Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy

Katie Twigger, Laura Vidal, Christine L. White, Johann S. De Bono, Shreerang Bhide, Matt Coffey, Brad Thompson, Richard Geoffrey Vile, Lucy Heinemann, Hardev S. Pandha, Fiona Errington, Alan A. Melcher, Kevin J. Harrington

Research output: Contribution to journalArticle

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Abstract

Purpose: To test combination treatment schedules of reovirus and radiation in human andmurine 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.

Original languageEnglish (US)
Pages (from-to)912-923
Number of pages12
JournalClinical Cancer Research
Volume14
Issue number3
DOIs
StatePublished - Feb 1 2008

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Radiotherapy
Radiation
Appointments and Schedules
Neoplasms
Cell Line
Therapeutics
Heterografts
Cell Cycle
Flow Cytometry
Research Design
In Vitro Techniques
Clinical Trials
Apoptosis
Infection

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Twigger, K., Vidal, L., White, C. L., De Bono, J. S., Bhide, S., Coffey, M., ... Harrington, K. J. (2008). Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy. Clinical Cancer Research, 14(3), 912-923. https://doi.org/10.1158/1078-0432.CCR-07-1400

Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy. / Twigger, Katie; Vidal, Laura; White, Christine L.; De Bono, Johann S.; Bhide, Shreerang; Coffey, Matt; Thompson, Brad; Vile, Richard Geoffrey; Heinemann, Lucy; Pandha, Hardev S.; Errington, Fiona; Melcher, Alan A.; Harrington, Kevin J.

In: Clinical Cancer Research, Vol. 14, No. 3, 01.02.2008, p. 912-923.

Research output: Contribution to journalArticle

Twigger, K, Vidal, L, White, CL, De Bono, JS, Bhide, S, Coffey, M, Thompson, B, Vile, RG, Heinemann, L, Pandha, HS, Errington, F, Melcher, AA & Harrington, KJ 2008, 'Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy', Clinical Cancer Research, vol. 14, no. 3, pp. 912-923. https://doi.org/10.1158/1078-0432.CCR-07-1400
Twigger, Katie ; Vidal, Laura ; White, Christine L. ; De Bono, Johann S. ; Bhide, Shreerang ; Coffey, Matt ; Thompson, Brad ; Vile, Richard Geoffrey ; Heinemann, Lucy ; Pandha, Hardev S. ; Errington, Fiona ; Melcher, Alan A. ; Harrington, Kevin J. / Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 3. pp. 912-923.
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AU - De Bono, Johann S.

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AU - Coffey, Matt

AU - Thompson, Brad

AU - Vile, Richard Geoffrey

AU - Heinemann, Lucy

AU - Pandha, Hardev S.

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