The mechanisms by which ionizing radiations exert their effects on mammalian cells and tissues, and the mechanisms by which endogenous or exogenous thiol compounds, or indeed radiomodifying agents in general, modulate these damaging effects are very poorly understood. It is the purpose of this study to further our understanding of these processes by investigating the effects of carefully selected thiols on the DNA-damaging and lethal effects of radiation in vitro. We propose to develop a detailed understanding of the relative effects of these selected compounds on survival and on various endpoints for damage to genomic DNA of oxic and hypoxic cells. These studies will utilize a series of DNA repair-deficient mutant mammalian cell lines in order to address the hypothesis that cell death may not always result from the induction and repair of a specific """"""""lethal lesion"""""""", but rather that, depending on the particular combination of genetic and redox factors, the lethal effects of different classes of DNA lesions may be differently expressed. In addition to exogenous thiols, we will also examine the effects of modifying the redox status of these cells lines by varying oxygen and glutathione levels and examining the associated effect on these relationships between DNA or chromosome damage and cell survival as exogenous thiol levels are altered. Through the understanding of the mechanism of action of radiomodifying compounds and its dependence on their structure, we will ultimately be able to place the rationale for the selection and development of radiomodifying agents on a logical mechanistic basis. Similarly, by examining the correlations between the effects of these radiomodifiers on the relationships between various types of DNA or chromosome damage and cell survival we will be able to shed light on the very basic mechanisms of radiation lethality. These data will also provide a foundation for future studies examining the relationships between stem/target cell survival and DNA or chromosome damage induction and repair processes in vivo.
