Abstract
The impact of the exact temporal pulse structure on the potential cell and tissue sparing of ultra-high dose-rate irradiation applied in FLASH studies has gained increasing attention. A previous version of our biophysical mechanistic model (UNIVERSE: UNIfied and VERSatile bio response Engine), based on the oxygen depletion hypothesis, has been extended in this work by considering oxygen-dependent damage fixation dynamics on the sub-milliseconds scale and introducing an explicit implementation of the temporal pulse structure. The model successfully reproduces in vitro experimental data on the fast kinetics of the oxygen effect in irradiated mammalian cells. The implemented changes result in a reduction in the assumed amount of oxygen depletion. Furthermore, its increase towards conventional dose-rates is parameterized based on experimental data from the literature. A recalculation of previous benchmarks shows that the model retains its predictive power, while the assumed amount of depleted oxygen approaches measured values. The updated UNIVERSE could be used to investigate the impact of different combinations of pulse structure parameters (e.g., dose per pulse, pulse frequency, number of pulses, etc.), thereby aiding the optimization of potential clinical application and the development of suitable accelerators.
Highlights
The biological effects of ultra-high dose-rate ionizing radiation has been investigated since at least the 1960s [1] but has lately been receiving ever-growing attention with numerous reports of the so-called FLASH effect, which is the observation of reduced normal tissue toxicity and preserved tumor control when uHDR are applied at a high dose per fraction [2–4]
In order to benchmark the extension of UNIVERSE presented here, we have compared its predictions against in vitro experimental data presented by Watts et al [14] and Ling et al [15]
We found that a cellline independent effective diffusion distance of 7 μm was able to match the data, while Ling et al found a shorter value of 4 μm. This discrepancy could be traced back to the fact that Ling et al equated the fractional oxygen that had rediffused into the system to the relative shift in the logarithm of survival [15], while, in UNIVERSE, the rediffused oxygen would be considered as an input to our non-linear parametrization of DNA doublestrand breaks (DSB) yield reduction (Equation (6)), which serves as a measure for the probability of a DSB becoming fixated at a given timepoint
Summary
The biological effects of ultra-high dose-rate (uHDR) ionizing radiation has been investigated since at least the 1960s [1] but has lately been receiving ever-growing attention with numerous reports of the so-called FLASH effect, which is the observation of reduced normal tissue toxicity and preserved tumor control when uHDR are applied at a high dose per fraction [2–4]. The underlying mechanism driving the differential sparing between normal tissue and the tumor remains unclear [4,5]. The radioprotective effect of hypoxia is commonly explained by the oxygen fixation hypothesis, whereby molecular oxygen interacts readily with radicals induced in the DNA (damage fixation), preventing their reaction with free H+, which would restore their previous state (chemical repair) [9,10]. Based on this mechanism or other radiochemical processes, such as radical recombination, models of biological radiation action have been recently proposed [7,8,11]. The validity of their prediction has yet to be extensively tested against experimental data
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