The long-term goal of this project is to develop in vivo NMR spectroscopic methods for the clinical prediction and detection of tumor response to radiation therapy and for the experimental study of radiation oncology. During the previous three year funding period the ability of 31-P NMR spectroscopy to detect changes in tumor oxygenation and radiosensitivity and to detect tumor response to radiation therapy was demonstrated in the RIF-1 tumor model, which has a very low radiobiological hypoxic fraction. In order to draw more general conclusions about both the clinical and experimental utility of NMR spectroscopy, we propose to extend these studies to the more hypoxic EMT6 tumor model. Three fundamental properties related to tumor radiosensitivity - - oxygenation, bioenergetics and proliferation - - will be examined through the integrated study of isolated perfused tumor cells, perfused multicellular spheroids and in vivo tumors in mice. Multinuclear NMR methods will be employed - - 31-P to monitor bioenergetics and pH; 13-C to measure flux through glycolysis, the hexose monophosphate shunt (HMPS) and the TCA cycle; and 1-H to monitor lactate with improved spatial resolution. The relative sensitivity of these methods to changes in tumor radiosensitivity and to tumor response to radiation therapy will be evaluated, and mechanisms underlying spectral changes during untreated growth and following radiation therapy will be investigated. We will test the hypothesis that relative flux through glycolysis and the TCA cycle is the most sensitive NMR indicator of changes in tumor oxygenation and radiosensitivity. We further hypothesize that acute spectral changes following gamma-irradiation result from tumor reoxygenation; chronic changes reflect therapeutic response. The utility of phosphate monoester levels and flux through the HMPS as indicators of tumor proliferative state will be evaluated. Tumor heterogeneity will be examined by 1-H NMR nicroscopy, 1-D 31-P chemical shift imaging, 2-D double quantum 1-H imaging of lactate, and perfusion imaging (monitoring Freon 23 wash-out or HDO wash-in). These NMR measurements will be correlated with tumor histology, radiosensitivity and autoradiographic measures of tumor perfusion and local pH.
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