Blood-tumor Barrier Permeability Research Articles

Blood-Brain Barrier Disruption by Low-Frequency Ultrasound

HomeStrokeVol. 38, No. 2Blood-Brain Barrier Disruption by Low-Frequency Ultrasound Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBBlood-Brain Barrier Disruption by Low-Frequency Ultrasound Tibo Gerriets, MD and Maureen Walberer, DVM Max Nedelmann, MD Georg Bachmann, MD Manfred Kaps, MD Tibo GerrietsTibo Gerriets Department of Neurology, Justus Liebig University Giessen, Giessen, Germany, Kerckhoff-Clinic Bad Nauheim, Experimental Neurology Research Group, Bad Nauheim, Germany Search for more papers by this author and Maureen WalbererMaureen Walberer Department of Neurology, Justus Liebig University Giessen, Giessen, Germany, Kerckhoff-Clinic Bad Nauheim, Experimental Neurology Research Group, Bad Nauheim, Germany Search for more papers by this author Max NedelmannMax Nedelmann Department of Neurology, Johannes Gutenberg-University Mainz, Mainz, Germany Search for more papers by this author Georg BachmannGeorg Bachmann Department of Radiology, Kerckhoff-Clinic Bad Nauheim, Experimental Neurology Research Group, Bad Nauheim, Germany Search for more papers by this author Manfred KapsManfred Kaps Department of Neurology, Justus Liebig University Giessen, Giessen, Germany Search for more papers by this author Originally published14 Dec 2006https://doi.org/10.1161/01.STR.0000254444.19772.33Stroke. 2007;38:251Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 14, 2006: Previous Version 1 To the Editor:Dr Reinhard and coworkers report a case of cerebral gadolinium extravasation after 300 kHz ultrasound “treatment” using the same device that has been applied in the Transcranial Low-Frequency Ultrasound Mediated Thrombolysis in Brain Ischemia Study (TRUMBI) trial.1,2 This interesting observation improves our understanding of the underlying pathophysiology of the hemorrhagic complications that occurred in stroke patients during the TRUMBI study. The assumption that low-frequency ultrasound might cause blood-brain barrier disruptions and thus increase the risk of intracerebral hemorrhage—particularly in the presence of recombinant tissue plasminogen activator—appears convincing and is corroborated by our rat experiments using 20 kHz ultrasound.3 In this MRI study, low-frequency insonation caused a dose-dependant increase in T2-relaxation time which serves as an indicator for vasogenic brain edema and thus indicates blood-brain barrier disruption. Increased ultrasound energy, furthermore, caused circumscript cortical hemorrhagic lesions that appeared like traumatic cerebral contusions histologically. These findings suggest that mechanical ultrasound effects might be responsible for blood-brain barrier disruptions and bleeding complications. Because mechanical effects decrease with higher frequencies, we would recommend the use of ultrasound frequencies in the upper kHz range (ie, >300 kHz) for treatment purposes. Extensive preclinical evaluation of new devices, however, is obligatory.DisclosuresNone.1 Reinhard M, Hetzel A, Kruger S, Kretzer S, Talazko J, Ziyeh S, Weber J, Els T. Blood-brain barrier disruption by low-frequency ultrasound. Stroke. 2006; 37: 1546–1548.LinkGoogle Scholar2 Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, Sedlaczek O, Koroshetz WJ, Hennerici MG. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke. 2005; 36: 1441–1446.LinkGoogle Scholar3 Schneider F, Gerriets T, Walberer M, Mueller C, Rolke R, Eicke BM, Bohl J, Kempski O, Kaps M, Bachmann G, Dieterich M, Nedelmann M. Brain edema and intracerebral necrosis caused by transcranial low-frequency 20-kHz ultrasound: a safety study in rats. Stroke. 2006; 37: 1301–1306.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Teng Y, Jin H, Nan D, Li M, Fan C, Liu Y, Lv P, Cui W, Sun Y, Hao H, Qu X, Yang Z and Huang Y (2018) In vivo evaluation of urokinase-loaded hollow nanogels for sonothrombolysis on suture embolization-induced acute ischemic stroke rat model, Bioactive Materials, 10.1016/j.bioactmat.2017.08.001, 3:1, (102-109), Online publication date: 1-Mar-2018. Fan L, Liu Y, Ying H, Xue Y, Zhang Z, Wang P, Liu L and Zhang H (2010) Increasing of Blood-tumor Barrier Permeability through Paracellular Pathway by Low-frequency Ultrasound Irradiation In Vitro, Journal of Molecular Neuroscience, 10.1007/s12031-010-9479-x, 43:3, (541-548), Online publication date: 1-Mar-2011. Kyle A (2010) Correlation of acoustic pressure with BBB disruption 2010 39th Annual Ultrasonic Industry Association Symposium (UIA), 10.1109/UIA.2010.5506063, 978-1-4244-7947-4, (1-3) Nedelmann M, Gerriets T and Kaps M (2008) Therapeutische Ultraschallbehandlung des akuten HirnarterienverschlussesTherapeutic ultrasound of acute cerebral artery occlusion, Der Nervenarzt, 10.1007/s00115-008-2550-y, 79:12, (1399-1406), Online publication date: 1-Dec-2008. Nedelmann M, Reuter P, Walberer M, Sommer C, Alessandri B, Schiel D, Ritschel N, Kempski O, Kaps M, Mueller C, Bachmann G and Gerriets T (2008) Detrimental Effects of 60 kHz Sonothrombolysis in Rats with Middle Cerebral Artery Occlusion, Ultrasound in Medicine & Biology, 10.1016/j.ultrasmedbio.2008.06.003, 34:12, (2019-2027), Online publication date: 1-Dec-2008. February 2007Vol 38, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/01.STR.0000254444.19772.33PMID: 17170362 Originally publishedDecember 14, 2006 PDF download Advertisement

