Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition

Yann Touchefeu, Aadil A. Khan, Gerben Borst, Shane H. Zaidi, Martin McLaughlin, Victoria Roulstone, David Mansfield, Joan Kyula, Tim Pencavel, Eleni M. Karapanagiotou, Jamie Clayton, Mark J. Federspiel, Steve J. Russell, Michelle Garrett, Ian Collins, Kevin J. Harrington

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Background and purpose We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. Materials and methods Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. Results EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated 131I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed 131I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. Conclusion This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.

Original languageEnglish (US)
Pages (from-to)24-31
Number of pages8
JournalRadiotherapy and Oncology
Volume108
Issue number1
DOIs
StatePublished - Jul 1 2013

Keywords

  • External beam radiation therapy
  • Oncolytic measles virus
  • Radiation-sensitizing agents
  • Radiovirotherapy

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Radiology Nuclear Medicine and imaging

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