Research Project
3167175
Human tumor cells differ in radiosensitivity, between cell lines of different histological types and also within each histological type. Differences are clearly seen in the low-dose region of the acute radiation survival curve and they are greatly magnified by irradiation at low dose rate (around 1-5cGy/min). These differences are large enough to influence success or failure in clinical radiotherapy. This project seeks to explore differences among cell lines from tumors of the cervix, bladder, skin, and nervous system, among others. Cell survival will be assessed by means of established cell cloning assays. The dose-rate effect will be studied and the data evaluated in terms of the relative roles of recoverable and non-recoverable damage. Multiple split-dose experiments will be performed at a range of dose levels and compared with similar studies of delayed-plating recovery. These studies will critically evaluate our current evidence that recovery increases with radiosensitivity (in contrast to the accepted view) and that the alpha/beta ratio for human tumor cells is roughly constant. The aim is to obtain a reliable overview of the therapeutic importance of recoverable and nonrecoverable damage in human tumor cells. Selected human tumor cell lines of differing radiosensitivity, also human normal and AT fibroblasts, will be sychronised by mitotic selection and the variation of sensitivity and recovery through the cell cycle will be examined. The results will be carefully analyzed for evidence on the variation in the initial slope of the survival curve with cell-cycle phase. The main thrust of the work will be towards a deeper understanding of the initial slope of cell survival curves. Since there are grounds for believing that this slope is similar to the slope of the cell survival curve at low dose rate, we regard this as reflecting non-repaired 'residual' cellular damage. We will explore this by documenting non-repaired PCC breaks and micronucleus formation across a range of human tumor cell lines. In addition, we will study the sensitivity of the cells to mutation at specific loci in order to ask more detailed questions about the nature of residual genetic damage.
