The therapeutic action of Tumor Necrosis Factor (TNF) will be studied using spatially resolved, noninvasive Magnetic Resonance (MR) methods. The following model for the effect of TNF on solid tumors will be tested.' TNF causes rapid damage of tumor vasculature within 1 - 4 hours; the subsequent ischemia leads to cell death in the center of the tumor. The outer rim of the tumor is unaffected by the early ischemic episode, Cells in this region may be killed by a delayed (24 - 72 hours) response to TNF, but often survive, and repopulate the tumor. The experiments will be designed to Provide a practical understanding of the factors which lead to TNF-induced tumor regression.
The specific aims of the proposed work are: 1. Development and testing of MR methods: The ability of spatially resolved MR measurements of tumor blood flow and metabolism to detect hypoxia, necrosis, and hemorrhagic lesions will be developed and evaluated. 2. Therapeutic action of TNT: a) Importance of acute and delayed effects.- Murine Meth A tumors win be studied by MR at 4 hours, 24 hours, 72 hours, and 1 week after the beginning of treatment with TNF. The acute and delayed effects of TNF will be identified by MR on the basis of their effects on tumor blood flow, metabolite levels, and anatomy. The data wt be analyzed to determine the relative importance of the acute and delayed effects for causing tumor regression, and identify other factors which are important in causing tumor regression.. b) Resistant cell populations: MR will be used to identify those tumor zones in which cells survive the effects of TNF and may rePoPulate the tumor. Characterization of these cells may lead to improved treatment protocols. 3. Improved treatment protocols: Based data from the initial studies (above), modified schedules for administration of TNF, alone and in combination with other therapeutic agents, will be designed and evaluated using MR methods.