Enhancement of blood-tumor barrier permeability by Sar-[D-Phe8]des-Arg9BK, a metabolically resistant bradykinin B1 agonist, in a rat C6 glioma model.

BackgroundWhile it is well known that bradykinin B2 agonists increase plasma protein extravasation (PPE) in brain tumors, the bradykinin B1 agonists tested thus far are unable to produce this effect. Here we examine the effect of the selective B1 agonist bradykinin (BK) Sar-[D-Phe8]des-Arg9BK (SAR), a compound resistant to enzymatic degradation with prolonged activity on PPE in the blood circulation in the C6 rat glioma model.ResultsSAR administration significantly enhanced PPE in C6 rat brain glioma compared to saline or BK (p < 0.01). Pre-administration of the bradykinin B1 antagonist [Leu8]-des-Arg (100 nmol/Kg) blocked the SAR-induced PPE in the tumor area.ConclusionsOur data suggest that the B1 receptor modulates PPE in the blood tumor barrier of C6 glioma. A possible role for the use of SAR in the chemotherapy of gliomas deserves further study.

Increased endothelial vesicular transport correlates with increased blood-tumor barrier permeability induced by bradykinin and leukotriene C4.

Bradykinin and leukotriene C4 (LTC4) have been shown to increase molecular transport across the blood-tumor barrier (BTB). The aim of this study was to quantitatively assess whether an increase in vesicular transport or opening of tight junctions was responsible for this increase in permeability. Wistar rats bearing RG2 or C6 gliomas were infused with bradykinin or LTC4 through the right carotid artery for 15 min and then perfused to achieve fixation. Prepared specimens were observed using transmission electron microscopy. Infusion of either bradykinin or LTC4 resulted in significantly increased vesicular density in capillary endothelial cells of the BTB but not in normal brain capillaries. The opening of tight junctions, assessed by determining a cleft index, was found to be greater in tumor capillaries compared to normal controls. However, neither bradykinin nor LTC4 produce variations in the cleft index. A significant accumulation of horseradish peroxidase was seen in the intercellular peri-capillary spaces and in endothelial transport vesicles after infusion of bradykinin, demonstrating that the formation of vesicles was associated with macromolecular transcytosis. These findings suggest that pinocytotic vesicular transport is the primary means by which luminal to abluminal transport occurs in response to vasomodulation with bradykinin or LTC4.

Repeated, short-term ischemia augments bradykinin-mediated opening of the blood–tumor barrier in rats with RG2 glioma

