Understanding the mechanisms that regulate blood-brain barrier (BBB) and blood-tumor barrier (BTB) permeability and an ability to selectively modulate BTB permeability biochemically would have important therapeutic implications. Leukotrienes (LTs) have been shown: 1) to increase BBB permeability when injected directly into the brain parenchyma; 2) LTC4 levels in brain tumors in man are correlated with the amount of edema surrounding the tumors; 3) high affinity binding sites for LTC4 have been demonstrated on isolated brain capillaries; and 4) arachidonic acid (AA) induced edema can be decreased by blocking the conversion of AA to LTs. Utilizing experimental brain tumors (C6 glioma, RG 2 glioma and Walker 256) in rats we will investigate whether pretreatment with 5-lipoxygenase (5-LO) inhibitors (the enzyme that converts AA to LTs) will decrease BTB permeability measured by quantitative autoradiography using 14C AIB. Potentially, 5-LO inhibitors could be utilized in the treatment of vasogenic brain edema associated with brain tumors. Conversely, increasing LT levels in tumors might selectively increase BTB permeability and increase the intravascular delivery of anti-tumor moieties to tumor tissue. To investigate this hypothesis rats with experimental tumors will be pretreated with cyclooxygenase and thromboxane synthetase inhibitors with or without concurrent infusions of intravenous AA to increase LT formation within tumor tissue or rats will be given intraarterial LT infusions and BTB permeability and the delivery of radiolabelled chemotherapeutic compounds will be determined by autoradiography. To further study the mode and mechanisms of action by which LTs increase BBB permeability, the ability of LT and other vasoactive compounds (such as bradykinin and plasminogenic activator) to increase the permeability of cerebral endothelial cells in vitro with or without co-culture of astrocytes will be determined using a two-chamber system for quantitative analysis of endothelium permeability. The ability of LTs and other vasoactive compounds to increase BBB permeability in vivo will also be determined using autoradiography. Whether high affinity binding site for LTs exist on endothelial cells in culture and whether astrocytes influence the development of these binding sites will be determined.
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