The main objective of this application is to use multinuclear NMR spectroscopy to provide detailed knowledge of the dynamic response of tumor biology to hyperthermia and hyperglycemia. This information will be used to: 1) elucidate the mechanism by which hyperglycemia enhances the sensitivity of tumors to hyperthermia; 2) determine the physiological parameters which affect tumor metabolism under conditions of hyperthermia and hyperglycemia; and 3) evaluate the efficacy of NMR spectroscopy as a monitor and predictor of tumor response to hyperthermia and hyperglycemia. Implicit in the pursuit of these goals is the requirement to better understand how tumor physiology is reflected in NMR spectra in vivo. The mechanism by which hyperglycemia reduces tumor pH and blood flow and the effect of these two factors on thermal sensitivity will be examined by assessing the importance of a) glycolysis (determined by measuring rates of glucose consumption and lactic acid production using 13C labelled substrates and 13C NMR and observing the effect of mannitol, a non-metabolizable carbohydrate, on tumor pH, blood flow, and thermal sensitivity) and b) reduced blood flow (determined by observing the effect of hyperglycemia on the same factors when a perfluorocarbon blood substitute is used). The contributions of cells, in different environments in a tumor, to the in vivo 31p NMR spectrum will be examined by observing the effects of pH, pO2, nutrient concentration, flow rate and temperature on the spectrum of a homogeneous population of cells in vitro. Physiological parameters which affect tumor metabolism under conditions of mild (40 degrees-42 degrees C) or severe (greater than 45 degrees C) hyperthermia (+- hyperglycemia) will be determined by correlating the changes observed by NMR with measured values of tumor blood flow (determined by 15-0 activation and 19F NMR techniques) and well-perfused fraction (determined by 15-0 activation technique), and tumor response to treatment (determined by tumor growth delay and the fraction of clonogenic cells surviving treatment). The clinical efficacy of NMR as a monitor and predictor of tumor response to hyperthermia and hyperglycemia will be assessed by evaluating the ability of the NMR markers, determined from the above studies, to monitor and predict tumor response to treatment in individual mice using two tumors of different thermal sensitivities (i.e., RIF-1 in C3H mice and EMT6 in BALB/c mice) and a tumor with a substrain-dependent response to hyperglycemia (i.e., RIF-1 in C3H/Anf and C3H/Hej mice).
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