The objective of this proposal is to determine whether radiation induced vascular permeability can be modified through the use of chemical agents applied at the time of irradiation. We will use the rat brain vasculature as our model of a vascular system, and brain methotrexate (MTX) levels as a measure of the vascular permeability. This model is selected since 1) it technically is capable of providing answers to the questions of interest, 2) it acts as a valid representation of the vasculature, and as such can be used to identify basic pathologic mechanisms, 3) it uses MTX, a clinically valuable drug which has well-studied pharmacokinetics, and 4) it is potentially relevant to the clinical problem of leukoencephalopathy which is the most significant long-term complication of the current therapy of acute lymphocytic leukemia. MTX levels in the brain after systemic administration will be measured with the dihydrofolate reductase inhibition assay. After first determining the temporal course of radiation-increased permeability to MTX, compounds antagonistic to endogenous agents which increase vascular permeability will be studied. The compounds will come from seven classes of drugs -- 1) anti-inflammatory steroids, 2) prostaglandin synthesis inhibitors, 3) antihistamines, 4) protease inhibitors, 5) complement depletors, 6) radioprotectors, and 7) the newly discovered leukotriene synthesis inhibitors. Agents from those classes found to be effective in reducing permeability will then be combined in an attempt to 1) further reduce permeability, and 2) further elucidate the basic mechanisms of radiation induced vascular permeability. Finally, a long term experiment will be conducted in which rats will be treated with brain-only irradiation plus systemic MTX with or without the optimal permeability-reducing treatment. This final experiment will test whether such treatment does indeed reduce the incidence of leukoencephalopic-like neurohistopathologic changes.
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