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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS026523-02
Application #
3477546
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-08-01
Project End
1993-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Black, K L; Chio, C C (1992) Increased opening of blood-tumour barrier by leukotriene C4 is dependent on size of molecules. Neurol Res 14:402-4
Ikezaki, K; Black, K L; Conklin, S G et al. (1992) Histochemical evaluation of energy metabolism in rat glioma. Neurol Res 14:289-93
Chio, C C; Baba, T; Black, K L (1992) Selective blood-tumor barrier disruption by leukotrienes. J Neurosurg 77:407-10
Baba, T; Chio, C C; Black, K L (1992) The effect of 5-lipoxygenase inhibition on blood-brain barrier permeability in experimental brain tumors. J Neurosurg 77:403-6
Boado, R J; Pardridge, W M; Vinters, H V et al. (1992) Differential expression of arachidonate 5-lipoxygenase transcripts in human brain tumors: evidence for the expression of a multitranscript family. Proc Natl Acad Sci U S A 89:9044-8
Baba, T; Black, K L; Ikezaki, K et al. (1991) Intracarotid infusion of leukotriene C4 selectively increases blood-brain barrier permeability after focal ischemia in rats. J Cereb Blood Flow Metab 11:638-43
Black, K L; King, W A; Ikezaki, K (1990) Selective opening of the blood-tumor barrier by intracarotid infusion of leukotriene C4. J Neurosurg 72:912-6
Ikezaki, K; Black, K L (1990) Stimulation of cell growth and DNA synthesis by peripheral benzodiazepine. Cancer Lett 49:115-20
Ikezaki, K; Black, K L; Santori, E M et al. (1990) Three-dimensional comparison of peripheral benzodiazepine binding and histological findings in rat brain tumor. Neurosurgery 27:78-82
Black, K L; Ikezaki, K; Santori, E et al. (1990) Specific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumors in rat and man. Cancer 65:93-7

Showing the most recent 10 out of 12 publications