Methods which enhance radiation-induced killing of tumor cells while causing less or no damage to normal cells must be developed in order to improve the use of radiation therapy in the treatment of cancer. One such method which has received increasing attention in recent years is the use of chemical agents which protect against radiation damage in normal tissues while having less or no effect on tumor cells. Compounds which contain sulfhydryl (SH) groups are efficient radioprotectors, but these compounds offer no therapeutic gain because of their lack of preferential radioprotection for normal tissues over tumors, their low protection factors in vivo and their high toxicity. Recently, however, interest in the potential clinical use of radioprotectors has been renewed with the demonstration that WR-2721, a less toxic, phosphorylated derivative of cysteamine, protects several normal mouse tissues while having little or no protective effect on tumors. Knowledge of the mechanisms whereby these SH compounds exert their radioprotective effects is very incomplete. They may protect due to systemic effects such as alterations in blood flow or concentrations of compounds in normal and tumor tissues or because of chemical and biochemical effects within cells. This study is designed to further elucidate possible chemical and biochemical mechanisms of radioprotection and toxicity of sulfhydryl and related compounds. First, we will examine in detail the chemical actions and interactions of SH compounds and radiation in an in vitro cellular system using both cell survival and DNA damage induction as endpoints. A number of compounds over a range of concentrations will be studied. We will look for correlations between the radioprotective ability of the various compounds and their abilities to enter cells, scavenge OH radicals, donate H atoms or consume oxygen. We will test the hypothesis that radioprotection by SH compounds depends on endogenous non-protein sulfhydryl levels in cells. Second, we will determine whether SH compounds alter the ability of cells to repair radiation-induced sublethal, potentially lethal and DNA damage. Third, we will further examine the unusual toxicity of some SH compounds in tissue culture, elucidate possible mechanisms of this toxicity and question the clinical relevance of it. The mechanistic information gained in this study should provide a chemical/biochemical basis for rational development of other potential radioprotectors, will add to our knowledge of the mechanisms of action of SH compounds and of radiation and will enhance proper clinical use of radioprotectors.
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