumor models in vivo .
Results: Characterization of reovirus cytotoxicity in a panel of cell lines yielded a range of sensitivities. Combined reovirus and
radiotherapy yielded statistically significantly increased cytotoxicity, particularly in cell lines with moderate susceptibility
to reovirus alone. The enhanced cytotoxicity of the combination occurred independently of treatment sequence or schedule.
Radiation did not affect viral replication and only reduced reoviral cytotoxicity after clinically irrelevant single doses
(>50 Gy). Combination index analysis revealed synergy between radiation (3-10 Gy) and reovirus at multiplicities of infection
between 0.001 and 1. Combination treatment significantly increased apoptosis in tumor cells relative to either single-agent
treatment. In vivo studies using xenograft and syngeneic tumors showed enhanced activity of the combination relative to reovirus or radiation
alone ( P < 0.001).
Conclusions: Combining reovirus and radiotherapy synergistically enhances cytotoxicity in a variety of tumor cells in vitro and in vivo . These results offer strong support for translational clinical trials of reovirus plus radiotherapy that have been initiated
in the clinic. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-07-1400 |