The blood-brain tumor barrier (BTB) limits the delivery of therapeutic drugs to brain tumors. We demonstrate in a rat brain tumor (RG2) model an enhanced drug delivery to brain tumor following intracarotid infusion of bradykinin (BK), nitric oxide (NO) donors, or agonists of soluble guanylate cyclase (sGC) and calcium-dependent potassium (K Ca ) channels. We modulated K Ca channels by specific agonists and agents that produce NO and cGMP in situ to obtain sustained enhancement of selective drug delivery to brain tumors. Immunoblot and immunolocalization studies demonstrate overexpression of K Ca channels in tumor cells and capillaries compared with normal brain. The potentiometric assays demonstrate the functional activity of K Ca channels in rat brain endothelial and glioma cells. Additionally, we show that BK and NS-1619 significantly increased the density of transport vesicles in the cytoplasm of brain tumor capillary endothelia and tumor cells. The cleft indices and cleft area indices in rat tumor capillaries were significantly higher than in normal brain capillaries, and BK infusion did not alter these indices. These data demonstrate that the cellular mechanism for K Ca channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport drugs across BTB. We conclude that K Ca channels serve as a convergence point in the biochemical regulation of BTB permeability.The blood-brain tumor barrier (BTB), formed by brain tumor capillaries, significantly limits delivery of therapeutic drugs to brain tumors (Groothuis, 2000). During the past decade, a considerable effort has been made and various strategies have been used to deliver selectively therapeutic drugs to brain tumors and injured brain. We developed the biochemical approach to increase BTB permeability and to enhance delivery of therapeutic drugs or small-to large-sized substances to brain tumors, including contrast-enhancing agents, antitumor compounds, therapeutic proteins, and viral vectors (Inamura et al

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We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram (DSF). These results indicate that BCAL alone decreases GSH content and limits glutathione reductase (GR) activity, and these changes were enhanced by DSF pretreatment. Similar observations were recorded with DSF alone. GR activity (74.3 ± 4.0 µmol min^–1 mg^–1 tissue; p < 0.001) and GSH content (1.23 ± 0.06 µmol min^–1 g^–1 tissue; p < 0.001) was attenuated in rats subjected to synergistic effect of BCAL and DSF with a concomitant increase of GSSG (0.006 ± 0.006 µmol min^–1 g^–1 tissue; p < 0.001). Recovery of GSH/GSSG level and GR activity during reperfusion following 30 min BCAL was considerably delayed (96 h) in the BCAL and DSF group as compared to the recovery time of 24 h in the group subjected to BCAL-reperfusion alone. Perturbation of GSH/GSSG homeostasis as a result of BCAL was augmented by DSF. These findings clearly demonstrate central nervous system oxidative stress due to a BCAL-DSF synergistic effect. Based on the results obtained with this model, we conclude that DSF increases brain oxidative stress and this may be detrimental to alcoholics who might drink and develop an acetaldehyde-induced hypotension while taking DSF.

We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram (DSF). These results indicate that BCAL alone decreases GSH content and limits glutathione reductase (GR) activity, and these changes were enhanced by DSF pretreatment. Similar observations were recorded with DSF alone. GR activity (74.3 +/- 4.0 micromol min(-1) mg(-1) tissue; p < 0.001) and GSH content (1.23 +/- 0.06 micromol min(-1) g(-1) tissue; p < 0.001) was attenuated in rats subjected to synergistic effect of BCAL and DSF with a concomitant increase of GSSG (0.006 +/- 0.006 micromol min(-1) g(-1) tissue; p < 0.001). Recovery of GSH/GSSG level and GR activity during reperfusion following 30 min BCAL was considerably delayed (96 h) in the BCAL and DSF group as compared to the recovery time of 24 h in the group subjected to BCAL-reperfusion alone. Perturbation of GSH/GSSG homeostasis as a result of BCAL was augmented by DSF. These findings clearly demonstrate central nervous system oxidative stress due to a BCAL-DSF synergistic effect. Based on the results obtained with this model, we conclude that DSF increases brain oxidative stress and this may be detrimental to alcoholics who might drink and develop an acetaldehyde-induced hypotension while taking DSF.

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