The long term goal of this project is to develop in vivo MRS for the clinical management of cancer chemotherapy and for the experimental study of tumor models in vivo and in culture. The central hypothesis is that H1 and C13 can reliably and noninvasively predict and detect tumor response to chemotherapy. The principal goals of this project are to use two well-defined tumor models- a human mammary carcinoma (MCF7) and a radiation-induced murine fibrosarcoma (RIF1) -to monitor tumor heterogeneity with respect to glucose metabolism , vascular volume, blood flow and proliferative capacity during untreated growth and following treatment with a range of chemotherapeutic agents that are commonly employed in the treatment of human cancer. This proposal will evaluate the unique capabilities of H1 and C13 MRS- improved spatial resolution and ability to monitor metabolic flux. The program will use methods developed during the current funding period: 1] H1 MRS techniques capable of efficiently suppressing water and lipid resonances; 2] C13 MRS methods with improved sensitivity achieved through heteronuclear polarization transfer or through H1 MRS detection of H1-C13 multiple quantum coherence; 3] diffusion MRS methods that distinguish intra and extra cellular metabolites in perfused cell systems; and 4] macromolecular MRI contrast agents to measure tumor vascular volume. Studies of in vivo tumors as well as perfused isolated cells will elucidate the mechanism underlying growth and therapy induced spectral changes. 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 tumor metabolites. A simple two compartment model will used for studies of in vivo tumors exhibiting only glycolysis. Pilot 1H MRS studies will be performed on human subjects with carcinoma of the breast to compare the characteristics of these tumors with those of the model tumors before treatment and after chemotherapy (of breast tumor metastases).
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