Combined Use of Monte Carlo DNA Damage Simulations and Deterministic Repair Models to Examine Putative Mechanisms of Cell Killing

Abstract

A kinetic repair-misrepair-fixation (RMF) model is developed to better link double-strand break (DSB) induction to reproductive cell death. Formulas linking linear-quadratic (LQ) model radiosensitivity parameters to DSB induction and repair explicitly account for the contribution to cell killing of unrejoinable DSBs, misrepaired and fixed DSBs, and exchanges formed through intra- and intertrack DSB interactions. Information from Monte Carlo simulations is used to determine the initial yields and complexity of DSBs formed by low- and high-LET radiations. Our analysis of published survival data for human kidney cells suggests that intratrack DSB interactions are negligible for low-LET radiations but increase rapidly with increasing LET. The analysis suggests that no class of DSB is intrinsically unrejoinable or that DSB reparability is not strictly determined by the number of lesions forming the DSB. For radiations with LET >110 keV/mum, the model predicts that the relative cell killing efficiency, per unit absorbed dose, should continue to increase, whereas data from published experiments indicate a reduced cell killing efficiency. This observation suggests that the Monte Carlo simulation overestimates the DSB yield beyond 110 keV/microm or that other biological phenomena not included in the model, such as proximity effects, are important. For 200-250 kVp X rays ( approximately 1.9 keV/microm), only about 1% of the one-track killing is attributed to intratrack binary misrepair interactions. The analysis indicates that the remaining 99% of the lethal damage is due to other types of one-track damage, including possible unrepairable, misrepaired and fixed damage. Compared to the analysis of the X-ray results, 48% of the one-track lethal damage caused by 5.1 MeV alpha particles (approximately 88 keV/microm) is due to intratrack DSB interactions while the remainder is due to other forms of one-track damage.

Energy dependent track structure parametrisations for protons and carbon ions based on nanometric simulations

“…The ionisation cluster size distributions and the associated statistical parameters are measurable quantities [23][24][25][26][27] and could in the future − when practical instruments have been developed − be used in the clinic to characterise track structure and radiation quality of the treatment beam. In combination with a model predicting the radiobiological outcome − for example the RMF model that is linking double-strand break induction to reproductive cell death [28,29] − these parametrisations can be useful to achieve a higher accuracy for biological optimisation of treatment plans.…”

In silico comparasion of 11 different radioisotopes for palliative treatment of bone metastases

“…Previous studies have demonstrated that the complex damage repair by excision can lead to an increased number of DSBs [22], [26]. It is well known that DNA DSBs are frequently associated with apoptosis induction [18]. The damage induced by 223 Ra α particles and 177 Lu β -particles seem to have hampered the successful repair of the DNA by BER or NER, presenting a high probability for DSB formation and low probability for correct repair.…”

“…The model generates a number of damage configurations expected within the DNA of one cell, where the algorithm processes information in two main steps: first, it randomly distributes, in a DNA segment, the expected amount of damage produced in a cell; then, it subdivides the distribution of damage in that particular DNA segment. A detailed description of the MCDS model as well as additional discussions about the validity and limitations this method are presented in [17] and [18].…”

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

“…45,50 It is well known that DNA DSBs are frequently associated with apoptosis induction. 41 The damage induced by 223 Ra α particles and 177 Lu β -particles seem to have hampered the successful repair of the DNA by BER or NER, presenting a high probability for DSB formation and low probability for correct repair.…”