The objective of this study was to investigate the effects of repeated, short-term ischemia on bradykininmediated permeability of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB). The mechanism by which bradykinin transiently opens the BTB, involves B2 receptors, Ca2+ flux, nitric oxide (NO) and cyclic GMP (cGMP). Since global and focal cerebral ischemia are known to increase levels of brain nitric oxide synthase (bNOS) and endothelial nitric oxide synthase (eNOS) we tested the hypothesis that bradykinin may increase the BTB permeability to a greater extent under ischemic rather than nonischemic conditions. The vertebral arteries in female Wistar rats were coagulated immediately after intracerebral implantation of RG2 glioma. Short-term ischemia was produced in some rats by a modification of the fourvessel occlusion procedure for incomplete forebrain ischemia, in which the common carotid arteries were clamped daily for 15 min on days 7, 8 and 9 after tumor implantation, after which reperfusion was allowed. On day 10 after tumor implantation, bradykinin (10 µg kg-1 min-1) or phosphate-buffered saline (PBS) was infused for 15 min into the right carotid artery of anesthetized, sham-operated (nonischemic controls) and ischemic rats, followed by an intravenous bolus (100 µCi kg-1) each of [14C]-iodo-antipyrine (IAP), [14C]dextran or [14C]-aminoisobutyric acid (AIB) to measure regional cerebral blood flow (rCBF), blood volume, or unidirectional transfer constant Ki, respectively, by quantitative autoradiography. A single 15-min ischemic episode significantly decreased rCBF in the tumor center (158.9 ± 17.33 in control vs. 58.78 ± 24.45 ml 100 g-1 min-1 in ischemic group; p < 0.01) and in the tumor periphery (106.82 ± 7.34 in control vs. 70.55 ± 26.66 ml 100 g-1 min-1 in ischemic group; p < 0.05). Respective mean blood volume in tumors (11.7 ± 13.3, 12.7 ± 14.0, and 13.3 ± 14.5 µlg-1) from ischemic-PBS, nonischemic-bradykinin, and ischemic-bradykinin groups, respectively, was not significantly different; mean blood volume in normal brain (3.7, 3.1 and 3.8 µlg-1) was not significantly different among these groups either. Intracarotid infusion of bradykinin following repeated ischemia significantly increased mean Ki, as compared to bradykinin infusion in nonischemic controls, in both the tumor center (36.60 ± 8.4 vs. 22.90 ± 4.61 µlg-1 min-1, p < 0.05) and in tumor periphery (17.70 ± 5.93 vs. 8.50 ± 4.42 µlg-1 min-1, p < 0.05). Mean Ki values for tumor center and tumor periphery of ischemic rats receiving intracarotid bradykinin were 3-fold greater than those of nonischemic rats infused with PBS. Immunohistochemical and Western blot analyses showed that repeated, short-term ischemia significantly increased the levels of bNOS in tumor cells and eNOS in tumor capillaries, but neither induced iNOS nor affected B2 receptor levels in tumor cells in vivo, as compared with nonischemic controls. Taken together, these results demonstrate for the first time that repeated, short-term ischemia augments bradykinin-mediated opening of the BTB. We conclude that the elevated intratumoral levels of bNOS and eNOS may 'prime' the NO generating capacity of tumor cells. Consequently, increased de novo synthesis and a correspondingly elevated concentration of NO within the tumor, therefore, may be one mechanistic explanation for the significantly increased, bradykinin-mediated BTB opening under ischemic conditions, reported here. [Neurol Res 2001; 23: 631-640]

Correlation between bradykinin-induced blood–tumor barrier permeability and B2 receptor expression in experimental brain tumors

Localization of B2 receptors in brain tumor cells and microvessel endothelial cells of the brain tumors was investigated to study the differential sensitivity of brain tumors to bradykinin. The present study shows that B2 receptor expression levels vary in cultured RG2, C6 and 9L glioma cells as well as in the intracerebral tumors established with these cell lines in rats. The double immunohistochemical data indicate that B2 receptors are localized to tumor cells and not to the tumor capillaries. Immunostaining and Western blot analysis for B2 receptor showed that the B2 receptor expression was in the order C6>RG2>9L. The permeability studies on RG2, C6 and 9L tumors in rats showed that C6 tumor had the highest increase (178%) in Ki (unidirectional transport across blood–brain barrier (BBB)/blood–tumor barrier (BTB)), while 9L tumor had the least increase of Ki (35%) over the control group, following intracarotid infusion of bradykinin. We found a positive correlation (r = 0.965, p<0.001) between B2 receptor levels and bradykinin-induced increase in BTB permeability. We conclude that B2 receptors are localized to tumor cells and not to normal or tumor capillary endothelial cells. C6 tumor with highest B2 receptor expression was most responsive to bradykinin, while RG2 and 9L tumors with lower B2 receptor expression level were less sensitive to bradykinin with regard to BTB permeability.

