RESUMEN

The outcome of the exposure of living organisms to ionizing radiation is determined by the distribution of the associated energy deposition at different spatial scales. Radiation proceeds through ionizations and excitations of hit molecules with an ~ nm spacing. Approaches such as nanodosimetry/microdosimetry and Monte Carlo track-structure simulations have been successfully adopted to investigate radiation quality effects: they allow to explore correlations between the spatial clustering of such energy depositions at the scales of DNA or chromosome domains and their biological consequences at the cellular level. Physical features alone, however, are not enough to assess the entity and complexity of radiation-induced DNA damage: this latter is the result of an interplay between radiation track structure and the spatial architecture of chromatin, and further depends on the chromatin dynamic response, affecting the activation and efficiency of the repair machinery. The heterogeneity of radiation energy depositions at the single-cell level affects the trade-off between cell inactivation and induction of viable mutations and hence influences radiation-induced carcinogenesis. In radiation therapy, where the goal is cancer cell inactivation, the delivery of a homogenous dose to the tumour has been the traditional approach in clinical practice. However, evidence is accumulating that introducing heterogeneity with spatially fractionated beams (mini- and microbeam therapy) can lead to significant advantages, particularly in sparing normal tissues. Such findings cannot be explained in merely physical terms, and their interpretation requires considering the scales at play in the underlying biological mechanisms, suggesting a systemic response to radiation.

Asunto(s)

RESUMEN

Ionizing radiation causes chromosome aberrations, which are possible biomarkers to assess space radiation cancer risks. Using the Monte Carlo codes Relativistic Ion Tracks (RITRACKS) and Radiation-Induced Tracks, Chromosome Aberrations, Repair and Damage (RITCARD), we investigated how geometrical properties of the cell nucleus, irradiated with ion beams of linear energy transfer (LET) ranging from 0.22 keV/µm to 195 keV/µm, influence the yield of simple and complex exchanges. We focused on the effect of (1) nuclear volume by considering spherical nuclei of varying radii; (2) nuclear shape by considering ellipsoidal nuclei of varying thicknesses; (3) beam orientation; and (4) chromosome intermingling by constraining or not constraining chromosomes in non-overlapping domains. In general, small nuclear volumes yield a higher number of complex exchanges, as compared to larger nuclear volumes, and a higher number of simple exchanges for LET < 40 keV/µm. Nuclear flattening reduces complex exchanges for high-LET beams when irradiated along the flattened axis. The beam orientation also affects yields for ellipsoidal nuclei. Reducing chromosome intermingling decreases both simple and complex exchanges. Our results suggest that the beam orientation, the geometry of the cell nucleus, and the organization of the chromosomes within are important parameters for the formation of aberrations that must be considered to model and translate in vitro results to in vivo risks.

Asunto(s)

RESUMEN

To understand the biological effects of radiation, it is important to determine how ionizing radiation deposits energy in micrometric targets. The energy deposited in a target located in an irradiated tissue is a function of several factors such as the radiation type and the irradiated volume size. We simulated the energy deposited by energetic ions in spherical targets of 1, 2, 4, and 8 µm radii encompassed in irradiated parallelepiped volumes of various sizes using the stochastic radiation track structure code Relativistic Ion Tracks (RITRACKS). Because cells are usually part of a tissue when they are irradiated, electrons originating from radiation tracks in neighboring volumes also contribute to energy deposition in the target. To account for this contribution, we used periodic boundary conditions in the simulations. We found that the single-ion spectra of energy deposition in targets comprises two components: the direct ion hits to the targets, which is identical in all irradiation conditions, and the contribution of hits from electrons from neighboring volumes, which depends on the irradiated volume. We also calculated an analytical expression of the indirect hit contributions using the local effect model, which showed results similar to those obtained with RITRACKS.

RESUMEN

BACKGROUND AND PURPOSE: Recent observations in animal models show that ultra-high dose rate ("FLASH") radiation treatment significantly reduces normal tissue toxicity maintaining an equivalent tumor control. The dependence of this "FLASH" effect on target oxygenation has led to the assumption that oxygen "depletion" could be its major driving force. MATERIALS AND METHODS: In a bottom-up approach starting from the chemical track evolution of 1 MeV electrons in oxygenated water simulated with the TRAX-CHEM Monte Carlo code, we determine the oxygen consumption and radiolytic reactive oxygen species production following a short radiation pulse. Based on these values, the effective dose weighted by oxygen enhancement ratio (OER) or the in vitro cell survival under dynamic oxygen pressure is calculated and compared to that of conventional exposures, at constant OER. RESULTS: We find an excellent agreement of our Monte Carlo predictions with the experimental value for radiolytic oxygen removal from oxygenated water. However, the application of the present model to published radiobiological experiment conditions shows that oxygen depletion can only have a negligible impact on radiosensitivity through oxygen enhancement, especially at typical experimental oxygenations where a FLASH effect has been observed. CONCLUSION: We show that the magnitude and dependence of the "oxygen depletion" hypothesis are not consistent with the observed biological effects of FLASH irradiation. While oxygenation plays an undoubted role in mediating the FLASH effect, we conclude that state-of-the-art radiation chemistry models do not support oxygen depletion and radiation-induced transient hypoxia as the main mechanism.

Asunto(s)

RESUMEN

A computational model of radiation-induced chromosome aberrations in human cells within the PARTRAC Monte Carlo simulation framework is presented. The model starts from radiation-induced DNA damage assessed by overlapping radiation track structures with multi-scale DNA and chromatin models, ranging from DNA double-helix in atomic resolution to chromatin fibre loops, heterochromatic and euchromatic regions, and chromosome territories. The repair of DNA double-strand breaks via non-homologous end-joining is followed. Initial spatial distribution and complexity, diffusive motion, enzymatic processing, synapsis and ligation of individual DNA ends from the breaks are simulated. To enable scoring of different chromosome aberration types resulting from improper joining of DNA fragments, the repair module has been complemented by tracking the chromosome origin of the ligated fragments and the positions of centromeres. The modelled motion of DNA ends has sub-diffusive characteristics and corresponds to measured chromatin mobility within time-scales of a few hours. The calculated formation of dicentrics after photon and α-particle irradiation in human fibroblasts is compared to experimental data (Cornforth et al., 2002, Radiat Res 158, 43). The predicted yields of dicentrics overestimate the measurements by factors of five for γ-rays and two for α-particle irradiation. Nevertheless, the observed relative dependence on radiation dose is correctly reproduced. Calculated yields and size distributions of other aberration types are discussed. The present work represents a first mechanistic approach to chromosome aberrations and their kinetics, combining full track structure simulations with detailed models of chromatin and accounting for the kinetics of DNA repair.

Asunto(s)