Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Specific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumors in rat and man. 215 52

The effects of peripheral benzodiazepine receptor ligands on cell proliferation were evaluated. PK11195 increased the growth rate of C6 glioma cells by 20-30% in the nanomolar range in serum free medium. [3H]thymidine incorporation into C6 glioma cells also were increased 22% and 25% after treatment by PK11195 and Ro5-4864, respectively. The effect of PK11195 as a mitogenic agent was estimated by mitogenic agent was estimated by [3H]thymidine incorporation using Swiss 3T3 cells. PK11195 increased DNA synthesis 170% over control at 10 nM. Higher concentrations of benzodiazepines showed inhibition of the DNA synthesis. Peripheral benzodiazepine binding sites underwent downregulation after exposure to serum free medium or to 10 nM PK11195. These findings suggest that peripheral benzodiazepines may be involved in the regulation of cell proliferation as a growth factor in lower concentration and as a antiproliferative agent in higher concentration.
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PMID:Stimulation of cell growth and DNA synthesis by peripheral benzodiazepine. 215 58

Peripheral benzodiazepine binding constants for transplanted RG-2 gliomas and HD and LK Walker 256 tumors (metastatic breast carcinoma) were determined in Wistar rats using autoradiography. In addition, Kd and Bmax parameters for peripheral benzodiazepine receptors on RG-2 tumors were directly visualized using digital image analysis of autoradiograms. High specific binding of [3H]PK11195, a selective peripheral benzodiazepine ligand, had excellent topographical correlation to areas of histologically verified tumor. Scatchard analysis suggested a single class of peripheral binding sites with similar binding affinities in RG-2 and LK Walker 256 tumors and normal cortex. Bmax was 20-fold greater in glial tumors and 11.6- and 10.6-fold greater in LK and HK Walker 256 tumors, respectively, compared to normal cortex. The location of metastatic tumors, either intracerebrally or subcutaneously, did not effect their Kd or Bmax values. Kd and Bmax values for RG-2 tumors were similar whether determined densitometrically or by direct visualization with image analysis. Binding parameters within normal brain were difficult to visualize by image analysis due to the low level of specific binding. The ability to label specifically intracerebral tumor cells and to characterize the binding parameters shown in this study suggest that peripheral benzodiazepine receptor ligands could be utilized by PET to analyze directly a variety of tumors in humans.
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PMID:Imaging peripheral benzodiazepine receptors in brain tumors in rats: in vitro binding characteristics. 216 15

Experiments were undertaken to determine the in vivo utility of the mixed benzodiazepine ligand [3H]flunitrazepam and the selective peripheral benzodiazepine ligand [3H]PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] to outline the borders of rat C6 glial tumors in three dimensions. Intravenous injection of [3H]flunitrazepam resulted in a tumor/cortex ratio of radioactive densities between 2.7 and 1.5 within the first 60 minutes after injection. [3H]PK 11195 demonstrated a higher tumor/cortex ratio (5.3) than [3H]flunitrazepam. For three-dimensional studies, images were generated from thionin-stained histological sections and autoradiograms. The mixed type benzodiazepine ligand [3H]flunitrazepam was superior in showing some of the normal anatomical structures surrounding the tumor, whereas [3H]PK 11195, a specific peripheral ligand, demonstrated higher tumor/brain contrast and superior topographical correlation between histological and autoradiographic images. Implications of peripheral benzodiazepine receptor ligands for positron emission tomography are discussed.
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PMID:Three-dimensional comparison of peripheral benzodiazepine binding and histological findings in rat brain tumor. 216 76

