Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The composition of the free amino acid pools in various brain tumors and in normal brains obtained at surgery or at autopsy is determined with an automatic amino acid analyzer and the results statistically evaluated. The tumors have lower ratios of GABA in the pools than the normal brain; tumors with higher GABA ratios are found in those which are in close contact with and have an invasive nature to brain tissue. In gliomas, the more malignant a tumor becomes, the more different the composition in that tumor is from that in normal brain tissue. But conversely, the ratio of GABA is highest in glioblastoma. The composition of the pool in oligodendroglioma is not significantly different from that in the normal brain. Metastatic brain tumors show the highest ratios of phenylalanine, tyrosine and methionine in the pool among the tumors and the normal brain. From the viewpoint of the composition of the free amino acid pools, like from that of the histological aspects, brain tumors seem to be classified into four groups: glioma, neurinoma, meningioma and metastatic tumors.
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PMID:Composition of free amino acids in brain tumors. 54 90

C6 rat glioblastoma cells are able to attach to and to spread on culture dishes which are coated with purified central nervous system myelin, in contrast to normal astrocytes, fibroblasts or neurons which adhere poorly and are unable to spread on this substrate. The metalloprotease blockers o-phenanthroline and a newly developed oligopeptide could specifically inhibit C6 cell spreading on central nervous system myelin, suggesting a crucial role for a metalloprotease. Here we characterize this metalloproteolytic activity of C6 cells using a peptide degradation assay with the iodinated tetrapeptide carbobenzoxy-Phe-Ala-Phe-125I-Tyr-amide as a substrate. Purified, salt-washed C6 plasma membranes cleaved the peptide between alanine and phenylalanine, an effect which is strongly inhibited by o-phenanthroline, but not by thiol-blocking agents or aspartic and serine protease inhibitors. The metalloendoprotease is highly sensitive to phosphoramidon but insensitive to thiorphan. The enzyme is tightly bound to the plasma membrane but not G protein-phosphatidylinositol linked. It can be solubilized in part by the detergents 3-(3-cholamidopropyldimethylamino)-1-propanesulfonate or Triton X-114. Gel filtration chromatography using the Triton X-114-solubilized proteins or the proteins removed by a short trypsin treatment revealed a molecular weight range for the C6 enzyme of 60,000-100,000. Polymerase chain reaction with primers corresponding to endopeptidase 24.11 or to the highly conserved motif of the "astacin family" showed that both enzymes were not detectable in the C6 glioblastoma cells.
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PMID:Characterization of a membrane-bound metalloendoprotease of rat C6 glioblastoma cells. 803 33

Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.
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PMID:Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. 831 77

Boron-neutron capture therapy (BNCT) is currently under investigation as a novel therapeutic modality for glioblastoma. This study was undertaken to determine whether boron-containing compounds 4-borono-2-fluoro-D,L-phenylalanine (FBPA) and FBPA-fructose have direct effects upon kinetics of A172, a glioblastoma cell line. Flow cytometry analyzed cell-cycle distribution and S-phase kinetics (bromo deoxyuridine [BUdR] incorporation). BUdR incorporation was increased during a 1-hr pulse after 24-hr or 72-hr exposure of cells to varying concentrations of FBPA or FBPA-fructose. Results suggest that boron-containing compounds may effect cell kinetics apart from neutron activation, and this effect should be further evaluated for potential impact upon tumor responsiveness to BNCT.
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PMID:In vitro effects of boron-containing compounds upon glioblastoma cells. 940 53

The binding of monomeric (Hp) and oligomeric (PHE) forms of porphyrin to glioblastoma (U-87MG) cells and the photosensitization of these cells have been studied. Upon binding to U-87MG cells, Hp and PHE exhibited fluorescence bands at 615 and 636 nm, respectively. The fluorescence and absorption spectra of Hp, HpD and PHE, measured in different solvents, suggest that the 615 nm band may arise due to the binding of monomeric as well as aggregated forms of porphyrin to the hydrophilic sites in the cells whereas the 636 nm band may be due to the binding of an aggregated form of porphyrin to the hydrophobic sites. The photosensitivity of cells and photo-induced lipid peroxidation were measured as a function of light dose. Cells were found most photosensitive to PHE followed by HpD and Hp. The photosensitivity of cells correlates well with the fluorescence intensity of cell bound dye at 636 nm. These results suggest that the binding of the oligomeric component of HpD to hydrophobic sites in the cells is responsible for the enhancement in the photosensitivity.
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PMID:Binding of monomeric and oligomeric porphyrins to human glioblastoma (U-87MG) cells and their photosensitivity. 957 Mar 85