Scatter factor/hepatocyte growth factor gene transfer increases rat blood–glioma barrier permeability

Malignant gliomas are associated with a dysfunctional blood–tumor barrier (BTB) that causes substantial morbidity. Scatter factor/hepatocyte growth factor (SF/HGF) is a multifunctional growth factor that correlates with glioma malignancy and has several biological properties that suggest a role in enhancing blood–glioma barrier permeability. In this study, we examined the effects of glioma cell SF/HGF expression on BTB permeability to horseradish peroxidase (HRP). Fischer 344 rats bearing intrastriatal 9L tumors engineered to secrete SF/HGF (9L-SF) and SF/HGF-negative control tumors (9L-neo) received intracardiac injections of HRP and were rapidly decapitated. Densitometric analysis of brain sections reacted with diaminobenzidine showed significantly greater extravascular HRP surrounding SF/HGF-secreting tumors than 9L-neo tumors of comparable size ( p<0.05). HRP enzymatic activity associated with striata containing SF/HGF-expressing tumors was 1.6-fold greater than that of striata containing control tumors ( p<0.05). Northern analysis showed that expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) did not differ between 9L-neo and 9L-SF tumors. These data demonstrate that SF/HGF expression by intracerebral glial tumors can enhance BTB permeability independent of changes in VEGF/VPF expression.

Early changes measured by magnetic resonance imaging in cerebral blood flow, blood volume, and blood-brain barrier permeability following dexamethasone treatment in patients with brain tumors.

In this study the authors assessed the early changes in brain tumor physiology associated with glucocorticoid administration. Glucocorticoids have a dramatic effect on symptoms in patients with brain tumors over a time scale ranging from minutes to a few hours. Previous studies have indicated that glucocorticoids may act either by decreasing cerebral blood volume (CBV) or blood-tumor barrier (BTB) permeability and thereby the degree of vasogenic edema. Using magnetic resonance (MR) imaging, the authors examined the acute changes in CBV, cerebral blood flow (CBF), and BTB permeability to gadolinium-diethylenetriamine pentaacetic acid after administration of dexamethasone in six patients with brain tumors. In patients with acute decreases in BTB permeability after dexamethasone administration, changes in the degree of edema were assessed using the apparent diffusion coefficient of water. Dexamethasone was found to cause a dramatic decrease in BTB permeability and regional CBV but no significant changes in CBF or the degree of edema. The authors found that MR imaging provides a powerful tool for investigating the pathophysiological changes associated with the clinical effects of glucocorticoids.

Nitric oxide and cyclic GMP attenuate sensitivity of the blood-tumor barrier permeability to bradykinin

Intracarotid infusion of bradykinin and its analogue, RMP-7, selectively increase the permeability of brain tumor capillaries though the nitrix oxide (NO) and cyclic GMP pathway. Maximum blood-tumor barrier (BTB) permeability induced by bradykinin is observed at 75 min after intracarotid infusion and this effect is decreased even if the infusion continues. The mechanism for this decreased effect with long term infusion has not been clearly defined. This study sought to determine the involvement of the NO-cyclic GMP pathway in this event. Regional permeability was investigated in 44 Wistar rats with implanted RG2 gliomas, usinq quantitative autoradiography to determine the unidirectional transfer constant (Ki) of radiolabeled 14C-dextran. Tumor bearing rats were treated by intracarotid infusion of bradykinin (70 p.g kg-1 min-1) with or without pretreatment with bradykinin, the NO donor s-nitrosoglutathione (70nmolkg-1 min-1), or the cyclic GMP analogue, BBr-cyclic GMP (200µgkg-1 min-1). At 30min of bradykinin infusion, BTB permeability was significantly lower compared to 75 min of bradykinin infusion (3.79± 0.99 vs. 76.20± 3.43µ1 g-1 min-1, p<0.00l). Pretreatment with an NO donor significantly decreased BTB permeability in bradykinin infused rats (5.09±2.61 vs. 13.57±4.79µlg-1 min-1, p<0.00l), as did pretreatment with a cyclic GMP analogue (4.4B±0.95 vs. 12.31±3.90µlg-1 min-1, p<0.00l). There was no increased permeability in nontumor brain areas. Increased tumor permeability by bradykinin appears to be regulated by NO and cyclic GMP which are second messengers involved in the bradykinin B2 receptor mediated cascade. [Neural Res 1998; 20: 559-563]

Leukotriene E4 selectively increase the delivery of methotrexate to the C6 gliomas in rats

