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Title
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Acute hypoxia does not alter tumor sensitivity to FLASH radiation therapy
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Author
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Abstract
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| Purpose: Tumor hypoxia is a major cause of treatment resistance, especially to radiation therapy at conventional dose rate (CONV), and we wanted to assess whether hypoxia does alter tumor sensitivity to FLASH. Methods and Materials: We engrafted several tumor types (glioblastoma [GBM], head and neck cancer, and lung adenocarcinoma) subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply via vascular clamping or carbogen breathing. We irradiated tumors using a single 20-Gy fraction at either CONV or FLASH, measured oxygen tension, monitored tumor growth, and sampled tumors for bulk RNAseq and pimonidazole analysis. Next, we inhibited glycolysis with trametinib in GBM tumors to enhance FLASH efficacy. fi cacy. Results: Using various subcutaneous tumor models, and in contrast to CONV, FLASH retained antitumor efficacy fi cacy under acute hypoxia. These fi ndings show that in addition to normal tissue sparing, FLASH could overcome hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNAseq profiling fi ling uncovered a FLASH-specific fi c profile fi le in human GBM that involved cell-cycle arrest, decreased ribosomal biogenesis, and a switch from oxidative phosphorylation to glycolysis. Glycolysis inhibition by trametinib enhanced FLASH efficacy fi cacy in both normal and clamped conditions. Conclusions: These data provide new and specific fi c insights showing the efficacy fi cacy of FLASH in a radiation-resistant context, proving an additional benefit fi t of FLASH over CONV. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
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Language
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English
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Source (journal)
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International journal of radiation oncology, biology, physics. - Bedford
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Publication
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Bedford
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2024
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ISSN
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0360-3016
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DOI
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10.1016/J.IJROBP.2024.02.015
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Volume/pages
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119
:5
(2024)
, p. 1493-1505
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ISI
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001278319300001
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Pubmed ID
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38387809
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Full text (Publisher's DOI)
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Full text (open access)
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