Cell cycle-related effects on the radiation survival responses of human tumor cells

Cell cycle-related phenomena have profound effects on the ability of cells to survive exposure to ionizing radiation. These phenomena are important because they shed light on the underlying mechanisms of the cell cycle, and because they provide avenues to improve the efficacy of clinical radiotherapy. Radiobiologists have developed a partial picture of how and why radiosensitivity varies during the cell cycle. Nevertheless, our understanding of the role of cell cycle effects on the radiosensitivity of human cells is still far from complete.;In this thesis, cell populations which were synchronized at specific points in the mitotic cycle were used to explore cell cycle-related effects on the radiosensitivity of human tumor cells in vitro. The survival of synchronized cells after irradiation was measured at low doses which are relevant to radiation therapy, using the cell-sorter assay, which utilizes a cell-counting flow cytometer to reduce the uncertainties associated with traditional survival assays.;The radiosensitivity of three human tumor cell lines varied significantly over the course of the cell cycle, in a manner which was in general agreement with earlier studies by others who examined the responses of rodent, and some human, cell types, using similar synchronization techniques. However, discrepancies were found with other studies which used alternative synchronization methods.;The widely-used linear quadratic model of cell survival was tested in synchronized cell populations. Consistent, significant deviations from the model were found. A mathematical model of synchronized cell radiosensitivity was developed to explore these deviations. Departures from the linear-quadratic model in two cell lines could be adequately explained by cell cycle-related heterogeneity in experimental cell populations. In a third cell line, however, the deviations from the linear-quadratic model were not attributable to cell heterogeneity alone.;One of the three human tumor cell lines examined here underwent a prolonged arrest in the G1 phase of the cell cycle after irradiation. The arrest was characterized by following the progression of synchronized cells after irradiation at different times in G1 phase. The characteristics of the arrest were consistent with a "checkpoint" in late G 1 phase where radiation-damaged cells stopped cycling for an extended period.