Mechanistic Modeling of Dose and Dose Rate Dependences of Radiation-Induced DNA Double Strand Break Rejoining Kinetics in XXXX .

@entity1 @entity137 @entity5 @entity1161 @entity375
UNASSIGNED: Mechanistic modeling of DNA double strand break (DSB) rejoining is important for quantifying and medically exploiting radiation-induced @entity137 (e.g. in @entity5 radiotherapy). Most radiation-induced DSBs are quickly-rejoinable and are rejoined within the first 1-2 hours after irradiation. Others are slowly-rejoinable (persist for several hours), and yet others are essentially unrejoinable (persist for >24 hours). The dependences of DSB rejoining kinetics on radiation dose and dose rate remain incompletely understood. We hypothesize that the fraction of slowly-rejoinable and/or unrejoinable DSBs increases with increasing dose/dose rate. This @entity1161 ( @entity1161 ) model was implemented using differential equations for three DSB classes: quickly-rejoinable, slowly-rejoinable and unrejoinable. Radiation converts quickly-rejoinable to slowly-rejoinable, and slowly-rejoinable to unrejoinable DSBs. We used large published data sets on DSB rejoining in @entity375 exposed to sparsely-ionizing (electrons and y-rays, single or split-doses, high or low dose rates) and densely-ionizing (a-particles) radiation to compare the performances of the proposed @entity1161 formalism and the established two-lesion kinetic (TLK) model. These @entity375 DSB rejoining data were measured within the radiation dose range relevant for clonogenic cell survival, whereas in @entity1 cells DSB rejoining is usually measured only at supra-lethal doses for technical reasons. The @entity1161 model described both sparsely-ionizing and densely-ionizing radiation data much better than the TLK model: by 217 and 14 sample-size-adjusted Akaike information criterion units, respectively. This occurred because: the @entity1161 (but not the TLK) model reproduced the observed upwardly-curving dose responses for slowly-rejoinable/unrejoinable DSBs at long times after irradiation; the @entity1161 model adequately described DSB yields at both high and low dose rates using one parameter set, whereas the TLK model overestimated low dose rate data. These results support the hypothesis that DSB rejoining is progressively impeded at increasing radiation doses/dose rates.
