A theoretical investigation of cell cycle effects and interspecies radiosensitivities

One limitation of radiobiological models currently used to quantify the cell killing effects of ionizing radiation is that they use ad hoc parameters to account for the aggregate effects of many biological and molecular processes. Such models do not provide any insight into the biological basis for cell cycle effects or for differences in cell killing among cell types. The usefulness of these models is thus severely limited. In this work, a new molecular-level model is proposed. This model accounts for the heterogeneous formation and repair of DNA damage among various types of chromatin, damage-induced cell-cycle blocking, temporal changes in the structure of a cell's chromatin, and cell desynchronization effects in groups of proliferating cells. One important aspect of the model is that all of the associated model parameters can, in principle, be estimated from ab initio calculations, measurements, or at least constrained to some meaningful range of values.;The proposed radiobiological model has been used to investigate the cell killing effects of ionizing radiation in groups of stationary-phase and proliferating Chinese Hamster cells. A series of sensitivity studies illustrating the cell killing effects associated with biological processes such as DNA damage repair, cell cycle blocking, and DNA replication have also been conducted. Finally, interspecies differences in cell killing associated with cell DNA content and the rate of cell proliferation have been investigated. The results of these studies indicate that the attempt to model the cell killing effects of ionizing radiation at a molecular level has been successful. Model results suggest that changes in the structure of a cell's chromatin during the cell cycle produce cyclic changes in the yield of damage produced in a cell. Cyclic changes in a cell's chromatin also produce cyclic changes in the rates of damage repair, fixation, and pairwise damage interaction. It is concluded that these phenomena are responsible for observed cell cycle effects. The results presented here also indicate that a portion of the DNA damage responsible for cell killing has a characteristic repair half-time between 9 and 10 hours and that damage repair is coupled to DNA replication.