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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estramustine-phosphate (EMP), a combination of nornitrogen mustard and 17 beta-estradiol, has been demonstrated to exert specific antiproliferative effects on human glioma cells in vitro. The cytotoxic effect is, at least partially, mediated by inhibiting microtubule function. In this study the combined effect of EMP and radiation was evaluated in the human glioma cell-lines, 251-MG and 105-MG, in vitro, and in the rat glioma BT4C in vitro and in vivo. In all cell-lines an additive effect of EMP and radiation was obtained in vitro. Assuming equal effect of EMP is obtained in subsequent radiation fractions, the cell kill will be increased from 2-3 to 5-10 logs if delivering 30 fractions of 2 Gy combined with EMP. In the BT4C rat model the combined effect was found to be synergistic. Flow cytometry demonstrated an arrest in G2/M phase in all cell-lines after EMP treatment. This block in G2/M phase in addition to the previously demonstrated induction of free oxygen radicals, and the increase of blood flow with an assumed subsequent increase of oxygenation, might provide an explanation for the observed radiosensitizing effect of estramustine.
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PMID:Radiosensitizing effect of estramustine in malignant glioma in vitro and in vivo. 767 81

In neuroblastoma x glioma hybrid NG108-15 cells, ATP induced a concentration-dependent increase in the intracellular Ca2+ concentration ([Ca2+]i), accompanied by inositol phosphate formation. Under the same conditions, we found a marked increase in cAMP levels produced by ATP at concentrations similar to those required to increase [Ca2+]i. The Ca2+ ionophore A23187 or bradykinin, which evoked inositol phosphate formation and increases in [Ca2+]i, did not increase, and instead slightly decreased, cAMP content, indicating that ATP-induced cAMP accumulation was not due to activation of Ca(2+)-sensitive adenylyl cyclase. The effect of ATP on cAMP production was not dependent on generation of adenosine caused by ATP hydrolysis. Among several P2 purinoceptor agonists, adenosine-5'-O-(3-thio)triphosphate, 5'-adenylylimidodiphosphate, and adenosine-5'-O-(2-thio)diphosphate evoked both cAMP accumulation and Ca2+ mobilization. In contrast, beta,gamma-methylene-ATP selectively elicited cAMP accumulation, whereas 2-methylthio-ATP and UTP induced only Ca2+ mobilization, without affecting cAMP levels. The potent P2x purinoceptor agonist alpha,beta-methylene-ATP did not induce cAMP accumulation or Ca2+ mobilization. The cAMP accumulation induced by ATP was not affected by the P2 receptor antagonist suramin but was inhibited by P1 receptor antagonists such as 8-(p-sulfophenyl)theophylline, 3-isobutyl-1-methylxanthine, and xanthine amine congener. However, the ATP-induced increase in [Ca2+]i was not affected by suramin or xanthine amine congener. Taken together, these results indicate that ATP activates two distinct purinoceptors that are coupled to different signal transduction systems, one being adenylyl cyclase and the other phospholipase C, in NG108-15 cells. Furthermore, pharmacological profiles of the adenylyl cyclase-coupled receptor were quite different from those of any known purinoceptor subtypes, especially in the unusual sensitivity of the receptor to P1 and P2 receptor agonists and antagonists. It is therefore suggested that ATP-induced cAMP accumulation may be mediated by a novel subtype of purinoceptor in NG108-15 cells.
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PMID:Extracellular ATP stimulates adenylyl cyclase and phospholipase C through distinct purinoceptors in NG108-15 cells. 772 48

A new type of ligand for the study of P2-purinergic receptor subtypes was synthesized by combining and modifying conventional nucleoside chemistry with Fmoc solid phase peptide synthesis techniques. The tri- and tetra-aspartic acid derivatives of adenosine-5'-carboxylic acid (AdoCAsp3 and AdoCAsp4) were found to act as weak agonists at P2-purinergic receptors, (activated by ATP and UTP respectively) present on C6 glioma cells. AdoCAsp4 induced inositol 1,4,5-trisphosphate formation in the C6 cells with an EC50 of 73 microM. In addition, AdoCAsp4 was found to inhibit (IC50 approximately 80 microM) ATP-induced cytosolic [Ca2+] transients in these glioma cells. The glycine derivative, AdoCGly, increased evoked release of noradrenaline from mouse vas deferens slices, probably due to the blockade of presynaptic P2-autoreceptors. The possibility that aspartic, glutamic or gamma-carboxyglutamic residues may be used to replace phosphate groups on an ATP receptor ligand, opens up new ways in ligand design.
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PMID:A new class of compounds, peptide derivatives of adenosine 5'-carboxylic acid, includes inhibitors of ATP receptor-mediated responses. 777 27

