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K L Black

Publications and source records attributed to K L Black.

At least 19 recordsLinked to original sources
PubMed1992

Differential expression of arachidonate 5-lipoxygenase transcripts in human brain tumors: evidence for the expression of a multitranscript family.

In addition to the important role of leukotrienes as mediators in allergy and inflammation, these compounds are also linked to pathophysiological events in the brain including cerebral ischemia, brain edema, and increased permeability of the blood-brain barrier in brain tumors. Although brain tumors have been shown to secrete leukotrienes, no studies to date have provided evidence for the tumor expression of genes encoding enzymes involved in leukotriene production. Therefore, the present study determined the abundance of the mRNA for arachidonate 5-lipoxygenase (5-LO; arachidonate:oxygen 5-oxidoreductase, EC 1.13.11.34), which is the rate-limiting enzyme in leukotriene synthesis, in a series of human brain tumors. Macrophage/monocyte infiltration of the tumor was estimated by measuring the abundance of the transcript for the 91-kDa glycoprotein phagocyte-specific oxidase (gp91-phox), which is the phagocyte-specific cytochrome b heavy chain. The present study shows that (i) the 5-LO transcript is expressed in normal bovine brain and in human brain tumors; (ii) the 5-LO gene in human brain tumors and in the dimethyl sulfoxide-induced promyelocytic human leukemic HL-60 cells is expressed as a multitranscript family (2.7, 3.1, 4.8, 6.4, 8.6 kilobases); and (iii) the abundance of 5-LO transcripts, the expression of the larger transcripts, and the 5-LO/gp91-phox ratio correlate with the tumor malignancy. Overall, the present study supports the hypothesis that the 5-LO gene product may play a role in human tumor-induced brain edemas and provides evidence for tumor-associated expression of high molecular weight 5-LO transcripts in human brain tumors.

Arachidonate 5-Lipoxygenase↗
PubMed1992

Response of microglial cells to experimental rat glioma.

The response of indigenous CNS microglia to an experimentally induced glioma has been studied in rat brain using lectin histochemistry with the Griffonia simplicifolia B4-isolectin. The study was undertaken 2 weeks after tumor cell injection when tumor size was near maximal. Reactive microglial cells formed a dense band that surrounded most of the well-circumscribed tumor mass, and extended along the corpus callosum into the contralateral cerebral hemisphere. From the periphery inward, reactive microglia extended into the tumor tissue, where large numbers of them were found to be present as microglia-derived macrophages. The lectin stain, which also labels endothelial cells, revealed a highly vascularized tumor with ongoing neovascularization apparent as vascular sprouts. Moderate numbers of lectin-stained blood monocytes were localized primarily inside the vessel lumina. Our results show that microglial cells react to brain tumors; however, it remains to be determined whether the microglial response represents an active antitumor defense mechanism that could be manipulated during immunotherapeutic approaches.

Animals↗
PubMed1992

Immunophenotypic analysis of infiltrating leukocytes and microglia in an experimental rat glioma.

The appearance and cellular distribution of major histocompatibility complex (MHC), as well as lymphocytic and macrophage antigens has been studied in a fully developed experimental rat forebrain glioma. Activated microglial cells and microglia-derived macrophages expressing CR3 complement receptor molecules and MHC class II (Ia) antigen were found throughout the tumor, and with increased density along the tumor's periphery. MHC class I antigen expression was entirely absent from tumor cells, and found only occasionally on microglia. The expression of leukocyte common antigen, and CD4 and CD8 antigens was conspicuous throughout the tumor, and associated with lymphocytes, perivascular cells, and microglia. Cells expressing the ED2 macrophage epitope were almost exclusively of the perivascular type and revealed a distribution dissimilar to that of cells positive for Ia antigen. The ED2 epitope was found sporadically on ramified microglial cells. The results show that despite heavy infiltration with blood mononuclear and CNS microglial cells, the tumor showed no evidence of destruction caused by inflammatory cells. Possible mechanisms of tumor immunosuppressive activity preventing the full immunological activation of microglia and blood mononuclear cells are discussed.

Animals↗
PubMed1992

Topographic mapping of somatosensory evoked potentials helps identify motor cortex more quickly in the operating room.

