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Biological effects in normal cells exposed to FLASH dose rate protons. | LitMetric
Background : 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.Methods : 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.Results : 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.Conclusions : 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.
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