Leukotriene E4 (LTE4) infused into the carotid artery ipsilateral to an experimental glial tumor will selectively increase the blood-tumor permeability within the tumor. In this study the effects of intracarotid infusion of LTE4 on blood-tumor barrier (BTB) permeability for intravenously administered 14C-aminoisobutyric acid, 14C-5-fluorouracil (5-FU) 14C-sucrose and 3H-methotrexate (MTX) were examined in C6 gliomas of rats. The intracarotic administration of LTE4 selectively opened the BTB, without affecting permeability of normal brain tissue, to all of the above tracers. Intracarotid infusion of LTE4 had the tendency to increase the uptake of intravenously administered 5-FU within the tumor, but this effect was not statistically significant. The intracarotid infusion of LTE4, however, increased the uptake of intravenously injected MTX about twofolds within the tumor (Ki = 19.48 +/- 1.06 vs 10.12 +/- 1.19, p < 0.01) without increasing the uptake in the normal brain tissue.

Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors

This study investigated the effects of bradykinin on blood-tumor barrier (BTB) permeability in transplanted 9L gliosarcomas (9L) and C6 gliomas (C6) in rats. Permeability, expressed as the unidirectional transfer constant, Ki μl/g/min), was measured by quantitative autoradiography. Tracers used to examined permeability included radiolabeled α-aminoisobutyric acid ([14C]AIB), sucrose ([14C]sucrose) and dextran ([14C]dextran). Intracarotid infusion of bradykinin (10 mg/kg/min) significantly increased the BTB permeability in both 9L and C6 tumors to [14C]AIB and [14C]sucrose, but did not increase permeability to [14C]dextran. Blood-brain barrier (BBB) permeability in normal (non-tumor) brain was not significantly increased to any of the tracers by intracarotid bradykinin infusion. Ki values for [14C]AIB, [14C]sucrose and [14C]dextran of 9L tumors in the bradykinin group versus control group were 14.6 ± 12.6vs.24.8 ± 6.30 (P < 0.02), 17.5 ± 9.34vs.9.05 ± 4.36 (P < 0.05), and 3.90 ± 2.59 vs. 2.42 ± 1.76,respectively (mean±S.D.. Ki values to [14C]AIB, [14C]sucrose and [14C]dextran of 6C tumors in the bradykinin group versus control group were 41.4 ± 19.0vs.19.5 ± 11.4 (P < 0.01) 18.0 ± 8.88vs.7.06 ± 3.05 (P < 0.01), and 4.07 ± 1.45 vs. 2.27 ± 1.26, respectively (mean±S.D.). Intracarotid infusion of bradykinin did not significantly increase the blood volume in tumor or brain tissue despite its known vasodilative effect. Intracarotid infusion of bradykinin may be a useful technique for selective delivery of compounds to brain tumors.

Selective increase in blood-tumor barrier permeability by calcium antagonists in transplanted rat brain tumors.

To clarify the altered response of calcium antagonists on pathological vessels, we investigated the effect of intracarotid infusion of nifedipine on the blood-brain barrier (BBB) permeability using a rat glioma model. Animals were treated with 0, 0.1, 1, 5, and 10 micrograms/kg/min of intracarotid continuous infusion of nifedipine. 2% Evans blue (EB, 2 ml/kg) was injected intravenously immediately after nifedipine infusion. BBB and blood-tumor barrier (BTB) permeability were evaluated by direct visual and histological observation. During the entire experiment, systemic parameters such as arterial blood pressure and blood analysis were not changed significantly. There was a dose-dependent increase of EB permeability selectively in the tumor tissue without affecting the normal brain. These results indicate that tumor vessels may show an altered response to calcium antagonists. Intracarotid administration of calcium antagonists contribute to a selective enhancement of drug delivery to malignant brain tumors without affecting the normal brain.

Targeting anticancer drugs to the brain: II. Physiological pharmacokinetic model of oxantrazole following intraarterial administration to rat glioma-2 (RG-2) bearing rats.

The disposition of the anticancer drug oxantrazole (OX) was characterized in rats bearing the rat glioma-2 (RG-2) brain tumor. Following intraarterial administration of 3 mg/kg of OX, serial sacrifices were completed from 5 min to 5 hr after administration. Blood and tissue samples collected at the time of sacrifice were processed and measured for OX concentrations by HPLC. The kidney had the greatest affinity for OX with the Cmax being 40.6 micrograms/ml at 15 min after administration. OX concentrations in brain tumor were higher than in normal right and left brain hemispheres, and consistent with enhanced drug blood-tumor barrier (BTB) permeability seen in experimental models for brain tumors. Observed heart, liver, lung, and spleen OX concentrations were similar, ranging from approximately 2 micrograms/ml to 20 micrograms/ml. A unique technique was used to develop a global physiological pharmacokinetic model for OX. A hybrid or forcing function method was used to estimate individual tissue compartment biochemical parameters (i.e., partition and mass transfer coefficients). A log likelihood optimization scheme was used to determine the best model structure and parameter sets for each tissue. Most tissues required a 3-subcompartment structure to adequately describe the observed data. The global model was then reconstructed with an arterial blood and rest of body compartments that provided predicted OX concentrations in agreement with the data. The model development strategy provides a systematic approach to physiological pharmacokinetic model development.

