The main objective of this application is to critically evaluate the potential for in vivo 31P and 1H NMR spectroscopy to provide a noninvasive, predictive assay of tumor response to radiation therapy before and/or during the course of treatment. Because NMR is nondestructive, the methodology developed and evaluated in these studies, using a murine tumor system, can be applied in the clinic. A clinical predictor of radiation response should: i) aid in the selection of groups for clinical trials of new treatment protocols targeted for radioresistant tumors thereby maximizing the probability of identifying effective treatment strategies; and ii) allow the response in individual patients to be utilized in designing more effective, individualized therapy. A special emphasis is placed on examining the relationship between radiobiological hypoxia and the NMR metabolic characteristics. The in vivo relationship will be examined by a direct comparison of the NMR metabolic characteristics and the radiobiological hypoxic fraction determined in the same tumor-bearing mice. The presence and importance of contributions to the NMR signal from cells which are not radiobiologically hypoxic, but have similar NMR metabolic characteristics, will be evaluated by: i) examining the relationship between the NMR metabolic characteristics and cellular radiosensitivity as a function of both PO2 and the length of time spent under hypoxic conditions in a system which allows NMR observation of tumor cells in a controlled, homogeneous environment (i.e., in vitro); and ii) examining the effects of the fraction of necrotic cells on the relationship between the NMR metabolic characteristics and the radiobiological hypoxic fraction in a system which allows NMR observation of tumor cells in a heterogeneous environment mimicing that found in tumors, but with control over the degre of heterogeneity (i.e., in spheroids). The hypoxic fraction information obtained from both NMR and measurement of radiolabeled-misonidazole binding will be compared by applying both techniques to the same tumor-bearing mice. The predictive ability of NMR will be evaluated by comparing the radiation response of individual tumor-bearing mice with their NMR metabolic characteristics and the changes in those characteristics in reponse to treatment, but before marked decreases in tumor size.
