Computational modeling and a Geant4-DNA study of the rejoining of direct and indirect DNA damage induced by low energy electrons and carbon ions.

PURPOSE: DNA double-strand breaks (DSBs) created by ionizing radiations are considered as the most detrimental lesion, which could result in the cell death or sterilization. As the empirical evidence gathered from the cellular and molecular radiation biology has demonstrated significant correlations between the initial and lasting levels of DSBs, gaining knowledge into the DSB repair mechanisms proves vital. Much effort has been invested into understanding the mechanisms triggering the repair and processes engaged after irradiation of cells. Given a mechanistic model, we performed - to our knowledge - the first Monte Carlo study of the expected repair kinetics of carbon ions and electrons using on the one hand Geant4-DNA simulations of electrons for benchmarking purposes and on the other hand quantifying the influence of direct and indirect damage. Our objective was to calculate the DSB repair rates using a repair mechanism for G1 and early S phases of the cell cycle in conjunction with simulations of the DNA damage. MATERIALS AND METHODS: Based on Geant4-DNA simulations of DSB damage caused by electrons and carbon ions - using a B-DNA model and a water sphere of 3 µm radius resembling the mean size of human cells - we derived the kinetics of various biochemical repair processes. RESULTS: The overall repair times of carbon ions increased with the DSB complexity. Comparison of the DSB complexity (DSBc) and repair times as a function of carbon-ion energy suggested that the repair time of no specific fraction of DSBs could solely be explained as a function of DSB complexity. CONCLUSION: Analysis of the carbon-ion repair kinetics indicated that, given a fraction of DSBs, decreasing the energy would result in an increase of the repair time. The disagreements of the calculated and experimental repair kinetics for electrons could, among others, be due to larger damage complexity predicted by simulations or created actually by electrons of comparable energies to x-rays. They are also due to the employed repair mechanisms, which introduce no inherent dependence on the radiation type but make direct use of the simulated DSBs.

DNA damage and microdosimetry for carbon ions: Track structure simulations as the key to quantitative modeling of radiation-induced damage.

PURPOSE: Dose distribution in carbon-ion irradiations is generally envisaged to have therapeutic advantages over protons, primarily due to the carbon ion's comparatively higher relative biological effectiveness in the tumor than in the encompassing healthy tissues. The objective of this work was to simulate the overall physical and chemical reactions of primary carbon ions impinging on liquid water and, as such, to investigate the DNA-damage yields in the form of strand breaks (SBs) and in connection with the expected microdosimetric quantities. MATERIALS AND METHODS: Using a B-DNA model and Geant4-DNA, we simulated the primary and secondary interactions in a spherical medium of water. Subsequently, we categorized DNA damages based on their complexity utilizing the concept of µ-randomness. We assumed a threshold of 17.5 eV for a direct SB and a probability of 0.13 for an indirect SB triggered by chemical reactions of hydroxyl radicals. Microdosimetric quantities were extracted for three cylindrical volumes representing typical subcellular organisms. RESULTS: For fully ionized carbons of 8-256 MeV/u, the yield results appeared to be considerably influenced by the chemical reactions-indicating the important role of secondary electrons in inflicting damage. However, it was mostly the direct-damage spectrum that determined the overall shape of the damage spectrum. At all primary energies, it was more probable to break each DNA strand at one point-the two points being less than 10 bp apart-than to break only one strand at two random points. Unlike proton's mean-specific-energy results, which showed more sensitivity to the volume increase of the smallest cylinder than of the larger ones, carbon-ion results showed no such sensitivity. CONCLUSION: The growth of the yield ratio of the single- and double-strand breaks (DSB) with the particle energy was estimated for protons to be about 2 times that of alphas and 92 times that of carbon ions. Unlike the proton results, which suggested significant correlations between the DSB yields and mean-specific (and lineal) energies, carbon ions exhibited no such correlations.

Calculation of microdosimetric spectra for protons using Geant4-DNA and a µ-randomness sampling algorithm for the nanometric structures.

