Many factors lead to treatment-resistance in cancer therapy. Some factors physical-chemical in nature: examples are hypoxia or the presence of high thiol content, which increase radiation resistance by well-known chemical principles. Others have a biochemical and molecular- biological basis: examples are endogenous radio-resistance, cell-cycle blocks or modified repair. The interactions of these factors are poorly understood in vivo, and studies of basic mechanisms of treatment resistance must have a very broad base of investigation. Several studies have suggested that low dose-rate, protracted ration (LDRR) can provide significant therapeutic advantages over conventional fractioned therapy, which consists of multiple discrete dose administrations, each of which is at high dose-rate. In order to apply this information to the clinic, however, an understanding is required regarding the interaction of LDRR with the chemical and biological modifiers of radioresistance. It is becoming increasingly apparent that hypoxia plays a key role in determining radioresistance, not only in the countless rodent studies over several decades, but in the current management of human cancer therapy. This project will test for the interaction of hypoxia with the radiation response of cells to LDRR. Several key questions will be addressed; 1) is there a normal dependence of radiation resistance on oxygen partial pressure for low dose-rate radiotherapy? 2) does low oxygen partial pressure affect the cell-cycle redistribution caused by low dose-rate radiation? and 3) is the response after low dose-rate radiation in vivo mediated through changes in tissue hypoxia or thiol content? 4) are hypoxic tumor cells sensitized by IUdR? It is hoped that these investigations will allow a firm rationale for the use of LDRR in tumors containing hypoxic cells.
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