The main objective of this application is to examine the role of tumor physiology in the therapeutic response of solid tumors to hyperthermia. In specific, the following interactions will be examined. a) The relationship between pretreatment tumor physiologic status and therapeutic response to heat. b) The effect of thermal sensitivity modulators (i.e., hyperglycemia or flavone acetic acid) on pretreatment tumor physiologic status and the effect of those changes on therapeutic response to heat. c) The effect of heat on tumor physiological status both during and after heating and the effect of the heat induced modulation of such metabolic status on therapeutic response. These complex interactions between tumor physiological status and therapeutic response. These complex interactions between tumor physiological status and therapeutic response to hyperthermia will be examined in a set of parallel in situ/in vitro experiments. In the in situ experiments, the pretreatment tumor physiological status and its dynamic response to thermal sensitizers and hyperthermia (at 41 degrees C, 43 degrees, or 45 degrees C) and the relationship of that physiological status to therapeutic response will be examined with multinuclear in vivo NMR spectroscopy; (i.e., 31P NMR will be used to measure tumor pH and the concentrations of ATP, PCr and Pi; 1H NMR will be used to measure tumor lactate concentration; and a 2H NMR technique recently developed and validated in the PI's laboratory will be used to measure tumor blood flow.) In a parallel set of in vitro experiments, the interrelated physiological variables will be independently controlled in an in vitro perfusion apparatus which allows the physiologic status of the cells to be monitored continuously and noninvasively with 31P and 1H NMR. Because these interactions may have an impact on the optimum sequencing and timing of hyperthermia when used as an adjuvant to either radiotherapy or chemotherapy and NMR spectroscopy can be used to examine human tumors, the results of these laboratory investigations should provide a framework for the implementation of NMR spectroscopy to aid in the clinical application of hyperthermia alone and in conjunction with other modalities of therapy.
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