The aim of this report is to present the spectrum of initial radiation-induced cellular DNA damage [with particular focus on non-double-strand break (DSB) damage] generated by computer simulations. The radiation types modeled in this study were monoenergetic electrons (100 eV-1.5 keV), ultrasoft X-ray photons Ck, AlK and TiK, as well as some selected ions including 3.2 MeV/u proton; 0.74 and 2.4 MeV/u helium ions; 29 MeV/u nitrogen ions and 950 MeV/u iron ions. Monte Carlo track structure methods were used to simulate damage induction by these radiation types in a cell-mimetic condition from a single-track action. The simulations took into account the action of direct energy deposition events and the reaction of hydroxyl radicals on atomistic linear B-DNA segments of a few helical turns including the water of hydration. Our results permitted the following conclusions: a. The absolute levels of different types of damage [base damage, simple and complex single-strand breaks (SSBs) and DSBs] vary depending on the radiation type; b. Within each damage class, the relative proportions of simple and complex damage vary with radiation type, the latter being higher with high-LET radiations; c. Overall, for both low- and high-LET radiations, the ratios of the yields of base damage to SSBs are similar, being about 3.0 ± 0.2; d. Base damage contributes more to the complexity of both SSBs and DSBs, than additional SSB damage and this is true for both low- and high-LET radiations; and e. The average SSB/DSB ratio for low-LET radiations is about 18, which is about 5 times higher than that for high-LET radiations. The hypothesis that clustered DNA damage is more difficult for cells to repair has gained currency among radiobiologists. However, as yet, there is no direct in vivo experimental method to validate the dependence of kinetics of DNA repair on DNA damage complexity (both DSB and non-DSB types). The data on the detailed spectrum of DNA damage presented here, in particular the non-DSB type, provide a good basis for testing mechanistic models of DNA repair kinetics such as base excision repair.
Ion beams radiotherapy with charged particles show greater relative biological effectiveness (RBE) compared to conventional photon therapy. This enhanced RBE is due to a localized energy deposition pattern, which is subject to large fluctuations on cellular scales. Fluorescent nuclear track detectors (FNTDs) based on AlO:C,Mg crystals coated with cells (Cell-Fit-HD) can provide information on individual cellular energy deposition. In this study we provide a theoretical framework to obtain the distribution of microscopic energy deposition and ionization density in cells exposed to ion beams and identifies contributions of five different sources of variations to the overall energy fluctuation at different depths of a biologically optimized spread-out Bragg peak. We show that fluctuation in the individual energy loss of the particles is the major source of variability while the fluctuation in particle hits plays a minor role. With the Cell-Fit-HD system the uncertainty arising from four of these sources, namely the nucleus area, the number of nuclear hits, the particle linear energy transfer and the chord length can be reduced and only energy loss straggling remains fundamentally unknown. The ability to quantify these factors results in a reduction of the uncertainty in cellular energy deposition from 24-55% down to only 7-12%. We have also shown current experimental results with FNTDs which show promising results, but need further improvements to reach the ideals predicted in this study.
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