Selective blood-tumor barrier disruption by leukotrienes.

The authors have previously reported that intracarotid infusion of 5 micrograms leukotriene C4 (LTC4) selectively increases blood-tumor barrier permeability in rat RG-2 tumors. In this study, rats harboring RG-2 tumors were given 15-minute intracarotid infusions of LTC4 at concentrations ranging from 0.5 microgram to 50.0 micrograms (seven rats in each dose group). Blood-tumor and blood-brain barrier permeability were determined by quantitative autoradiography using 14C aminoisobutyric acid. The transfer constant for permeability (Ki) within the tumors was increased twofold by LTC4 doses of 2.5, 5.0, and 50.0 micrograms compared to vehicle alone (90.00 +/- 21.14, 92.68 +/- 15.04, and 80.17 +/- 16.15 vs. 39.37 +/- 6.45 microliters/gm/min, respectively; mean +/- standard deviation; p less than 0.01). No significant change in Ki within the tumors was observed at the 0.5-microgram LTC4 dose. Blood-brain barrier permeability was selectively increased within the tumors. At no dose in this study did leukotrienes increase permeability within normal brain. To determine the duration of increased opening of the blood-tumor barrier by LTC4 administration, Ki was measured at 15, 30, and 60 minutes after termination of a 15-minute LTC4 infusion (seven rats at each time point). The mean Ki value was still high at 15 minutes (92.68 +/- 15.04 microliters/gm/min), but declined at 30 minutes (56.58 +/- 12.50 microliters/gm/min) and 60 minutes (55.40 +/- 8.10 microliters/gm/min) after the end of LTC4 infusion. Sulfidopeptide leukotrienes LTC4, LTD4, LTE4 and LTF4 were infused to compare their potency in opening the blood-tumor barrier. The mean leukotriene E4 was the most potent, increasing the permeability value 3 1/2-fold compared with vehicle alone (139.86 +/- 23.95 vs. 39.37 +/- 6.45 microliters/gm/min).

The effect of 5-lipoxygenase inhibition on blood-brain barrier permeability in experimental brain tumors.

To determine if leukotrienes are important mediators of vascular permeability in brain tumors, the effect of 5-lipoxygenase inhibitors on blood-tumor barrier permeability in rats harboring HK Walker 256 brain tumors was examined using quantitative autoradiography with alpha-14C-aminoisobutyric acid. The 5-lipoxygenase enzyme converts arachidonic acid to leukotrienes. Three 5-lipoxygenase inhibitors were utilized: BW755C, nordihydroguaiaretic acid, and AA-861. All three 5-lipoxygenase inhibitors significantly decreased vascular permeability both within the tumors and in brain adjacent to tumor. This suggests that capillary permeability in and adjacent to tumors is influenced by endogenous leukotrienes and that leukotrienes play an important role in brain tumor edema.

Tumor-associated neurological dysfunction prevented by lazaroids in rats

The efficacy of U-74006F and U-78517F in the treatment of blood-tumor barrier permeability and tumor-associated neurological dysfunction was evaluated in a brain-tumor model in rats. U-74006F is a 21-aminosteroid and U-78517F is a 2-methylamino chroman. Rats with stereotactically implanted Walker 256 tumors were treated with methylprednisolone, U-74006F, U-78517F, or vehicle (0.05 N HCl) on Days 6 through 10 following implantation. Neurological function and vascular permeability were assessed on Day 10. Methylprednisolone and U-74006F were equally effective at preventing neurological dysfunction compared to the control group (p less than 0.01); U-78517F was slightly less effective than U-74006F and methylprednisolone but was significantly better than vehicle in preventing neurological dysfunction. Delivery of methylprednisolone resulted in a significant decrease in tumor vascular permeability (p less than 0.006) while U-74006F and U-78517F had no effect on permeability. This suggests that U-74006F and U-78517F prevented tumor-associated neurological dysfunction by a mechanism other than decreasing permeability in tumor capillaries, and that U-74006F or U-78517F could prove useful in the treatment of brain tumors.