Median nerve somatosensory evoked potentials were recorded from exposed cerebral cortex during craniotomies. This technique is valuable when knowledge of the motor cortex location can influence surgical decisions about resection limits or biopsy sites. Two different recording techniques were compared: strips of electrodes and arrays of electrodes. The arrays recorded electrical potentials suitable for topographic mapping. We found that motor cortex could be identified more quickly when using the topographic mapping of SEPs from arrays. We conclude that topographic mapping of SEP from sensorimotor regions during craniotomies works well in general and can be done more quickly than the traditional electrode strip technique.

Adolescent↗
PubMed1992

Histochemical evaluation of energy metabolism in rat glioma.

The key enzymes of oxidative phosphorylation and glycolysis were evaluated histochemically in rat-implanted C6 gliomas using spot densitometry. Hexokinase, the initial enzyme for the glycolysis pathway, was 40% higher within tumour than the contralateral cerebral cortex. A similar increase within tumours for 2-deoxyglucose was observed by autoradiography. Glucose-6-phosphate dehydrogenase (G6PDH), which is the first enzyme in the pentose phosphate pathway, shunting glucose towards nucleic acid synthesis, was more than 300% higher in gliomas compared with the normal cortex. In contrast, enzymes in the energy producing tricarboxylic acid cycle (succinate-, isocitrate-, and malate-dehydrogenase) and in the electron-transport system (cytochrome c oxidase) were significantly reduced in tumour (58% less than the contralateral cortex). Lactate dehydrogenase activity, which converts pyruvate to lactate, was 50% higher within tumour. Significant reductions of enzymatic activities also occurred in non-neoplastic tissue in ipsilateral hemisphere, with larger tumours. Some enzymes showed heterogeneous activity within tumours, especially G6PDH. These results suggest that: (1) energy production is more dependent on lactate production than on oxidative phosphorylation in C6 glioma, and (2) a significant part of the increased glucose utilization in glioma cells is due to increased activity of the pentose phosphate shunt for increased DNA synthesis, and not energy production.

Animals↗
PubMed1992

Increased opening of blood-tumour barrier by leukotriene C4 is dependent on size of molecules.

Intracarotid injections of leukotriene C4 (LTC4) will increase blood-tumour barrier (BTB) permeability for 14C aminoisobutyric acid (AIB) in RG-2 tumours in rats. In this study, rats with RG-2 tumours were given 15 minute intracarotid infusions of LTC4 (5 micrograms total dose). Blood-tumour and BBB permeability were determined by quantitative autoradiography using different sized 14C tracers; AIB (103.1 daltons, radius = 2.8 A), Sucrose (342 daltons, radius = 5 A), Inulin (5000 daltons, radius = 15 A) and Dextran (70,000 daltons, radius = 60 A), respectively (n = 7 in each group). Permeability (Ki) within tumours for AIB, Sucrose and Inulin increased significantly after LTC4 infusion (92.7 +/- 15.0 vs 39.4 +/- 6.5, 47.8 +/- 5.2 vs 29.1 +/- 8.8, and 46.4 +/- 8.4 vs 26.4 +/- 4.8 microliters/gm/min, respectively, p < 0.01) (mean +/- SD). No significant change in Ki for 14C Dextran was observed. Increased permeability within tumours after LTC4 infusion is dependent on molecular size. This suggests that LTC4 opens tight junctions rather than increases vesicular transport through endothelial cells.

Aminoisobutyric Acids↗
PubMed1992

Inflammatory cell infiltrates vary in experimental primary and metastatic brain tumors.

