Do Pure Water-Radiolysis Experiments Truly Unlock the Secrets of the FLASH Effect? A Numerical Revelation

Background and AimsReduced production of Reactive Oxygen Species (ROS) offers a potential explanation for the FLASH effect observed at ultra-high dose rates (UHDR). Recent studies consistently demonstrate decreased hydrogen peroxide (H2O2) generation in pure water under UHDR conditions. Additionally, the nature of irradiating particles significantly influences this phenomenon. This research aims to investigate ROS formation and decay kinetics in both FLASH and conventional conditions, spanning various Linear Energy Transfer levels and particle types. MethodsIn this work, chemical concentrations are assessed by solving systems of Ordinary Differential Equations (ODEs). These ODEs are constructed based on (i) chemical reaction definitions and (ii) the production of radicals resulting from irradiation, as determined by radiolytic yields. Despite the simplification of modeling cells as homogeneous systems, this approach facilitates simulation of the temporal evolution of various ROS concentrations over an extended duration, spanning several minutes. Furthermore, this methodology enables insightful sensitivity analysis by selectively activating or deactivating components of the reaction schemes or adjusting the reaction rates of specific reactions, thereby highlighting their respective roles.ResultsThis study elucidates the chemical mechanisms governing H2O2 generation and consumption. A comparative analysis of irradiation effects on pure water and cellular biochemistry is conducted. The results for pure water closely align with experimental literature, showing reduced H2O2 levels with increasing dose rates. In contrast, when turning on more complex cellular biochemistry, the dose rate dependence diminishes significantly due to cells' capacity to scavenge ROS. ConclusionsA distinct correlation emerges between UHDR and decreased H2O2 levels in pure water, aligning with established experimental data. Nevertheless, the association wanes notably when enabling cellular systems, primarily due to the potent ROS scavenging abilities inherent to cells. The translational applicability of water radiolysis findings to biological contexts remains an open inquiry, carrying profound implications for our comprehension of the FLASH effect in radiotherapy.<br/

Do Pure Water-Radiolysis Experiments Truly Unlock the Secrets of the FLASH Effect? A Numerical Revelation

Background and AimsReduced production of Reactive Oxygen Species (ROS) offers a potential explanation for the FLASH effect observed at ultra-high dose rates (UHDR). Recent studies consistently demonstrate decreased hydrogen peroxide (H2O2) generation in pure water under UHDR conditions. Additionally, the nature of irradiating particles significantly influences this phenomenon. This research aims to investigate ROS formation and decay kinetics in both FLASH and conventional conditions, spanning various Linear Energy Transfer levels and particle types. MethodsIn this work, chemical concentrations are assessed by solving systems of Ordinary Differential Equations (ODEs). These ODEs are constructed based on (i) chemical reaction definitions and (ii) the production of radicals resulting from irradiation, as determined by radiolytic yields. Despite the simplification of modeling cells as homogeneous systems, this approach facilitates simulation of the temporal evolution of various ROS concentrations over an extended duration, spanning several minutes. Furthermore, this methodology enables insightful sensitivity analysis by selectively activating or deactivating components of the reaction schemes or adjusting the reaction rates of specific reactions, thereby highlighting their respective roles.ResultsThis study elucidates the chemical mechanisms governing H2O2 generation and consumption. A comparative analysis of irradiation effects on pure water and cellular biochemistry is conducted. The results for pure water closely align with experimental literature, showing reduced H2O2 levels with increasing dose rates. In contrast, when turning on more complex cellular biochemistry, the dose rate dependence diminishes significantly due to cells' capacity to scavenge ROS. ConclusionsA distinct correlation emerges between UHDR and decreased H2O2 levels in pure water, aligning with established experimental data. Nevertheless, the association wanes notably when enabling cellular systems, primarily due to the potent ROS scavenging abilities inherent to cells. The translational applicability of water radiolysis findings to biological contexts remains an open inquiry, carrying profound implications for our comprehension of the FLASH effect in radiotherapy.<br/

Low-LET proton irradiation of A549 non-small cell lung adenocarcinoma cells: dose response and RBE determination

Since 1957, broad proton beam radiotherapy with a spread out Bragg peak has been used for cancer treatment. More recently, studies on the use of proton therapy in the treatment of non-small cell lung cancer (NSCLC) were performed and although the benefit of using protons for the treatment of NSCLC is recognized, more work is needed to gather additional data for the understanding of cell response. Human A549 cell survival was evaluated by colony forming assay 11 days after 10 keV/μm proton beam irradiation at 0.1 and 1 Gy/min. The residual energy of the proton beam at the location of the irradiated cells was 3.9 MeV. In parallel, early effects on the cell viability and DNA damage were assessed and DNA synthesis was measured. The survival curve obtained was fitted with both the linear and the induced-repair models, as a hyper-radiosensitivity was evidenced at very low doses. Above 0.5 Gy, a linear shape was observed with the α parameter equal to 0.824 ± 0.029 Gy(-1). In addition, early cell death and cell proliferation arrest were enhanced. Moreover, a clear correlation between DNA damage and surviving fraction was observed. Finally, comparisons with X and γ ray results indicate that proton irradiation at 10 keV/μm enhanced the tumor radiosensitivity with a significant dose-dependent decrease in the survival fraction. The RBE value of 1.9 ± 0.4 obtained for a 10% survival support this observation

Low-Dose Hypersensitivity and Bystander Effect are Not Mutually Exclusive in A549 Lung Carcinoma Cells after Irradiation with Charged Particles

The purpose of this study was to measure survival fraction of A549 lung carcinoma cells irradiated with charged particles of various LET and to determine mechanisms responsible for enhanced cell killing in the low-dose region. A549 cells were irradiated with a broadbeam of either 10 and 25 keV/μm protons or 100 keV/μm alpha particles and then processed for clonogenic assays and phospho-histone H3 staining. The survival fraction of unirradiated A549 cells co-cultured with irradiated cells was also evaluated. A549 cells were shown to exhibit low-dose hypersensitivity (HRS) for both protons and alpha particles. The dose threshold at which HRS occurs decreased with increasing linear energy transfer (LET), whereas αs, the initial survival curve slope, increased with increasing LET. In addition, the enhanced cell killing observed after irradiation with alpha particles was partly attributed to the bystander effect, due to the low proportion of hit cells at very low doses. Co-culture experiments suggest a gap junction-mediated bystander signal. Our results indicate that HRS is likely to be dependent on LET, and that a bystander effect and low-dose hypersensitivity may co-exist within a given cell line

Thioredoxin Reductase Activity Predicts Gold Nanoparticle Radiosensitization Effect

Gold nanoparticles (GNPs) have been shown to be effective contrast agents for imaging and emerge as powerful radiosensitizers, constituting a promising theranostic agent for cancer. Although the radiosensitization effect was initially attributed to a physical mechanism, an increasing number of studies challenge this mechanistic hypothesis and evidence the importance of oxidative stress in this process. This work evidences the central role played by thioredoxin reductase (TrxR) in the GNP-induced radiosensitization. A cell type-dependent reduction in TrxR activity was measured in five different cell lines incubated with GNPs leading to differences in cell response to X-ray irradiation. Correlation analyses demonstrated that GNP uptake and TrxR activity inhibition are associated to a GNP radiosensitization effect. Finally, Kaplan-Meier analyses suggested that high TrxR expression is correlated to low patient survival in four different types of cancer. Altogether, these results enable a better understanding of the GNP radiosensitization mechanism, which remains a mandatory step towards further use in clinic. Moreover, they highlight the potential application of this new treatment in a personalized medicine context