Biological Effects in Normal Cells Exposed to FLASH Dose Rate Protons

Overview

Journal Radiother Oncol

Specialties Oncology
Radiology

Date 2019 Mar 10

PMID 30850209

Citations 86

Authors

Manuela Buonanno

Veljko Grilj

David J Brenner

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Effect of FLASH proton therapy on primary bronchial epithelial cell organoids.

Kuipers M, van Liefferinge F, van der Wal E, Rovituso M, Slats A, Hiemstra P Clin Transl Radiat Oncol. 2025; 52:100927.

PMID: 39968050 PMC: 11833640. DOI: 10.1016/j.ctro.2025.100927.

Molecular mechanisms of lung injury from ultra high and conventional dose rate pulsed radiation based on 4D DIA proteomics study.

Li M, Zhang L, Gao A, Xu J, Wang X, Liu X Sci Rep. 2025; 15(1):5425.

PMID: 39948392 PMC: 11825874. DOI: 10.1038/s41598-025-87247-6.

FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy.

Ni H, Reitman Z, Zou W, Akhtar M, Paul R, Huang M Nat Cancer. 2025; .

PMID: 39910249 DOI: 10.1038/s43018-025-00905-6.

Ultra‑high dose rate (FLASH) treatment: A novel radiotherapy modality (Review).

Huang J, Cheng J, Shi B, Du X, Tang S, Lin B Mol Clin Oncol. 2025; 22(3):23.

PMID: 39885864 PMC: 11775888. DOI: 10.3892/mco.2025.2818.

Probing Spatiotemporal Effects of Intertrack Recombination with a New Implementation of Simultaneous Multiple Tracks in TRAX-CHEM.

Castelli L, Camazzola G, Fuss M, Boscolo D, Kramer M, Tozzini V Int J Mol Sci. 2025; 26(2).

PMID: 39859287 PMC: 11765274. DOI: 10.3390/ijms26020571.

References

Zlobinskaya O, Dollinger G, Michalski D, Hable V, Greubel C, Du G . Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams. Radiat Environ Biophys. 2012; 51(1):23-32. DOI: 10.1007/s00411-011-0398-1. View

Zlobinskaya O, Siebenwirth C, Greubel C, Hable V, Hertenberger R, Humble N . The effects of ultra-high dose rate proton irradiation on growth delay in the treatment of human tumor xenografts in nude mice. Radiat Res. 2014; 181(2):177-83. DOI: 10.1667/RR13464.1. View

Colvett R, Rohrig N . Biophysical studies with spatially correlated ions. 2. Multiple scattering, experimental facility, and dosimetry. Radiat Res. 1979; 78(2):192-209. View

Pan H, Jiang J, Hoffman K, Tang C, Choi S, Nguyen Q . Comparative Toxicities and Cost of Intensity-Modulated Radiotherapy, Proton Radiation, and Stereotactic Body Radiotherapy Among Younger Men With Prostate Cancer. J Clin Oncol. 2018; 36(18):1823-1830. PMC: 6008105. DOI: 10.1200/JCO.2017.75.5371. View

Montay-Gruel P, Bouchet A, Jaccard M, Patin D, Serduc R, Aim W . X-rays can trigger the FLASH effect: Ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice. Radiother Oncol. 2018; 129(3):582-588. DOI: 10.1016/j.radonc.2018.08.016. View

Paganetti H . Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer. Phys Med Biol. 2014; 59(22):R419-72. DOI: 10.1088/0031-9155/59/22/R419. View

PUCK T, Marcus P . Action of x-rays on mammalian cells. J Exp Med. 1956; 103(5):653-66. PMC: 2136626. DOI: 10.1084/jem.103.5.653. View

Keene O . The log transformation is special. Stat Med. 1995; 14(8):811-9. DOI: 10.1002/sim.4780140810. View

Schmid T, Dollinger G, Hable V, Greubel C, Zlobinskaya O, Michalski D . The effectiveness of 20 mev protons at nanosecond pulse lengths in producing chromosome aberrations in human-hamster hybrid cells. Radiat Res. 2011; 175(6):719-27. DOI: 10.1667/RR2465.1. View

10.

Matsuura T, Egashira Y, Nishio T, Matsumoto Y, Wada M, Koike S . Apparent absence of a proton beam dose rate effect and possible differences in RBE between Bragg peak and plateau. Med Phys. 2010; 37(10):5376-81. DOI: 10.1118/1.3490086. View

11.

Bird R, Rohrig N, Colvett R, Geard C, Marino S . Inactivation of synchronized Chinese Hamster V79 cells with charged-particle track segments. Radiat Res. 1980; 82(2):277-89. View

12.

Vozenin M, De Fornel P, Petersson K, Favaudon V, Jaccard M, Germond J . The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients. Clin Cancer Res. 2018; 25(1):35-42. DOI: 10.1158/1078-0432.CCR-17-3375. View

13.

Kryston T, Georgiev A, Pissis P, Georgakilas A . Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res. 2011; 711(1-2):193-201. DOI: 10.1016/j.mrfmmm.2010.12.016. View

14.

Karsch L, Beyreuther E, Enghardt W, Gotz M, Masood U, Schramm U . Towards ion beam therapy based on laser plasma accelerators. Acta Oncol. 2017; 56(11):1359-1366. DOI: 10.1080/0284186X.2017.1355111. View

15.

Grilj V, Brenner D . LET dependent response of GafChromic films investigated with MeV ion beams. Phys Med Biol. 2018; 63(24):245021. PMC: 7586727. DOI: 10.1088/1361-6560/aaf34a. View

16.

Favaudon V, Caplier L, Monceau V, Pouzoulet F, Sayarath M, Fouillade C . Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med. 2014; 6(245):245ra93. DOI: 10.1126/scitranslmed.3008973. View

17.

Azzam E, Jay-Gerin J, Pain D . Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett. 2011; 327(1-2):48-60. PMC: 3980444. DOI: 10.1016/j.canlet.2011.12.012. View

18.

Buonanno M, de Toledo S, Pain D, Azzam E . Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress. Radiat Res. 2011; 175(4):405-15. PMC: 3106980. DOI: 10.1667/RR2461.1. View

19.

Citrin D, Shankavaram U, Horton J, Shield 3rd W, Zhao S, Asano H . Role of type II pneumocyte senescence in radiation-induced lung fibrosis. J Natl Cancer Inst. 2013; 105(19):1474-84. PMC: 3787909. DOI: 10.1093/jnci/djt212. View

20.

Auer S, Hable V, Greubel C, Drexler G, Schmid T, Belka C . Survival of tumor cells after proton irradiation with ultra-high dose rates. Radiat Oncol. 2011; 6:139. PMC: 3215966. DOI: 10.1186/1748-717X-6-139. View