GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany.
Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), Trento, Italy.
Radiother Oncol. 2021 Sep;162:68-75. doi: 10.1016/j.radonc.2021.06.031. Epub 2021 Jun 29.
Recent observations in animal models show that ultra-high dose rate ("FLASH") radiation treatment significantly reduces normal tissue toxicity maintaining an equivalent tumor control. The dependence of this "FLASH" effect on target oxygenation has led to the assumption that oxygen "depletion" could be its major driving force.
In a bottom-up approach starting from the chemical track evolution of 1 MeV electrons in oxygenated water simulated with the TRAX-CHEM Monte Carlo code, we determine the oxygen consumption and radiolytic reactive oxygen species production following a short radiation pulse. Based on these values, the effective dose weighted by oxygen enhancement ratio (OER) or the in vitro cell survival under dynamic oxygen pressure is calculated and compared to that of conventional exposures, at constant OER.
We find an excellent agreement of our Monte Carlo predictions with the experimental value for radiolytic oxygen removal from oxygenated water. However, the application of the present model to published radiobiological experiment conditions shows that oxygen depletion can only have a negligible impact on radiosensitivity through oxygen enhancement, especially at typical experimental oxygenations where a FLASH effect has been observed.
We show that the magnitude and dependence of the "oxygen depletion" hypothesis are not consistent with the observed biological effects of FLASH irradiation. While oxygenation plays an undoubted role in mediating the FLASH effect, we conclude that state-of-the-art radiation chemistry models do not support oxygen depletion and radiation-induced transient hypoxia as the main mechanism.
最近在动物模型中的观察表明，超高剂量率（“FLASH”）放射治疗可显著降低正常组织毒性，同时保持等效的肿瘤控制。这种“FLASH”效应依赖于靶氧合的观点导致了这样的假设，即氧“耗竭”可能是其主要驱动力。
我们采用自下而上的方法，从 TRAX-CHEM 蒙特卡罗代码模拟的含氧水中 1 MeV 电子的化学轨迹演化开始，确定了短辐射脉冲后氧消耗和放射分解产生的活性氧物种。基于这些值，计算了有效剂量（按氧增强比加权）或在动态氧压下的体外细胞存活率，并与恒定 OER 条件下的常规暴露进行了比较。
我们发现，我们的蒙特卡罗预测与含氧水中放射分解氧去除的实验值非常吻合。然而，将本模型应用于已发表的放射生物学实验条件表明，通过氧增强，氧耗竭对放射敏感性的影响可以忽略不计，特别是在已经观察到 FLASH 效应的典型实验氧合条件下。
我们表明，“氧耗竭”假说的大小和依赖性与 FLASH 照射的观察到的生物学效应不一致。虽然氧合作用在介导 FLASH 效应方面起着不可否认的作用，但我们得出的结论是，最先进的辐射化学模型不支持氧耗竭和辐射诱导的瞬时缺氧作为主要机制。
