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      Cancer Cells Can Exhibit a Sparing FLASH Effect at Low Doses Under Normoxic In Vitro-Conditions

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          Abstract

          Background

          Irradiation with ultra-high dose rate (FLASH) has been shown to spare normal tissue without hampering tumor control in several in vivo studies. Few cell lines have been investigated in vitro, and previous results are inconsistent. Assuming that oxygen depletion accounts for the FLASH sparing effect, no sparing should appear for cells irradiated with low doses in normoxia.

          Methods

          Seven cancer cell lines (MDA-MB-231, MCF7, WiDr, LU-HNSCC4, HeLa [early passage and subclone]) and normal lung fibroblasts (MRC-5) were irradiated with doses ranging from 0 to 12 Gy using FLASH (≥800 Gy/s) or conventional dose rates (CONV, 14 Gy/min), with a 10 MeV electron beam from a clinical linear accelerator. Surviving fraction (SF) was determined with clonogenic assays. Three cell lines were further studied for radiation-induced DNA-damage foci using a 53BP1-marker and for cell cycle synchronization after irradiation.

          Results

          A tendency of increased survival following FLASH compared with CONV was suggested for all cell lines, with significant differences for 4/7 cell lines. The magnitude of the FLASH-sparing expressed as a dose-modifying factor at SF=0.1 was around 1.1 for 6/7 cell lines and around 1.3 for the HeLa subclone. Similar cell cycle distributions and 53BP1-foci numbers were found comparing FLASH to CONV.

          Conclusion

          We have found a FLASH effect appearing at low doses under normoxic conditions for several cell lines in vitro. The magnitude of the FLASH effect differed between the cell lines, suggesting inherited biological susceptibilities for FLASH irradiation.

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          Most cited references38

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          Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.

          In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.
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            The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients

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              Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy/s.

              This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100Gy/s, whereas 10Gy WBI at a conventional radiotherapy dose rate (0.1Gy/s) totally impairs spatial memory.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                29 July 2021
                2021
                : 11
                : 686142
                Affiliations
                [1] 1Division of Oncology and Pathology, Clinical Sciences, Skåne University Hospital, Lund University , Lund, Sweden
                [2] 2Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital , Lund, Sweden
                [3] 3Department of Medical Radiation Physics, Clinical Sciences, Lund University , Lund, Sweden
                [4] 4Wallenberg Center for Molecular Medicine , Lund, Sweden
                [5] 5Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast , Belfast, United Kingdom
                [6] 6Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford , Oxford, United Kingdom
                Author notes

                Edited by: Lorenzo Manti, University of Naples Federico II, Italy

                Reviewed by: Pavel Blaha, National Institute of Nuclear Physics of Naples, Italy; Martina C. Fuss, GSI Helmholtz Center for Heavy Ion Research, Germany

                *Correspondence: Gabriel Adrian, gabriel.adrian@ 123456med.lu.se

                This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2021.686142
                8358772
                34395253
                410f4367-6417-4e91-83b2-618c25bbbdb2
                Copyright © 2021 Adrian, Konradsson, Beyer, Wittrup, Butterworth, McMahon, Ghita, Petersson and Ceberg

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 March 2021
                : 07 July 2021
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 38, Pages: 9, Words: 4152
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                flash,ultra-high dose rate irradiation,clonogenic assay,normoxia,radiotherapy,radiobiology,radioresistance,cancer cell lines

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