PURPOSE: Through introducing stochastic quantities that can be connected to the dimensions of the microscopic structures exposed to radiations, microdosimetry is concerned with the substantive specifications of radiation quality that could help gain insight into radiation effects. Utilizing the µ-randomness method and Geant4-DNA code, we calculated microdosimetry quantities for nanometric structures in a spherical body of water irradiated with protons. To gain more insight into the effects of radiation on microscopic structures and validate the code parameters, we made a comparison between our results obtained within Geant4-DNA and results from other simulations. MATERIALS AND METHODS: We calculated microdosimetric quantities through irradiating a spherical body of water of 6 µm diameter with 0.5-100 MeV protons. Microdosimetric quantities were derived for cylinders with diameter × height values of 23 × 23, 50 × 100, and 300 × 300 Å × Å, which would resemble the typical sizes of sub-cellular organisms such as the DNA, nucleosome, and chromatin fiber. We exploited the concept of µ-randomness to introduce convex bodies of random positions and directions for calculating microdosimetric quantities. We used the Geant4-DNA Monte Carlo simulation toolkit for transporting protons and secondary particles and calculating the frequency- and dose-mean lineal and specific energies in cylindrical volumes. Specifically, for same-sized cylindrical volumes, microdosimetric parameters obtained by Nikjoo et al. using the KURBUC code were used for evaluation. RESULTS: For the energy range investigated, the frequency-mean lineal energy, dose-mean lineal energy, frequency-mean specific energy, and dose-mean specific energy vary within [2.34,47.06] (keV/µm), [10.40,68.55] (keV/µm), [0.04,39.38] × 106 cGy, and [0.16,90.29] × 106 cGy, respectively. Regardless of the proton energy, our specific-energy results showed higher sensitivity to volume change, for smaller cylinder volumes rather than larger ones. Regardless of both proton energy and volume of the cylinder under study, we observed a generally better agreement between our frequency-mean, than dose-mean, specific energy results and the KURBUC results. CONCLUSION: Using Geant4-DNA to account for the stochastic nature of energy depositions due to physical interactions between radiation and matter, we calculated microdosimetry parameters concerning proton irradiation. By employing microdosimetry concepts in conjunction with simulation results of our previous work on radiation effects on the DNA, we pinpointed and quantified correlations between microdosimetry parameters and DNA damage. As such, for a volume with comparable mass and mean chord length to the DNA, we could observe the clear correspondence of the mean lineal and specific energy results with the double-strand-break yields of protons in Gy-1.Gbp-1.

Calculation of the initial DNA damage induced by alpha particles in comparison with protons and electrons using Geant4-DNA.

Purpose: Interaction of ionizing radiations with cells leads to single- and double-strand breaks (SSBs and DSBs) as well as base lesions of DNA. Employing the Geant4-DNA toolkit, we simulated the transportation of primary alphas and secondary particles in liquid water to study the damage in the form of SSBs and DSBs.Materials and Methods: Simulations were performed in a spherical water medium, where we used a B-DNA model and classified the DNA damage and its complexity. We assumed that in a certain vicinity of the DNA volume, energy depositions of more than 17.5 eV or hydroxyl radicals with a chemical-reaction probability of 0.13 would lead to strand breaks.Results: The results of 2 to 20 MeV alpha particles showed that more than 65% of the energy-deposition cases within the DNA volume would result in a form of break. The frequency pattern of higher-complexity damage types appeared to peak at higher deposited energies. Conclusion: We observed a reasonable agreement in terms of trend and value between our DSB yield results and experimental data. The yield results, as function of LET, suggested independence from particle type and converge to some extent at large LET. This manifests the dominant contribution of secondary electrons.

A simulation approach for determining the spectrum of DNA damage induced by protons.

To study the molecular damage induced in the form of single-strand and double-strand breaks by ionizing radiation at the DNA level, the Geant4-DNA Monte Carlo simulation code for complete transportation of primary protons and other secondary particles in liquid water has been employed in this work. To this aim, a B-DNA model and a thorough classification of the complexity of the DNA damage were used. Strand breaks were assumed to have primarily originated by direct physical interactions via energy depositions, assuming a threshold energy of 17.5 eV, or indirect chemical reactions of hydroxyl radicals, assuming a probability of 0.13. The simulation results on the complexity and frequency of various damages are computed for proton energies of 0.5-20 MeV. The yield results for a cell (Gy cell)-1 are presented, assuming 22 chromosomes per cell and a mean number of 245 Mbp per chromosome. The results show that for proton energies below 2 MeV, more than 50% of the energy depositions within the DNA volume resulted in strand breaks. For double-strand breaks (DSBs), there is considerable sensitivity of DSB frequency to the proton energy. A comparison of DSB frequencies predicted by different simulations and experiments is presented as a function of proton linear energy transfer (LET). We show that our yield results (Gy Gbp)-1 are generally comparable with various experimental data and there seems to be a better agreement between our results and a number of experimental studies when compared to other simulations.