Rothwell Bethany, Cooper Christian R, Jones Donald J L, Merchant Michael J, Kirkby Norman F, Kirkby Karen J, Petersson Kristoffer, Schuemann Jan, Jones George D D
Physics Division, Department of Radiation Oncology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, United States.
Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
Br J Radiol. 2025 Jul 1;98(1171):1032-1037. doi: 10.1093/bjr/tqaf097.
FLASH irradiation demonstrates notable normal-tissue protective effects, including reduced damage in vitro. Radiochemical mechanisms proposed include radical-radical recombination and transient oxygen depletion (TOD), but the relative contributions remain unclear. This study compares FLASH-mediated DNA damage reduction in vitro with oxygen depletion for FLASH radiotherapy modelled in silico, to (i) investigate the contribution of TOD towards the reduced damage burden in vitro, and (ii) evaluate its contribution to the broader FLASH effect in vivo.
An in silico model was used to identify and compare the parameter space for FLASH-induced oxygen depletion in an in-vitro setup with experimental DNA damage reduction data, previously determined using the alkaline comet assay ex vivo.
Correlation analysis revealed a strong relationship between model-predicted oxygen depletion and experimentally-observed DNA damage reduction (Spearman's = 0.87, P = 2 × 10-6; Pearson's = 0.85, P = 4 × 10-6).
Findings support a significant role for TOD in the FLASH-induced reduction in damage in vitro at low oxygen tensions. However, parameter spaces identified, for both oxygen depletion in silico and DNA damage reduction in vitro, suggest that TOD may only partially contribute to the wider-ranging FLASH sparing effects in vivo. Further work is required to clarify this.
Findings support TOD as a key mechanism for the reduced damage burden of FLASH in vitro. However, further work is required to demarcate the sparing effects of FLASH in vivo.
FLASH照射显示出显著的正常组织保护作用，包括在体外减少损伤。提出的放射化学机制包括自由基-自由基重组和短暂性氧耗竭（TOD），但其相对贡献仍不清楚。本研究将体外FLASH介导的DNA损伤减少与计算机模拟的FLASH放疗的氧耗竭进行比较，以（i）研究TOD对体外损伤负担减轻的贡献，以及（ii）评估其对体内更广泛的FLASH效应的贡献。
使用计算机模型来识别和比较体外设置中FLASH诱导的氧耗竭的参数空间与先前使用碱性彗星试验在体外确定的实验性DNA损伤减少数据。
相关性分析显示模型预测的氧耗竭与实验观察到的DNA损伤减少之间存在很强的关系（斯皮尔曼相关系数=0.87，P=2×10⁻⁶；皮尔逊相关系数=0.85，P=4×10⁻⁶）。
研究结果支持TOD在低氧张力下FLASH诱导的体外损伤减少中起重要作用。然而，计算机模拟的氧耗竭和体外DNA损伤减少所确定的参数空间表明，TOD可能仅部分促成体内更广泛的FLASH保护效应。需要进一步的工作来阐明这一点。
研究结果支持TOD作为FLASH体外减轻损伤负担的关键机制。然而，需要进一步的工作来界定FLASH在体内的保护作用。