Glioma C6 cells were incubated with [14C]arachidonate to label membrane phospholipids. Muscimol, a selective gamma-aminobutyric acid A receptor agonist, but not (-)-baclofen, a selective gamma-aminobutyric acid B receptor agonist, stimulates [14C]arachidonate release from C6 cells as a result of hydrolysis of a small pool of phosphatidylcholine and phosphatidylethanolamine by phospholipase A2. This release is facilitated by diazepam and a number of other benzodiazepines such as flunitrazepam, medazepam and midazolam (but very little by clonazepam), although these benzodiazepines per se are inactive in causing the release. In addition to increasing the release of [14C]arachidonate, diazepam in the presence of muscimol promotes the release of [14C] prostaglandin D2. Bicuculline inhibits the action of muscimol and facilitation by diazepam. "Peripheral" benzodiazepine ligand, RO 5-4864 (4'-chlordiazepam) antagonizes the action of diazepam, whereas "central" ligand, RO 15-1788, is inactive. The release of arachidonate metabolites stimulated by muscimol and diazepam is unaffected by Cl- channel blockers, picrotoxin and pentylenetetrazol. Based on these results we propose that in glioma C6 cells (and presumably in normal glia) peripheral benzodiazepine receptor interacts functionally with gamma-aminobutyric acid A type of receptor, which appears not to be linked to picrotoxin sensitive Cl- channel, and may be linked to phospholipase A2.
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PMID:Benzodiazepines enhance the muscimol-dependent activation of phospholipase A2 in glioma C6 cells. 285 84

Recent studies have disclosed that Mn-TPPS, a paramagnetic metalloporphyrin, may be a tumor-specific contrast media for magnetic resonance (MR) imaging. We investigated whether or not Mn-TPPS enhancement of the glioma could be mediated by peripheral benzodiazepine receptor. Using a transplanted rat C6 glioma model, Mn-TPPS enhancement was performed with or without pretreatment by peripheral or central benzodiazepine-specific receptor ligands. Signal intensity analysis disclosed that the enhancement was not inhibited by these ligands. Post-contrast replacement studies showed that neither of these ligands reduced Mn-TPPS enhancement. Although the tissue concentration of Mn-TPPS was significantly higher in the glioma than in the contralateral brain, PK11195 pretreatment did not replace the intratumoral Mn-TPPS. This data suggested that the tumor-specific enhancement of Mn-TPPS was not mediated by peripheral type benzodiazepine receptor.
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PMID:MRI contrast enhancement by Mn-TPPS in experimental rat brain tumor with peripheral benzodiazepine receptors. 797 88

When human glioma cells were incubated for 24 hr in serum-free medium with nanomolar concentrations of 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195), a specific ligand of the peripheral benzodiazepine receptor (PBR), a significant increase in the membrane fluidity of mitochondria isolated from these cells was registered. These effects were not observed with a shorter incubation time (2 hr) of the cells with PK11195 nor in the presence of serum. Other significant associated changes were observed: a significant increase of 16+/-4% of [3H]thymidine incorporation into DNA was detected in cells in the presence of PK11195 in serum-free medium, and an increase of 33+/-5% as compared to controls in nonyl acridine orange uptake, as indicator of mitochondrial mass, was also registered in cells treated with 10 nM PK11195. [3H]PK11195 binding was decreased in cells incubated with PK11195; a 45% decrease compared to controls was obtained. In view of the effect of PBR ligands on DNA synthesis, changes in mitochondrial lipid metabolism through interaction with PBRs might lead to biogenesis of mitochondria to support the increased metabolic requirements for cell division, which is even higher in malignant cells.
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PMID:Effect of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK11195), a specific ligand of the peripheral benzodiazepine receptor, on the lipid fluidity of mitochondria in human glioma cells. 1041 11