Cis-Octahydro-14H-benzo[g]quinolino[2,3-a]quinolidines 6 were obtained in 6 steps from L-phenylalanine. The key step utilizes a diastereoselective intramolecular EtAlCl2-catalyzed hetero-Diels-Alder reaction. Compounds 6a-f were tested in vitro against human medulloblastoma D283 Med and glioblastoma A-172 and T98G cell lines and showed improved cytotoxicity compared to the corresponding, less rigid pyrido[1,2-b]isoquinolines 1.
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PMID:Diastereoselective synthesis of octahydro-14H-benzo[g]quinolino-[2,3-a]quinolidines. Improved cytotoxic activity against human brain tumor cell lines as a result of the increased rigidity of the molecular backbone. 987 41

A trypsin-like serine proteinase was purified from the incubation medium of rat brain slices by gelatin zymography. The purification consisted of ammonium sulfate precipitation, benzamidine-Sepharose 6B affinity chromatography, and carboxymethyl-cellulose and gel filtration chromatographies. The gelatinolytic activity, identified at 22 kDa (P22) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions, was eluted as one active peak throughout the purification, and the final preparation gave a single protein peak on reverse-phase HPLC. Diisopropyl fluorophosphate, benzamidine, p-toluenesulfonyl-L-lysine chloromethyl ketone, and aprotinin completely inhibited the activity of P22, whereas phenanthroline, p-toluene-sulfonyl-L-phenylalanine chloromethyl ketone, and elastinal did not. P22 efficiently digested the extracellular matrix proteins laminin and type IV collagen. P22 produced an increase in intracellular Ca2+ concentration in A172 glioblastoma, which was desensitized through prior stimulation with protease-activated receptor-2 agonist peptide SLIGKV, indicating that P22 can stimulate protease-activated receptor-2. Rat brain penetration injury induced gelatinolytic activity in the lesioned area whose molecular size was consistent with that of P22. These results indicated that on incubation of rat brain slices, a trypsin-like serine proteinase was secreted into the medium that was capable of digesting extracellular matrix and stimulating protease-activated receptor-2. It is suggested that the gelatinolytic activity induced by brain injury might be that of P22.
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PMID:Purification and characterization of a trypsin-like serine proteinase from rat brain slices that degrades laminin and type IV collagen and stimulates protease-activated receptor-2. 1073 32

In developing iodine-123-labelled amino acid derivatives for imaging cerebral gliomas by single-photon emission tomography (SPET), we compared p-[123I]iodo-L-phenylalanine (IPA), L-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T3868 cells, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the 123I-iodinated agents for use as SPET radiopharmaceuticals was evaluated in healthy experimental rats as well as in rats with stereotactically implanted C6 gliomas. The radiopharmaceutical uptake into glioblastoma cells was rapid, temperature and pH dependent, and linear during the first 5 min. Equilibrium was reached after 15-20 min, except in the case of ITIC, the initial uptake of which gradually decreased from 15 min onwards. The radioactivity concentration in glioma cells following 30-min incubation at 37 degrees C (pH 7.4) varied from 11% to 35% of the total activity per million cells (ITIC < IMT < or = IPA). Competitive inhibition experiments using alpha-(methylamino)-isobutyric acid and 2-amino-2-norbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transported by system ASC, indicated that IPA, like IMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of the A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analysis of uptake under conditions that change the cell membrane potential, i.e. in high K+ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of valinomycin or nigericin induces a slight increase or decrease in the radiopharmaceutical uptake, suggesting a minor contribution of the mitochondria in the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereafter showed efflux from the brain. The radioactivity concentration in healthy rat brain 15 min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactically implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15 min p.i.), with tumour-to-background ratios greater than 4. These data indicate that IPA and ITIC, like IMT, exhibit interesting biological characteristics which hold promise for in vivo brain tumour investigations by SPET.
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PMID:Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats. 1108 45

