Combined use of Monte Carlo DNA damage simulations and deterministic repair models to examine putative mechanisms of cell killing.

D.J. Carlson, R. D. Stewart, V.A. Semenenko and G.A. Sandison
Radiation Research 169, 447-459 (2008)
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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 inter-track 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 intra-track 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/mm, 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/mm or that other biological phenomena not included in the model, such as proximity effects, are important.  For 200-250 kVp x-rays (~1.9 keV/mm), only about 1% of the one-track killing is attributed to intra-track 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.  In comparison to the analysis of the x-ray results, 48% of the one-track lethal damage caused by 5.1 MeV a-particles (~88 keV/mm) is due to intra-track DSB interactions while the remainder is due to other forms of one-track damage.

Keywords: linear-quadratic model, LQ, survival, DSB, RBE, LET, radiosensitivity

Last updated: January 14, 2013