We have studied the cellular immune response that accompanies primary and metastatic brain cancers induced experimentally in rats by inoculation of RG-2 glioma and Walker 256 (W256) carcinoma cells, respectively. The inflammatory cell infiltrates were characterized with lectin histochemistry to visualize microglial cells and macrophages and with immunohistochemistry, using a panel of monoclonal antibodies, to detect major histocompatibility complex (MHC), lymphocytic, and macrophage antigens. The metastatic tumor was composed of a loose stroma with multiple, often large, necrotic areas, whereas the RG-2 glioma was composed of a dense collection of tumor cells showing only rare necrotic foci. Both tumor types were heavily infiltrated with microglia and/or macrophages, and these were positive for MHC Class II (Ia) antigens. Expression of MHC Class I antigens was absent from RG-2 glioma cells, but it was present in W256 metastatic carcinoma cells. The metastatic tumor was also characterized by a much heavier infiltrate of lymphocytes, as shown by the presence of cells positive for CD4, CD8, and leukocyte common antigens. These lymphocytic markers were absent from reactive microglia in the W256 carcinoma, whereas they were present in the RG-2 glioma. Polymorphonuclear leukocytes were seen only in the metastatic tumor. Our study delineates differences between the inflammatory cell infiltrates found in metastatic brain tumors and those found in primary brain tumors. The differences in cell composition and immunophenotype may indicate a more effective antitumor response in the metastatic tumor that could account for the observed tissue destruction.

Animals↗
PubMed1992

Inflammatory leukocytes associated with increased immunosuppression by glioblastoma.

In order to determine the in vivo immune response in glioblastoma, monoclonal and polyclonal antibodies specific for inflammatory leukocytes and immunoregulatory products were utilized to stain tissue from four surgical specimens. The more activated the inflammatory cells, the more activated the tumors appeared to be. In the tumor with the largest infiltration (Case 3), inflammatory cells were stained for interferon-gamma, interleukin-2, interleukin-1 beta, lymphotoxin, tumor necrosis factor-alpha, and transforming growth factor-beta. The tumor cells also expressed interleukin-1 beta, interleukin-6, transforming growth factor-beta, tumor necrosis factor-alpha, and prostaglandin E. In contrast, in the tumor with the least inflammatory response (Case 1), the tumor cells did not express any cytokines. Expression of cytokines by glioma cells was modest in the two cases with modest inflammatory responses. Cellular inflammation, primarily consisting of T cells and macrophages with few or no B cells or natural killer cells, was two- to 15-fold greater outside the tumor than within. In contrast to leukocytes outside the tumor, which were activated and expressing class II major histocompatibility antigens, leukocytes within the tumor parenchyma or at the tumor's edge were negative for these antigens. In the four specimens studied here, the tumor cells themselves were also negative for class II major histocompatibility antigens. These findings, although preliminary, suggest that inflammatory cells within gliomas are inactivated and that glioma cells may increase the expression of immunosuppressive cytokines in response to an increased lymphocyte infiltrate. This observation, if corroborated by more extensive studies, may help to explain the failure of immune treatments in glioblastoma multiforme.

Adult↗
PubMed1992

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.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1992

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).

Analysis of Variance↗
PubMed1992

Blood-brain barrier and new approaches to brain drug delivery.

Morbidity caused by brain dysfunction affects more than 50 million persons in the United States. Although new neuropharmaceuticals have the potential for treating specific brain diseases, they may not effectively enter brain from blood. Safe strategies are needed for drug delivery through the brain capillary wall, which makes up the blood-brain barrier in vivo. Two of these strategies are reviewed, as are related new developments in the molecular and cell biology of the brain capillary endothelium. The production of chimeric peptides represents a physiologic-based strategy for drug delivery. It entails the covalent coupling of the neuropharmaceutical to a brain transport vector, allowing transportation through the blood-brain barrier. Another strategy is biochemical opening of the blood-brain barrier: intracarotid leukotriene infusion is a method for selectively increasing blood-brain barrier permeability in brain tumors without affecting barrier permeability in normal brain tissue.

Animals↗
PubMed1991

Peripheral benzodiazepine induces morphological changes and proliferation of mitochondria in glioma cells.

Peripheral benzodiazepine (PBD) receptors are localized on the mitochondrial membrane and are highly expressed in brain tumors compared to normal brain. To elucidate the biological role of the PBD receptor on mitochondria, we examined the effect of PBDs on mitochondrial morphology in C6 and T98G glioma cells using rhodamine 123 and quantitative electron microscopy. In cells incubated in serum-free medium alone, mitochondria were distributed in a filamentous pattern throughout the cytoplasm. By contrast, the mitochondria aggregated in the perinuclear region in PK11195 or Ro5-4864 (10 nM) treated cells. Quantitative electron micrography revealed a 250% increased in the number of mitochondria with elongated cristae and a fivefold increase in dividing mitochondria in PK11195-treated cells compared with cells incubated in serum-free medium alone. PBD treatment also resulted in vacuolation within the matrix and mitochondrial swelling. These data suggest that PBDs influence mitochondrial morphology and induce mitochondrial replication in cultured glioma cells.