1. Stimulation of P2Y-purinoceptors on turkey erythrocytes and many other cell types results in activation of phospholipase C. In contrast, we have observed recently that P2Y-purinoceptors on C6 rat glioma cells are not coupled to phospholipase C, but rather, inhibit adenylyl cyclase. 2. In this study we investigated the pharmacological selectivity of the P2-purinoceptor antagonists, suramin, reactive blue 2, and pyridoxal phosphate 6-azophenyl 2',4'-disulphonic acid (PPADS) for phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors. 3. In C6 glioma cells, suramin and reactive blue 2 competitively antagonized the inhibitory effect of 2MeSATP on adenylyl cyclase (pKB = 5.4 +/- 0.2 and 7.6 +/- 0.1, respectively), whereas PPADS at concentrations up to 100 microM had no effect. 4. In contrast, in the turkey erythrocyte preparation, PPADS at concentrations up to 30 microM was a competitive antagonist of P2Y-purinoceptor-stimulated phospholipase C activity (pKB = 5.9 +/- 0.1). Suramin and reactive blue 2 produced both a shift to the right of the concentration-effect of 2MeSATP for the activation of phospholipase C and a significant decrease in the maximal inositol phosphate response. 5. Turkey erythrocytes also express a phospholipase C-coupled beta-adrenoceptor. Concentrations of PPADS that competitively inhibited the P2Y-purinoceptor-mediated response had only minimal effects on the activation of phospholipase C by beta-adrenoceptors. In contrast, suramin and reactive blue 2 produced a non-competitive inhibition, characterized by decreases in the maximal response to isoprenaline with no change in the potency of this beta-adrenoceptor agonist. 6. The differential effect of PPADS on P2Y-purinoceptors of C6 glioma cells and turkey erythrocytes adds further support to the idea that different P2Y-purinoceptor subtypes mediate coupling to adenylylcyclic and phospholipase C.
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PMID:Differential effects of P2-purinoceptor antagonists on phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors. 783 15

Cerebral pentose phosphate pathway (PPP) activity has been linked to NADPH-dependent anabolic pathways, turnover of neurotransmitters, and protection from oxidative stress. Research on this potentially important pathway has been hampered, however, because measurement of regional cerebral PPP activity in vivo has not been possible. Our efforts to address this need focused on the use of a novel isotopically substituted glucose molecule, [1,6-13C2,6,6-2H2]glucose, in conjunction with microdialysis techniques, to measure cerebral PPP activity in vivo, in freely moving rats. Metabolism of [1,6-13C2,6,6-2H2]glucose through glycolysis produces [3-13C]lactate and [3-13C,3,3-2H2]lactate, whereas metabolism through the PPP produces [3-13C,3,3-2H2]lactate and unlabeled lactate. The ratios of these lactate isotopomers can be quantified using gas chromatography/mass spectrometry (GC/MS) for calculation of PPP activity, which is reported as the percentage of glucose metabolized to lactate that passed through the PPP. Following addition of [1,6-13C2,6,6-2H2]glucose to the perfusate, labeled lactate was easily detectable in dialysate using GC/MS. Basal forebrain and intracerebral 9L glioma PPP values (mean +/- SD) were 3.5 +/- 0.4 (n = 4) and 6.2 +/- 0.9% (n = 4), respectively. Furthermore, PPP activity could be stimulated in vivo by addition of phenazine methosulfate, an artificial electron acceptor for NADPH, to the perfusion stream. These results show that the activity of the PPP can now be measured dynamically and regionally in the brains of conscious animals in vivo.
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PMID:Dynamic measurements of cerebral pentose phosphate pathway activity in vivo using [1,6-13C2,6,6-2H2]glucose and microdialysis. 786 Nov 66

