title: Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition.
abstract: OBJECTIVE
  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.
  
  
  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 (131)I-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 (131)I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts.
  
  
  CONCLUSIONS
  This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.
authors.affiliation: The Institute of Cancer Research, Division of Cancer Biology, London, United Kingdom.
authors.forename: Yann
authors.initials: Y
authors.lastname: Touchefeu
authors.forename: Aadil A
authors.initials: AA
authors.lastname: Khan
authors.forename: Gerben
authors.initials: G
authors.lastname: Borst
authors.forename: Shane H
authors.initials: SH
authors.lastname: Zaidi
authors.forename: Martin
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Victoria
authors.initials: V
authors.lastname: Roulstone
authors.forename: David
authors.initials: D
authors.lastname: Mansfield
authors.forename: Joan
authors.initials: J
authors.lastname: Kyula
authors.forename: Tim
authors.initials: T
authors.lastname: Pencavel
authors.forename: Eleni M
authors.initials: EM
authors.lastname: Karapanagiotou
authors.forename: Jamie
authors.initials: J
authors.lastname: Clayton
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Federspiel
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Russell
authors.forename: Michelle
authors.initials: M
authors.lastname: Garrett
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D015179:Colorectal Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D008459:Measles virus / Q000502:physiology*; D051379:Mice; D050130:Oncolytic Virotherapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000502:physiology*; D011719:Pyrazines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D027981:Symporters / Q000235:genetics; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D000071877:Checkpoint Kinase 1; D007457:Iodine Radioisotopes; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C547874:SAR 020106; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse
keywords: External beam radiation therapy; Oncolytic measles virus; Radiation-sensitizing agents; Radiovirotherapy