Modeling Cell Survival In Ion Beam Flash Irradiation through DNA Damage Distribution In 3D Genome
Abstract
Purpose
Ion beam radiotherapy (helium and carbon) has opened new frontiers for FLASH research by introducing LET as a critical physical parameter for mechanistic investigation. However, current FLASH effect models are restricted to low-LET irradiation, and high-LET adaptations remain empirical, deriving from oxygen enhancement ratio approximations without underlying biological mechanisms. We propose a generalized theoretical framework that bridges this gap, enabling mechanistic extension of low-LET FLASH models to high-LET ion beams.
Methods
We extended a 3D genome-based cell survival model to a generalized framework characterizing radiochemical effects on DNA damage across a range of LET values. The probability-modifying factor (PMF) was introduced as a unified metric for FLASH-induced DNA damage alterations. This framework predicted ion beam FLASH effects by mechanistically integrating oxygen depletion and radical recombination hypotheses, with explicit consideration of LET-dependent radical yields.
Results
Computed PMF and DMF profiles across different LET values demonstrated a PMF elevation as LET increases, a trend attributed to reduced oxygen depletion and diminished peroxyl radical production. Meanwhile, DMF invariance within the intermediate LET range indicated parity in FLASH effects between the plateau and spread-out Bragg peak (excluding the distal end). These predictions are consistent with existing ion beam FLASH experimental results.
Conclusion
We established a unified mechanistic framework rooted in DNA damage-related pathways to investigate the mechanisms of the ion beam FLASH effect. By extending FLASH modeling to ion beam irradiation, this framework enables the validation of mechanistic hypotheses against experimental ion beam data and the quantitative prediction of the ion beam FLASH effect.