1. The effects of histamine receptor agonists and antagonists on phospholipid hydrolysis in rat-derived C6 glioma cells have been investigated. 2. Histamine H1 receptor-stimulation caused a concentration-dependent increase in the accumulation of total [3H]-inositol phosphates in cells prelabelled with [3H]-myo-inositol. The rank order of agonist potencies was histamine (EC50 = 24 microM) > N alpha-methylhistamine (EC50 = 31 microM) > 2-thiazolylethylamine (EC50 = 91 microM). 3. The response to 0.1 mM histamine was antagonized in a concentration-dependent manner by the H1-antagonists, mepyramine (apparent Kd = 1 nM) and (+)-chlorpheniramine (apparent Kd = 4 nM). In addition, (-)-chlorpheniramine was more than two orders of magnitude less potent than its (+)-stereoisomer. 4. Elevation of intracellular cyclic AMP accumulation with forskolin (10 microM, EC50 = 0.3 microM), isoprenaline (1 microM, EC50 = 4 nM) or rolipram (0.5 mM), significantly reduced the histamine-mediated (0.1 mM) inositol phosphate response by 37%, 43% and 26% respectively. In contrast, 1,9-dideoxyforskolin did not increase cyclic AMP accumulation and had no effect on the phosphoinositide response to histamine. 5. These data indicate the presence of functionally coupled, endogenous histamine H1 receptors in C6 glioma cells. Furthermore, the results also indicate that H1 receptor-mediated phospholipid hydrolysis is inhibited by the elevation of cyclic AMP levels in these cells.
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PMID:Endogenous expression of histamine H1 receptors functionally coupled to phosphoinositide hydrolysis in C6 glioma cells: regulation by cyclic AMP. 788 13

Phospholipid metabolism was studied in N1E-115 neuroblastoma and C6 glioma cells exposed to thapsigargin, a selective inhibitor of endoplasmic reticulum Ca(2+)-ATPase that raises the cytosolic free Ca2+ concentration [Ca2+]i. Thapsigargin caused only a transient increase of [Ca2+]i (< 1 min) in N1E-115 cells similar in magnitude and duration to agonist-induced calcium release mediated by inositol trisphosphate. Sustained elevation of [Ca2+]i due to influx of extracellular calcium, as occurs in most other cell lines including C6 cells, did not occur in N1E-115 cells. Increased uptake of inorganic phosphate (Pi) associated calcium influx was observed in C6 but not in N1E-115 cells. Thapsigargin affected phospholipid synthesis in both cell lines, most likely by inhibiting phosphatidic acid phosphohydrolase as indicated by diversion of [3H]oleic acid incorporation from triacylglycerol to phospholipid synthesis and stimulation of [32P]Pi incorporation into anionic phospholipids at the expense of phosphatidylcholine synthesis. The response to increased phosphatidate/phosphatidyl-CMP availability was cell specific. Thapsigargin (> 100 nM) selectively stimulated phosphatidylglycerol synthesis 20-30-fold in N1E-115 neuroblastoma cells while phosphatidylinositol synthesis was increased < 2-fold. In contrast, phosphatidylglycerol was not affected in C6 glioma cells and phosphatidylinositol synthesis was stimulated 8-fold by thapsigargin (> 1 microM). Agonist-stimulated calcium release did not increase phosphatidylglycerol synthesis in N1E-115 cells. Thapsigargin-stimulated phosphatidylglycerol synthesis and agonist-stimulated phosphatidylinositol synthesis could occur at the same time. Similar results were obtained with TMB-8, an inhibitor of intracellular Ca2+ release that decreases diacylglycerol utilization by blocking choline uptake and phosphatidylcholine synthesis without affecting resting [Ca2+]i. Thus [Ca2+]i does not directly mediate the effects of thapsigargin, TMB-8 or agonist stimulation on anionic phospholipid metabolism. These additional effects may limit the use of thapsigargin to assess Ca(2+)-dependence of phospholipid metabolism associated with Ca(2+)-mediated signal transduction.
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PMID:Thapsigargin selectively stimulates synthesis of phosphatidylglycerol in N1E-115 neuroblastoma cells and phosphatidylinositol in C6 glioma cells. 794 3

