Thermal Radiosensitization Beyond Misrepair: A Mechanistic Model of Temperature-Enhanced DNA Vulnerability

TL;DR

This study presents a biophysical model demonstrating that thermal radiosensitization in cancer treatment results from both DNA repair inhibition and increased physical vulnerability of DNA due to temperature-induced structural fluctuations, guiding optimization of thermoradiotherapy.

Contribution

The paper introduces a mechanistic biophysical model that incorporates temperature-dependent physical factors affecting DNA vulnerability, extending beyond traditional repair-based explanations.

Findings

Model reproduces observed TER values under simultaneous HT and RT.

Temperature-dependent DNA-ion interaction cross-section significantly enhances radiosensitization.

Physical DNA vulnerability contributes alongside misrepair to treatment efficacy.

Abstract

Objective: Hyperthermia (HT), characterized by elevated tissue temperatures above physiological levels, is a well-established radiosensitizer. When combined with radiotherapy (RT), forming thermoradiotherapy (TRT), a synergistic effect is observed across in vitro, in vivo, and clinical studies. The greatest radiosensitization occurs when HT and RT are applied simultaneously. This work aims to explore physical mechanisms -- beyond DNA repair inhibition -- that contribute to this synergy. Approach: We developed a biophysical model for the thermal enhancement ratio (TER), incorporating temperature-dependent variations in the number of vulnerable DNA sites, the DNA-ion/particle interaction cross-section, and other physicochemical parameters. These include ion production rate, diffusion processes, and medium density. The model includes misrepair effects phenomenologically, which make it consistent with other studies. Main results: The model reproduces TER values observed under simultaneous HT and RT in isolated plasmids with variable temperature. Our results indicate that, in addition to misrepair, other physical factors contribute to radiosensitization under concurrent treatment. Among these, the temperature-dependent amplification of DNA-ion/particle interaction cross-section -- driven by enhanced DNA thermal fluctuations structure -- emerges as the second most influential factor. Significance: These findings suggest that thermal radiosensitization arises not only from impaired repair, but also from increased physical vulnerability of the DNA. The model provides mechanistic insight for optimizing TRT parameters.