期刊
CANCERS
卷 12, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/cancers12040798
关键词
oncolytic viruses; radiotherapy; virotherapy; combination therapy; DNA damage repair; ionizing radiation
类别
资金
- CANCER RESEARCH UK [C557/A17720, C552/A29106, C34326/A19590]
- EPSRC & BBSRC Centre for Doctoral Training in Synthetic Biology grant [EP/L016494/1]
- MRC Centre for Doctoral Training grant [MR/N013468/1]
- MRC [MR/N013468/1, MR/K501256/1]
- CRUK/MRC [C5255/A23755]
- Jesus College, Oxford
- Brain Research UK
- Sir Paul Nurse Junior Research Fellowship from Linacre College, Oxford
Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double-stranded viral DNA genomes as cellular dsDNA breaks. We hypothesise that combining adenovirus treatment with radiotherapy has the potential for enhancing tumour-specific cytotoxicity through inhibition of the DDR and augmentation of virus production. We show that EnAd, an Ad3/Ad11p chimeric oncolytic adenovirus currently being trialled in colorectal and other cancers, targets the DDR pathway at a number of junctures. Infection is associated with a decrease in irradiation-induced 53BP1 and Rad51 foci formation, and in total DNA ligase IV levels. We also demonstrate a radiation-associated increase in EnAd production in vitro and in a pilot in vivo experiment. Given the current limitations of in vitro techniques in assessing for synergy between these treatments, we adapted the plaque assay to allow monitoring of viral plaque size and growth and utilised the xCELLigence cell adhesion assay to measure cytotoxicity. Our study provides further evidence on the interaction between adenovirus and radiation in vitro and in vivo and suggests these have at least an additive, and possibly a synergistic, impact on cytotoxicity.
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