sar-020106 and Head-and-Neck-Neoplasms

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.. 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.. 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.. This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.

Topics: Animals; Cell Line, Tumor; Checkpoint Kinase 1; Colorectal Neoplasms; Combined Modality Therapy; Head and Neck Neoplasms; Humans; Iodine Radioisotopes; Isoquinolines; Measles virus; Mice; Oncolytic Virotherapy; Protein Kinase Inhibitors; Protein Kinases; Pyrazines; Radiation-Sensitizing Agents; Symporters; Virus Replication; Xenograft Model Antitumor Assays