Abstract Objective. This research outlines a time-resolved analytical model that predicts the chance of fixation of radiation-induced DNA double-strand breaks (DSBs) according to oxygen concentration, linear energy transfer (LET), and time of fixation. The objective is to construct a mechanistically founded conceptual framework for interpreting and optimizing heavy-ion radiotherapy in hypoxic tumour microenvironments. Approach. A steady-state solution to the nonlinear oxygen diffusion–reaction equation with Michaelis–Menten metabolic kinetics was employed to estimate the spatial oxygen pressure profile in the nucleus before irradiation. Oxygen-augmented post-irradiation fixation of DSBs was simulated as an LET-dependent, time-evolving exponential process with molecular oxygen availability and local ionization density as controlling variables. Analytical solutions were achieved for carbon ions (C-12) and compared with hypoxic survival and RBE experimental data, with parameter values constrained by empirical trends. Main results. The model shows that DSB fixation probability is controlled by oxygen partial pressure, post-irradiation exposure time, and LET. Densely clustered DSBs in high LET require more oxygen exposure for full stabilization, while modest increments in oxygen tension greatly increase fixation efficiency in hypoxic environments. To provide a peaked overkill correction function ψ(LET) to model the saturation in biological effectiveness in high LET, an additional scaling factor, the effective lethal efficiency factor η, accommodates the finding that not all fixed DSBs give rise to clonogenic death. Together, these enhancements lead to excellent agreement with experimental survival fractions and RBE values for carbon-ion irradiation for the whole LET range. Significance. The model is a mechanistically transparent and computationally efficient analytical tool that links radiation track structure, oxygen kinetics, and biological response. With the inclusion of oxygen-dependent and oxygen-independent fixation, overkill attenuation, and lethal efficiency, the model reproduces RBE turnover and survival recovery at high LET and offers a predictive tool for biologically optimized, LET-directed particle therapy in hypoxic and treatment-refractory tumors.
Ladan Rezaee (Thu,) studied this question.