Animals↗
PubMed1991

Intracarotid infusion of leukotriene C4 selectively increases blood-brain barrier permeability after focal ischemia in rats.

Intracarotid infusions of leukotriene C4 (LTC4) were used to open selectively the blood-brain barrier (BBB) in ischemic tissue after middle cerebral artery (MCA) occlusion in rats. BBB permeability was determined by quantitative autoradiography using [14C]aminoisobutyric acid. Seventy-two hours after MCA occlusion, LTC4 (4 micrograms total dose) infused into the carotid artery ipsilateral to the MCA occlusion selectively increased the unidirectional transfer constant for permeability Ki approximately threefold within core ischemic tissue and tissue adjacent ot the ischemic core. No effect on BBB permeability was seen within nonischemic brain tissue or in ischemic tissue after only 24 h after MCA occlusion. gamma-Glutamyl transpeptidase (gamma-GTP) activity was decreased in capillaries in ischemic tissue at 48 and 72 h after infarction, compared to high gamma-GTP in normal brain capillaries and moderate gamma-GTP in capillaries in the ischemic tissue at 24 h after infarction. These findings suggest that normal brain capillaries resist the vasogenic effects of LTC4. In contrast, LTC4 increases permeability in capillaries of ischemic tissue, where gamma-GTP is decreased. gamma-Glutamyl transpeptidase, an enzyme that inactivates LTC4 to LTD4 and LTE4 to LTF4, may act as an "enzymatic barrier" in normal brain capillaries to leukotrienes.

Animals↗
PubMed1991

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.

Animals↗
PubMed1991

Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas.

Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent, BCNU (carmustine), has considerable systemic toxicity and a short half-life in serum. To obviate these problems, a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I-II study, 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively, upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks. Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself. The average survival period after reoperation was 65 weeks for the first dose group, 64 weeks for the second dose group, and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology, blood chemistry, and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy. Since the therapy is well tolerated and safe, a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.

Brain Neoplasms↗
PubMed1991

Brain tumors.

Recent advances in experimental tumor biology are being applied to critical clinical problems of primary brain tumors. The expression of peripheral benzodiazepine receptors, which are sparse in normal brain, is increased as much as 20-fold in brain tumors. Experimental studies show promise in using labeled ligands to these receptors to identify the outer margins of malignant brain tumors. Whereas positron emission tomography has improved the dynamic understanding of tumors, the labeled selective tumor receptors with positron emitters will enhance the ability to specifically diagnose and greatly aid in the pretreatment planning for tumors. Modulation of these receptors will also affect tumor growth and metabolism. Novel methods to deliver antitumor agents to the brain and new approaches using biologic response modifiers also hold promise to further improve the management of brain tumors.

Brain Chemistry↗
PubMed1990

Specific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumors in rat and man.

Two types of benzodiazepine receptors have been identified in mammalian tissues: a central type which is localized to neuronal elements in the brain, and a peripheral type which is present on glial cells and in tissues outside the central nervous system such as kidney. The authors report an increase in specific binding of peripheral benzodiazepine receptor ligands in certain human brain tumors using computer assisted quantitative image analysis of autoradiograms. Higher densities of binding sites to a 3H-labeled selective peripheral benzodiazepine ligand, PK11195 [1-(2-chlorophenyl-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] were observed in human gliomas as the malignancy of these tumors increased. Specific binding was also present in some non-glial tumors but little binding was demonstrated in necrotic tissue or normal brain. In in vitro binding studies in rats, there was a significant increase in Bmax (1089.3 +/- 232.2 fmol/mg tissue) in C6 glial tumors and LK Walker 256 metastatic tumors (924.2 +/- 183.7) compared with normal brain (62.1 +/- 12.8 fmol/mg tissue). Binding affinities were, however, similar (Kd = 2.09, 2.17, and 2.04 nmol/l, respectively). These findings suggest that the number of peripheral benzodiazepine receptors are increased in brain tumors. These receptors could be utilized in positron emission tomography to image brain tumors.

Animals↗