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 (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. CONCLUSION: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.
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 (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. CONCLUSION: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.
Authors: Michelle J Wilkinson; Henry G Smith; Gráinne McEntee; Joan Kyula-Currie; Tim D Pencavel; David C Mansfield; Aadil A Khan; Victoria Roulstone; Andrew J Hayes; Kevin J Harrington Journal: Oncotarget Date: 2016-12-06
Authors: Matthew O Old; Trisha Wise-Draper; Chadwick L Wright; Balveen Kaur; Theodoros Teknos Journal: World J Otorhinolaryngol Head Neck Surg Date: 2016-07-22