Sparing of DNA irradiated with Ultra-High Dose-Rates under Physiological Oxygen and Salt conditions

Abstract

Cancer treatment with radiotherapy aims to kill tumor cells and spare healthy tissue.Thus,the experimentally observed sparing of healthy tissue by the FLASH effect during irradiations with ultra-high dose rates (UHDR) enables clinicians to extend the therapeutic window.However, the underlying radiobiological and chemical mechanisms are far from being understood.DNA is one of the main molecular targets for radiotherapy.Ionizing radiation damage to DNA in water depends strongly on salt,pH,buffer and oxygen content of the solvent.Here we present a study of plasmid DNA pUC19,irradiated with 18MeV electrons at low dose rates (LDR) and UHDR under tightly controlled ambient and physiological oxygen conditions in PBS at pH 7.4.For the first time a sparing effect of DNA strand-break induction between UHDR(>10MGy/s) and LDR(<0.1Gy/s) irradiated plasmid DNA under physiological oxygen, salt and pH is observed for total doses above 10Gy.Under physiological oxygen (physoxia,5%O2,40mmHg),more single (SSB) and double strand-breaks (DSB) are observed when exposed to LDR, than to UHDR.This behaviour is absent for ambient oxygen (normoxia,21%O2,150-160mmHg).The experiments are accompanied by TOPAS-nBio based particle-scattering and chemical MCS to obtain information about the yields of reactive oxygen species (ROS).Hereby,an extended set of chemical reactions was considered, which improved upon the discrepancy between experiment and simulations of previous works, and allowed to predict DR dependent g-values of hydrogen peroxide (H2O2).To explain the observed DNA sparing effect under FLASH conditions at physoxia,the following model was proposed:The interplay of O2 with OH induced H-abstraction at the phosphate backbone,and the conversion of DNA base-damage to SSB,under consideration of the dose-rate dependent H3O+ yield via beta elimination processes is accounted for, to explain the observed behavior.