Brachytherapy - the implantation of sealed sources of radionuclides - is an effective method of treatment for human cancers. Further improvement in the efficacy of this approach is desireable and possible. The goal of this research is to increase our understanding of in vitro radiobiological response at low irradiation dose rate, to explore methods to enhance low dose rate radioresponse, and to suggest strategy to provide therapeutic advantage to brachytherapy so as to improve clinical results. We specifically propose to study the possible circumvention of hypoxia induced radioresistance with the use of the thiol depletion agent BSO and radiosensitizers SR2508 at brachytherapy dose rates. Each method by itself (i.e. thiol depletion, oxygen mimetic sensitization, and low dose rate irradiation) can reduce the oxygen dependence of cellular radiosensitivity. Combining these approaches may be extremely effective in reducing the oxygen enhancement ratio and selectively sensitizing hypoxic cells. Studies will also be carried out in the low dose region at acute dose rate, to complement the low dose rate work. This is important for clinical application of thiol depletion and radiosensitizers to fractionated teletherapy. In addition, comparing the above results will yield insight on the hypothesis that survival characteristics obtained under low irradiation dose rates simulate the low dose region of acute dose rate data. This hypothesis, often assumed but which has not been studied carefully, is important to our overall understanding of dose rate effect in radiobiology. Lastly, we propose to study the effect of hyperthermia on low dose rate radioresponse, simulating clinical parameters, with a view to providing a basis for optimizing clinical application. While clinical trials combining hyperthermia and brachytherapy are ongoing, important questions such as optimum sequencing, relative efficacy of single vs. multiple heating sessions, influence of dose rate, are still not adequately understood. Experiments are proposed to examine these issues.
