Rabeya Israth, Meesungnoen Jintana, Jay-Gerin Jean-Paul
Department of Medical Imaging and Radiation Sciences, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
Antioxidants (Basel). 2025 Mar 28;14(4):406. doi: 10.3390/antiox14040406.
FLASH radiotherapy is a novel irradiation modality that employs ultra-high mean dose rates exceeding 40-150 Gy/s, far surpassing the typical ~0.03 Gy/s used in conventional radiotherapy. This advanced technology delivers high doses of radiation within milliseconds, effectively targeting tumors while minimizing damage to the surrounding healthy tissues. However, the precise mechanism that differentiates responses between tumor and normal tissues is not yet understood. This study primarily examines the ROD hypothesis, which posits that oxygen undergoes transient radiolytic depletion following a radiation pulse. We developed a computational model to investigate the effects of dose rate on radiolysis in an aqueous environment that mimics a confined cellular space subjected to instantaneous pulses of energetic protons. This study employed the multi-track chemistry Monte Carlo simulation code, IONLYS-IRT, which has been optimized to model this radiolysis in a homogeneous and aerated medium. This medium is composed primarily of water, alongside carbon-based biological molecules (RH), radiation-induced bio-radicals (R), glutathione (GSH), ascorbate (AH), nitric oxide (NO), and α-tocopherol (TOH). Our model closely monitors the temporal variations in these components, specifically focusing on oxygen consumption, from the initial picoseconds to one second after exposure. Simulations reveal that cellular oxygen is transiently depleted primarily through its reaction with R radicals, consistent with prior research, but also with glutathione disulfide radical anions (GSSG) in roughly equal proportions. Notably, we show that, contrary to some reports, the peroxyl radicals (ROO) formed are not neutralized by recombination reactions. Instead, these radicals are rapidly neutralized by antioxidants present in irradiated cells, with AH and NO proving to be the most effective in preventing the propagation of harmful peroxidation chain reactions. Moreover, our model identifies a critical dose rate threshold below which the FLASH effect, as predicted by the ROD hypothesis, cannot fully manifest. By comparing our findings with existing experimental data, we determine that the ROD hypothesis alone cannot entirely explain the observed FLASH effect. Our findings indicate that antioxidants might significantly contribute to the FLASH effect by mitigating radiation-induced cellular damage and, in turn, enhancing cellular radioprotection. Additionally, our model lends support to the hypothesis that transient oxygen depletion may partially contribute to the FLASH effect observed in radiotherapy. However, our findings indicate that this mechanism alone is insufficient to fully explain the phenomenon, suggesting the involvement of additional mechanisms or factors and warranting further investigation.
闪疗是一种新型的放疗方式，其采用超过40 - 150 Gy/s的超高平均剂量率，远远超过传统放疗中使用的典型的约0.03 Gy/s。这种先进技术能在数毫秒内给予高剂量辐射，有效靶向肿瘤，同时将对周围健康组织的损伤降至最低。然而，区分肿瘤组织和正常组织反应的精确机制尚不清楚。本研究主要考察了ROD假说，该假说认为在辐射脉冲后氧会经历瞬时辐射分解消耗。我们开发了一个计算模型，以研究剂量率对水相环境中辐射分解的影响，该水相环境模拟了受到高能质子瞬时脉冲作用的受限细胞空间。本研究采用了多径化学蒙特卡罗模拟代码IONLYS - IRT，该代码已针对在均匀且通气的介质中对这种辐射分解进行建模进行了优化。这种介质主要由水以及碳基生物分子（RH）、辐射诱导的生物自由基（R）、谷胱甘肽（GSH）、抗坏血酸盐（AH）、一氧化氮（NO）和α - 生育酚（TOH）组成。我们的模型密切监测这些成分的时间变化，特别关注从暴露后的最初皮秒到一秒内的氧消耗情况。模拟结果表明，细胞氧主要通过与R自由基反应而瞬时消耗，这与先前的研究一致，但与谷胱甘肽二硫化物自由基阴离子（GSSG）的反应比例大致相同。值得注意的是，我们发现，与一些报道相反，形成的过氧自由基（ROO）不会通过重组反应被中和。相反，这些自由基会被受辐照细胞中存在的抗氧化剂迅速中和，事实证明AH和NO在防止有害的过氧化链反应传播方面最为有效。此外，我们的模型确定了一个关键的剂量率阈值，低于该阈值，ROD假说所预测的闪效就无法完全显现。通过将我们的研究结果与现有的实验数据进行比较，我们确定仅ROD假说不能完全解释所观察到的闪效。我们的研究结果表明，抗氧化剂可能通过减轻辐射诱导的细胞损伤并进而增强细胞辐射防护作用，对闪效有显著贡献。此外，我们的模型支持了瞬时氧消耗可能部分导致放疗中观察到的闪效这一假说。然而，我们的研究结果表明，仅这一机制不足以完全解释该现象，这表明还涉及其他机制或因素，需要进一步研究。