Transfection of a human dopamine D3 receptor cDNA in a neuroblastoma-glioma hybrid cell line (NG 108-15) provided clonal cell lines stably expressing up to 600 fmol per mg protein of [125I]iodosulpiride binding sites. Dopamine and several agonists distinguished two receptor-affinity states in membranes. In the case of dopamine, the high-affinity state (Ki = 0.9 nM, 30% of total binding) was completely converted into a low-affinity state (Ki = 57 nM) in the presence of 10 microM guanosine-5'-O-(3-thiotriphosphate). In addition to these two sites, a site with a very low affinity for dopamine was evidenced in whole cells. The dopamine D3 receptor mediated two responses: c-fos activation, as measured by the appearance of Fos-like immunoreactivity, and increased mitogenesis, as measured by incorporation of [3H]thymidine. The Fos-like immunoreactivity appeared within 30 min, lasted 2 h and was blocked by the partially selective dopamine D3 receptor compound (+)-UH 232 (cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin). The mitogenic effect, which occurred after a lag time (over 2 h stimulation), was produced with subnanomolar potency and full intrinsic activity by several compounds previously identified as dopamine D2 receptor agonists, e.g. quinpirole, (+)-7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and RU 24926 (N-n-propyl-di-beta(3-hydroxyphenyl)-ethylamine), and was reversibly blocked by (+)-UH 232 (Ki = 9 nM). Talipexole (B-HT 920, 5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin) was identified as a partial agonist at the dopamine D3 receptor. Dopamine D3 receptor-mediated mitogenesis was potentiated by a phorbol ester and was abolished by pretreatment with pertussis toxin. A mitogenic effect of same amplitude was elicited by bradykinin or carbachol, both acting through constitutive receptors. Bradykinin markedly activated inositol phosphate turnover, and had no effect on forskolin-stimulated cyclic AMP accumulation. Carbachol inhibited forskolin-stimulated cyclic AMP accumulation and had no effect on inositol-phosphate turnover. Quinpirole had no effect on any of these second messenger pathways. Thus, in transfected NG 108-15 cells, the dopamine D3 receptor is coupled to a pertussis toxin-sensitive G protein and mediates two possibly unrelated biological effects, through initial biochemical events that remain to be identified.
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PMID:Functional coupling of the human dopamine D3 receptor in a transfected NG 108-15 neuroblastoma-glioma hybrid cell line. 795 35

The isotopically substituted molecule (6-13C, 1, 6, 6-2H3)glucose was evaluated to determine whether metabolic 2H loss would prevent its use in quantitating pentose phosphate pathway (PPP) activity. PPP activity causes the C1 of glucose to be lost as CO2, while C6 can appear in lactate. 2H NMR analysis of the lactate produced from this glucose can distinguish (3-2H)-lactate (from C1 of glucose) from (3-13C, 3, 3-2H2)lactate (from C6 of glucose). 2H NMR spectroscopic analysis of medium containing (6-13C, 1, 6, 6-2H3)glucose after incubation with cultured rat 9L glioma cells suggested a 30.8 +/- 2.1% PPP activity as compared with 6.0 +/- 0.8% from separate, parallel incubations with (1-13C)glucose and (6-13C)glucose. Subsequent experiments with other isotopically labeled glucose molecules suggest that this discrepancy is due to selective loss of 2H from the C1 position of glucose, catalyzed by phosphomannose isomerase. Failure to consider 2H exchange from the C1 and C6 positions of glucose can lead to incorrect conclusions in metabolic studies utilizing this and other deuterated or tritiated glucose molecules.
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PMID:Metabolic loss of deuterium from isotopically labeled glucose. 798 74

In C6 glioma cells, extracellular ATP and other nucleotide analogs stimulated phosphoinositide (PI) breakdown and inhibited isoproterenol-induced cyclic AMP (cAMP) accumulation. The rank orders of potencies of 15 nucleotide analogs for both responses were clearly different. ATP and adenosine 5'-O-(3-thiotriphosphate) are the most potent agonists for stimulating PI hydrolysis; 2-methylthio-ATP (2-MeSATP) is the most potent agonist for inhibiting cAMP accumulation. P1-mediated responses of PI turnover and cAMP formation are not present in C6 glioma cells. Pertussis toxin (PTX) blocked the nucleotide-induced inhibition of cAMP accumulation but exerted no effect on inositol phosphate formation. Short-term treatment with phorbol 12-myristate 13-acetate inhibited both signal transduction pathways. The effects of three P2 purinergic antagonists, suramin, reactive blue and 4,4'-diisothiocyanatostilbene sulfonic acid (DIDS), on ATP- and 2-MeSATP-induced stimulation of PI turnover and inhibition of cAMP formation, respectively, were compared. For stimulating PI turnover, suramin is a competitive antagonist (pA2, 4.4); reactive blue and DIDS are noncompetitive antagonists at 30 microM and 100 microM, respectively. For the inhibition of cAMP formation, reactive blue and DIDS competitively antagonized the response of 2-MeSATP (pA2 values, 6.3 for reactive blue and 5.7 for DIDS); suramin was only slightly effective at 100 microM. It was concluded that the nucleotide receptor is linked to phospholipase C by a PTX-insensitive Gp protein and the P2Y receptor is linked to adenylyl cyclase by a PTX-sensitive Gi protein. Suramin is a competitive antagonist for the nucleotide receptor; reactive blue and DIDS are more selective antagonists for the P2Y receptor.
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PMID:Different signal transduction pathways are coupled to the nucleotide receptor and the P2Y receptor in C6 glioma cells. 801 79


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