The development of hyperthermia as a viable tumor treatment has been hindered by the lack of adequate dosimetry. No satisfactory physical expression has been developed to express """"""""heat dose."""""""" Furthermore, with current techniques heat distribution is often inhomogenous and thermometry imprecise. This application seeks to explore the usefulness of in vivo nuclear magnetic resonance (NMR) spectroscopy to express thermal damage to tumors in biological terms. The NMR parameters to be monitored include the ratio ATP/Pi and intracellular pH, derived from 31P-NMR spectra; and the spin-lattice relaxation time (T1), derived from 1H-NMR spectroscopy. These parameters will be measured serially in mice with subcutaneous RIF-1 and Dunn osteosarcoma tumors. Our hypotheses are that the fluxes in these parameters can be related to a variety of important biologic events in the tumor, and can be used to monitor metabolic effects of hyperthermic therapy. Specific studies to be performed are as followed. 1. Correlation of change in NMR parameters with cell kill. Correlations will be sought between the degree of fall in ATP/Pi, or pH, with thermal cell kill as reflected in clonogenic cell content (RIF-1, OS) or circulating tumor marker (OS). The relationship between increase in tumor T1 and thermal cell kill will also be examined. 2. Correlation between change in NMR parameters and tumor blood flow. The relationship between thermally-induced fall in ATP, pH and loss of tumor blood flow will be examined. 3. Correlation between change in NMR parameters and cell cycle kinetics and thermal tolerance. The gradual recovery of ATP, pH seen after sublethal hyperthermia will be related to measurements of thermal tolerance (clonogenic assays) cell cycle kinetics (FACS analysis of DNA content, labelling index). 4. Prediction of cell kill from pretreatment NMR spectrum. Usefulness of pretreatment pH, ATP/Pi, tumor mass will be compared for prediction of cell kill with heat.
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