Evaluation of the potential utility of NMR spectroscopy to the clinical management of chemotherapy and to the delineation of fundamental processes in tumor biology has been the focus of this research program over the last decade. Our underlying hypothesis is that this method can reliably and noninvasively predict and detect tumor response to chemotherapy. The principal goals of this proposal are 1) to extend our studies to a representative human tumor (MCF-7 breast carcinoma) with histological and pharmacological properties complementary to that of murine radiation-induced fibrosarcoma (RIF-1) examined during the previous funding period, 2) to extend 31P NMR spectroscopic experiments to two nuclei offering unique advantages: 1H, improved spatial resolution and spectral sensitivity; 13C, ability to monitor flux through specific metabolic pathways, 3) to determine the mechanism underlying spectral changes during tumor growth and response to chemotherapy, and 4) to determine the effects of changes in tumor perfusion and proliferation on NMR detectable metabolic characteristics of tumors. Specifically, the utility of 31p, 1H, 13C and 19F NMR spectroscopy as methods for predicting and detecting tumor response to chemotherapy will be compared. A key hypothesis of this proposal is that metabolic flux, because of its sensitivity to perfusion, oxygenation and proliferation, is a more sensitive therapeutic index than steady state measurements of metabolite concentrations. 31p magnetization-transfer and 13C-isotopiC labeling experiments will be used to measure flux through key pathways of tumor energy metabolism. A mathematical model for calculation of flux through the TCA cycle, glycolysis and the hexose monophosphate shunt from the kinetics from '3C-labeling data will be developed. Chemical shift imaging of 31p, 1H and 13C and quantitative morphometry will be employed to examine metabolic heterogeneity. Studies of mechanisms underlying spectral changes will focus on measurements of tumor blood flow and cytokinetics and on in vitro studies of isolated tumor cells and spheroids. The effects of growth stimulation and inhibition on steady state levels of NMR detectable metabolites and flux through key pathways of energy metabolism will be investigated.
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