Geant4-DNA simulation of human cancer cells irradiation with helium ion beams.

PURPOSE: This study aimed to develop a computational environment for the accurate simulation of human cancer cell irradiation using Geant4-DNA. New cell geometrical models were developed and irradiated by alpha particle beams to induce DNA damage. The proposed approach may help further investigation of the benefits of external alpha irradiation therapy. METHODS: The Geant4-DNA Monte Carlo (MC) toolkit allows the simulation of cancer cell geometries that can be combined with accurate modelling of physical, physicochemical and chemical stages of liquid water irradiation, including radiolytic processes. Geant4-DNA is used to calculate direct and non-direct DNA damage yields, such as single and double strand breaks, produced by the deposition of energy or by the interaction of DNA with free radicals. RESULTS: In this study, the "molecularDNA" example application of Geant4-DNA was used to quantify early DNA damage in human cancer cells upon irradiation with alpha particle beams, as a function of linear energy transfer (LET). The MC simulation results are compared to experimental data, as well as previously published simulation data. The simulation results agree well with the experimental data on DSB yields in the lower LET range, while the experimental data on DSB yields are lower than the results obtained with the "molecularDNA" example in the higher LET range. CONCLUSION: This study explored and demonstrated the possibilities of the Geant4-DNA toolkit together with the "molecularDNA" example to simulate the helium beam irradiation of cancer cell lines, to quantify the early DNA damage, or even the following DNA damage response.

Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA.

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.

Fully integrated Monte Carlo simulation for evaluating radiation induced DNA damage and subsequent repair using Geant4-DNA.

Ionising radiation induced DNA damage and subsequent biological responses to it depend on the radiation's track-structure and its energy loss distribution pattern. To investigate the underlying biological mechanisms involved in such complex system, there is need of predicting biological response by integrated Monte Carlo (MC) simulations across physics, chemistry and biology. Hence, in this work, we have developed an application using the open source Geant4-DNA toolkit to propose a realistic "fully integrated" MC simulation to calculate both early DNA damage and subsequent biological responses with time. We had previously developed an application allowing simulations of radiation induced early DNA damage on a naked cell nucleus model. In the new version presented in this work, we have developed three additional important features: (1) modeling of a realistic cell geometry, (2) inclusion of a biological repair model, (3) refinement of DNA damage parameters for direct damage and indirect damage scoring. The simulation results are validated with experimental data in terms of Single Strand Break (SSB) yields for plasmid and Double Strand Break (DSB) yields for plasmid/human cell. In addition, the yields of indirect DSBs are compatible with the experimental scavengeable damage fraction. The simulation application also demonstrates agreement with experimental data of [Formula: see text]-H2AX yields for gamma ray irradiation. Using this application, it is now possible to predict biological response along time through track-structure MC simulations.

Evaluation of early radiation DNA damage in a fractal cell nucleus model using Geant4-DNA.

The advancement of multidisciplinary research fields dealing with ionising radiation induced biological damage - radiobiology, radiation physics, radiation protection and, in particular, medical physics - requires a clear mechanistic understanding of how cellular damage is induced by ionising radiation. Monte Carlo (MC) simulations provide a promising approach for the mechanistic simulation of radiation transport and radiation chemistry, towards the in silico simulation of early biological damage. We have recently developed a fully integrated MC simulation that calculates early single strand breaks (SSBs) and double strand breaks (DSBs) in a fractal chromatin based human cell nucleus model. The results of this simulation are almost equivalent to past MC simulations when considering direct/indirect strand break fraction, DSB yields and fragment distribution. The simulation results agree with experimental data on DSB yields within 13.6% on average and fragment distributions agree within an average of 34.8%.

Assessment of the inhibitory effects of different radiation qualities or chemotherapeutic agents on a human melanoma cell line.

The correlation between time dependent viabilities, after applying two radiation qualities and two alkylating agents on HTB140 melanoma cells, has been studied. Irradiations were performed with gamma-rays and 62 MeV protons, close to the Bragg peak maximum, delivering doses of 8-24 Gy. Treatments with fotemustine (FM) and dacarbazine (DTIC) were carried out with concentrations of 0.05-2mM. High radio-resistance of HTB140 cells revealed by a clonogenic assay was confirmed by microtetrasolium and sulforhodamine B, through the surviving fraction at 2 Gy (SF2), being 0.961-0.956 for gamma-rays and 0.931-0.887 for protons. A better efficiency of protons was illustrated by relative biological effectiveness at 2 Gy (RBE), ranging from 1.69 to 1.89. A kinetic study of concentration dependent cytotoxicity indicated that the best effect of the drugs, estimated as the concentration that produces 50% of growth inhibition (IC(50)), was obtained at 48 h, having values of 76 microM for DTIC and 145 microM for FM. The cytostatic ability of the drugs pointed out that the presence of DTIC at 24h, compared to FM, was insufficient to produce an effect. Protons and FM demonstrated their pro apoptotic capacity. Cross-resistance between treatments applied to the HTB140 cells was observed, protons being the most efficient, while DTIC, FM and gamma-rays demonstrated a lower level of cell inactivation.