Methotrexate-(MTX), a potent inhibitor or dihydrofolate reductase, is a cancer chemotherapeutic agent of major importance: however, its use either alone or with cranial radiation is often limited by neurotoxicity. The pathobiology of MTX neurotoxicity remains poorly understood, thus impairing clinical efforts to reduce or reverse these potentially serious or fatal treatment complications. Previous studies in our laboratory have suggested three possible mechanisms for MTX neurotoxicity including inhibition of cerebral glucose metabolism, injury to cerebral vascular endothelium, and inhibition of catecholamine neurotransmitter synthesis; others have implicated MTX depletion of brain folates in this process. To understand the pathobiological mechanisms underlying MTX neurotoxicity, the following Specific Aims are proposed: 1. Further characterize the neurotoxicity of MTX alone, MTX with cranial radiation, and selected newer antifolate drugs in an animal model by using quantitative autoradiography to measure regional cerebral glucose metabolism and/or protein synthesis. 2. Investigate MTX depletion and leucovorin repletion of brain folates by measuring brain folate and folate cofactors after MTX and leucovorin treatment by HPLC techniques. Whereas the exogenous folate leucovorin reverses acute high-dose MTX neurotoxicity in the rat, it is unknown whether leucovorin rescue is accomplished by a repletion of brain folates. 3. Further evaluate MTX alterations of blood-brain barrier permeability in rats by using in vivo quantitative autoradiography and in vitro capillary endothelial tissue culture techniques. The ability of dexamethasone to reverse MTX-induced increases in blood- brain barrier permeability will also be examined. 4. Investigate MTX inhibition of catecholamine synthesis by HPLC measurements of rat striatal catecholamines. Identification of neurotransmitter deficiencies will justify studies of neurotoxicity reversal by neurotransmitter precursor replacement therapy. A clearer understanding of these mechanisms will facilitate our long term goals of designing rational treatment plans to reduce the risk of neurotoxicity, permitting early diagnosis of neurotoxicity by noninvasive neuroimaging techniques (PET), and developing pharmacological approaches to reverse MTX neurotoxicity.
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| Phillips, P C; Than, T T; Cork, L C et al. (1992) Intrathecal 4-hydroperoxycyclophosphamide: neurotoxicity, cerebrospinal fluid pharmacokinetics, and antitumor activity in a rabbit model of VX2 leptomeningeal carcinomatosis. Cancer Res 52:6168-74 |