In developing radioiodinated agents for pancreatic and brain tumor imaging by single photon emission tomography (SPET), we prepared p-amino-3-[123I]iodo-l-phenylalanine (IAPA), p-[123I]iodo-l-phenylalanine (IPA), L-8-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyl-tyrosine (IMT) in radiochemical yields up to 95%, and we investigated their uptake in human pancreatic carcinoma and glioblastoma cells as well as the mechanisms promoting the tumor uptake. The radiopharmaceutical uptake into tumor cells was rapid (t(1/2) < or = 5 min) and temperature- and pH-dependent. The radioactivity concentration in tumor cells varied from 10 to 33% of the total activity (105-310 cpm/1000 cells) following a 30-min incubation at 37 degrees C (pH 7.4). In comparison, accumulation of the radiopharmaceuticals into normal brain and pancreatic tissue remained relatively low. Depolarizing the plasma membrane potential in high K+ buffer significantly altered the radioactivity concentration in the tumor cells, suggesting that membrane potential plays a certain role in the cellular uptake. Competitive inhibition experiments with specific amino acid transport inhibitors indicated that the uptake of IAPA, IPA and IMT into human pancreatic carcinoma and glioblastoma cells is predominantly mediated by the L and ASC transport systems, while no substantial involvement of the transport system A in their tumor uptake could be demonstrated. In contrast, results of the present investigation indicated that ITIC is not taken up into tumor cells via the common neutral amino acid carrier systems, including the A, L and ASC system. Furthermore, preloading with naturally occurring L-amino acids failed to stimulate the cellular uptake of the radiopharmaceuticals. These data indicate that the investigated radiopharmaceuticals exhibit interesting characteristics with promise for in vivo tumor investigations to ascertain their potential as radioligands for glioma and pancreatic carcinoma imaging by SPET.
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PMID:Preparation and investigation of tumor affinity, uptake kinetic and transport mechanism of iodine-123-labelled amino acid derivatives in human pancreatic carcinoma and glioblastoma cells. 1118 60

A human cDNA encoding an 841-aa guanine nucleotide-exchange protein (GEP) for ADP-ribosylation factors (ARFs), named ARF-GEP(100), which contains a Sec7 domain, a pleckstrin homology (PH)-like domain, and an incomplete IQ-motif, was identified. On Northern blot analysis of human tissues, a approximately 8-kb mRNA that hybridized with an ARF-GEP(100) cDNA was abundant in peripheral blood leukocytes, brain, and spleen. ARF-GEP(100) accelerated [(35)S]GTPgammaS binding to ARF1 (class I) and ARF5 (class II) 2- to 3-fold, and to ARF6 (class III) ca. 12-fold. The ARF-GEP(100) Sec7 domain contains Asp(543) and Met(555), corresponding to residues associated with sensitivity to the inhibitory effect of the fungal metabolite brefeldin A (BFA) in yeast Sec7, but also Phe(535) and Ala(536), associated with BFA-insensitivity. The PH-like domain differs greatly from those of other ARF GEPs in regions involved in phospholipid binding. Consistent with its structure, ARF-GEP(100) activity was not affected by BFA or phospholipids. After subcellular fractionation of cultured T98G human glioblastoma cells, ARF6 was almost entirely in the crude membrane fraction, whereas ARF-GEP(100), a 100-kDa protein detected with antipeptide antibodies, was cytosolic. On immunofluorescence microscopy, both proteins had a punctate pattern of distribution throughout the cells, with apparent colocalization only in peripheral areas. The coarse punctate distribution of EEA-1 in regions nearer the nucleus appeared to coincide with that of ARF-GEP(100) in those areas. No similar coincidence of ARF-GEP(100) with AP-1, AP-2, catenin, LAMP-1, or 58K was observed. The new human BFA-insensitive GEP may function with ARF6 in specific endocytic processes.
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PMID:ARF-GEP(100), a guanine nucleotide-exchange protein for ADP-ribosylation factor 6. 1122 53


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