Various approaches might be employed in an effort to increase efficacy of the chemotherapeutic treatment of cancer. Recently, various modulators of anticancer therapy effectiveness have been studied. Antiproliferative effects of peripheral benzodiazepine receptor (PBR) ligands might be exploited to enhance cytotoxic effect of a chemotherapeutic drug towards cancer cells. In this work, we sought to enhance cytotoxic effect of etoposide (VP-16) by a PBR ligand, diazepam (DZ) in U-87 MG human glioma cells. Cytotoxicity of VP-16, DZ and their combinations was assessed by using the microculture MTT assay. Cell survival, effective concentrations (EC) and the onset of cytotoxic effect were determined. After 72 h of cultivation, survival of U-87 MG cells was reduced to 57 +/- 7% in the presence of VP-16 at 12.5 microg/mL alone, whereas DZ at 10-4 mol/L alone caused 28 +/- 6% reduction in cell survival. Coincubation of VP-16 at 12.5 microg/mL with DZ at 10-4 mol/L led to a further decrease in cell survival to 45 +/- 6%. Furthermore, DZ at 10-4 mol/L significantly decreased effective concentrations, EC10, EC30 and EC50, of VP-16 and the dose-response curves were shifted to the left. Addition of DZ at 10-4 mol/L to VP-16 also facilitated the onset of its cytotoxic effect. The same decrease in survival was thus achieved approximately 30 h earlier in comparison with VP-16 alone. However, DZ at 10-9 mol/L failed both to exert any effect on glioma cells survival and enhance cytotoxic effect of VP-16. DZ at 10-4 mol/L was capable of both reducing U-87 MG glioma cells survival when applied alone and also enhancing the cytotoxic effect of VP-16. No such observation was made for the lower concentrations of DZ. Potential implementation of diazepam in the antiglioma/anticancer armamentarium awaits further experimentation but phase I and phase II clinical trials could be suggested.
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PMID:Diazepam enhances etoposide-induced cytotoxicity in U-87 MG human glioma cell line. 1146 31

The aetiology of the peritumoural brain dysfunction that is rectified by steroids is unknown. To determine potential aspects of its pathophysiological basis we performed metabolic, histochemical and neuroreceptor studies in rodents with striatal C6 glioma. This model is known to cause focal neurobehavioural and electrophysiological dysfunction. The fully quantitative [(14)C]-2-deoxyglucose autoradiographic technique of measuring local cerebral metabolism of glucose (LCMRglu) showed raised LCMRglu (22-29%) in the pallidum, substantia nigra and endopeduncular nucleus. Acetylcholinesterase (AChE) histochemistry and a range of ligand binding studies for dopamine type 1 and 2, and serotonergic 5-HT(2)receptors were negative in the tumour and normal in peritumoural brain. 5-HT uptake sites and strong peripheral benzodiazepine receptor expression were present in the tumour. There was extensive up-regulation of peripheral benzodiazepine receptor expression in the peritumoural brain. These studies show there is metabolic dysregulation in brain regions functionally connected to, but anatomically distant from the striatum. There is also a peritumoural region of up-regulated receptors that have many, predominantly inhibitory, functions. The relationship of these findings to peritumoural brain dysfunction is discussed.
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PMID:Mechanisms of peritumoural brain dysfunction: metabolic and neuroreceptor findings in striatal C6 glioma. 1153 11

The peripheral benzodiazepine receptor (PBR) is a component of a multiprotein complex, located at the contact site between the inner and outer mitochondrial membranes, which constitutes the mitochondrial permeability transition (MPT)-pore. The opening of the MPT-pore, leading to the transmembrane mitochondrial potential (DeltaPsi(m)) dissipation, is a critical event in the mechanism of apoptosis. In the present work, we investigated the ability of the specific PBR ligands, PK 11195 or Ro5-4864, to affect mitochondrial potential and to induce apoptotic cell death in rat C6 glioma cells. Both specific ligands inhibited cell survival in a dose- and time-dependent manner, as assessed by MTS conversion assay, whereas the non-site selective ligand Diazepam or the low-affinity benzodiazepine Clonazepam showed no significant effects. After cell exposure to PK 11195 or Ro5-4864 we evidenced typical alterations of apoptotic cell death such as DNA fragmentation and chromatin condensation assessed by flow cytometric and transmission electron microscopy (TEM) analysis, respectively. Activation of the "effector" caspase-3 confirmed the ability of specific PBR ligands to induce apoptosis. Moreover, PK 11195 and Ro5-4864 induced a decrease of DeltaPsi(m), as evidenced by JC-1 flow cytometry analysis. Our data demonstrate the pro-apoptotic effects of specific PBR ligands on rat C6 glioma cells.
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PMID:Peripheral benzodiazepine receptor ligands: mitochondrial transmembrane potential depolarization and apoptosis induction in rat C6 glioma cells. 1518 24


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