Radiological Research Accelerator Facility (RARAF), New York, United States.
Radiother Oncol. 2019 Oct;139:51-55. doi: 10.1016/j.radonc.2019.02.009. Epub 2019 Mar 5.
Radiotherapy outcomes are limited by toxicity in the healthy tissues surrounding the irradiated tumor. Recent pre-clinical studies have shown that irradiations with electrons or photons delivered at so called FLASH dose rates (i.e. >40 Gy/s) dramatically reduce adverse side effects in the normal tissues while being equally efficient for tumor control as irradiations at conventional dose rates (3-5 cGy/s). In the case of protons however, FLASH effects have not been investigated partially because of the limited availability of facilities that can achieve such high dose rates.
Using a novel irradiation platform, we measured acute and long-term biological effects in normal human lung fibroblasts (IMR90) exposed to therapeutically relevant doses of 4.5 MeV protons (LET = 10 keV/µm) delivered at dose rates spanning four orders of magnitude. Endpoints included clonogenic cell survival, γH2AX foci formation, induction of premature senescence (β-gal), and the expression of the pro-inflammatory marker TGFβ.
Proton dose rate had no influence on the cell survival, but for the highest dose rate used (i.e. 1000 Gy/s) foci formation saturated beyond 10 Gy. In the progeny of irradiated cells, an increase in dose (20 Gy vs. 10 Gy) and dose rate (1000 Gy/s vs. 0.05 Gy/s) positively affected the number of senescence cells and the expression of TGFβ1.
In normal lung fibroblasts proton dose rate had little impact on acute effects, but significantly influenced the expression of long-term biological responses in vitro. Compared to conventional dose rates, protons delivered at FLASH dose rates mitigated such delayed detrimental effects.
放射治疗的结果受到照射肿瘤周围健康组织毒性的限制。最近的临床前研究表明，以所谓的 FLASH 剂量率（即>40Gy/s）进行的电子或光子照射可以显著减少正常组织的不良反应，同时与常规剂量率（3-5cGy/s）相比，对肿瘤控制同样有效。然而，在质子的情况下，FLASH 效应尚未得到研究，部分原因是能够实现如此高剂量率的设施有限。
我们使用一种新型照射平台，测量了暴露于具有治疗相关性的 4.5MeV 质子（LET=10keV/μm）的正常人类肺成纤维细胞（IMR90）的急性和长期生物学效应，剂量率跨越了四个数量级。终点包括集落形成细胞存活、γH2AX 焦点形成、过早衰老（β-gal）的诱导以及促炎标志物 TGFβ 的表达。
质子剂量率对细胞存活没有影响，但对于使用的最高剂量率（即 1000Gy/s），焦点形成在超过 10Gy 时饱和。在照射细胞的后代中，剂量（20Gy 与 10Gy）和剂量率（1000Gy/s 与 0.05Gy/s）的增加对衰老细胞的数量和 TGFβ1 的表达有积极影响。
在正常肺成纤维细胞中，质子剂量率对急性效应影响不大，但对体外长期生物学反应的表达有显著影响。与常规剂量率相比，FLASH 剂量率下的质子照射减轻了这种延迟的有害效应。
