Article ; Online: Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
2021 Volume 166, Page(s) 162–170
Abstract: Background and purpose: Inhibitors of DNA-dependent protein kinase (DNA-PK) are effective radiation sensitisers in preclinical tumours, but little is known about risks of normal tissue radiosensitisation. Here, we evaluate radiosensitisation of head and ...
| Abstract | Background and purpose: Inhibitors of DNA-dependent protein kinase (DNA-PK) are effective radiation sensitisers in preclinical tumours, but little is known about risks of normal tissue radiosensitisation. Here, we evaluate radiosensitisation of head and neck squamous cell carcinoma (HNSCC) cells by DNA-PK inhibitor AZD7648 under oxia and anoxia in vitro, and tumour (SCCVII), oral mucosa and small intestine in mice. Materials and methods: Radiosensitisation of human (UT-SCC-54C) and murine (SCCVII) HNSCC cells by AZD7648 under oxia and anoxia was evaluated by clonogenic assay. Radiosensitisation of SCCVII tumours in C3H mice by oral AZD7648 (75 mg/kg) was determined by ex vivo clonogenic assay 3.5 days post-irradiation, with evaluation of normal tissue surrogate endpoints using 5-ethynyl-2'-deoxyuridine to facilitate detection of regenerating crypts in the ileum and repopulating S-phase cells in the ileum and oral mucosa of the same animals. Results: AZD7648 potently radiosensitised both cell lines, with similar sensitiser enhancement ratios for 10% survival (SER Conclusion: AZD7648 is a potent radiation sensitiser of both oxic and anoxic tumour cells, but also markedly radiosensitises stem cells in the small intestine and oral mucosa. |
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| MeSH term(s) | Animals ; DNA ; DNA-Activated Protein Kinase ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/radiotherapy ; Humans ; Hypoxia ; Mice ; Mice, Inbred C3H ; Purines ; Pyrans ; Squamous Cell Carcinoma of Head and Neck/radiotherapy ; Triazoles | |||||
| Chemical Substances | AZD7648 ; Purines ; Pyrans ; Triazoles ; DNA (9007-49-2) ; DNA-Activated Protein Kinase (EC 2.7.11.1) | |||||
| Language | English | |||||
| Publishing date | 2021-11-30 | |||||
| Publishing country | Ireland | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 605646-5 | |||||
| ISSN | 1879-0887 ; 0167-8140 | |||||
| ISSN (online) | 1879-0887 | |||||
| ISSN | 0167-8140 | |||||
| DOI | 10.1016/j.radonc.2021.11.027 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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