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)

Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE) proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67. 2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved by only 150.8 ng/ml human endostatin secreted from 2 x 10(5) encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts. Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types.
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PMID:Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. 1113 44

The pharmacological properties of a specific agmatine uptake mechanism were investigated in the human glioma cell line SK-MG-1 and compared with those of the putrescine transporter expressed by the same cells and with those of several other organic cation transport systems or ion channels reported in the literature. The specific accumulation of [14C]agmatine at 37 degrees C above nonspecific accumulation at 4 degrees C was energy-dependent and saturable with a Vmax of 64.3+/-3.5 nmol/min per mg protein and a Km of 8.6+/-1.4 microM. Specific accumulation was attenuated by replacement of extracellular Na+ by choline by 65%, not affected by lithium and enhanced by replacement by sucrose. Phentolamine, clonidine, 1,3-di(2-tolyl)guanidine, histamine, putrescine, spermine and spermidine were inhibitors of specific [14C]agmatine accumulation. In contrast, corticosterone, desipramine, O-methylisoprenaline, cirazoline, moxonidine, L-arginine, L-lysine, verapamil, nifedipine and CdCl2 at concentrations up to 10 mM failed to inhibit specific [14C]agmatine accumulation, thus excluding that the latter is mediated by amino acid or monoamine carriers, by Ca2+ channels or by the organic cation transporters OCT1, OCT2, OCT3, OCTN1 or OCTN2. The pattern of activity of inhibitory compounds was also different from that determined for specific putrescine accumulation found in the same cells (Km 1.3+/-0.1 microM, Vmax 26.1+/-0.4 nmol/min per mg protein) ruling out an identity of the specific [14C]agmatine and [14C]putrescine accumulation mechanisms. It is concluded that specific accumulation of agmatine in human glioma cells is mediated by a specific transporter whose pharmacological properties are not identical to those of the agmatine transporter previously identified in rat brain synaptosomes and to other so far known carrier mechanisms for organic cations and ion channels. The agmatine uptake system may be important for the regulation of the extracellular concentration of agmatine in man.
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PMID:Agmatine and putrescine uptake in the human glioma cell line SK-MG-1. 1141 62

We previously showed that enhanced expression of MMP-9, an endopeptidase that digests basement-membrane type IV collagen, is related to tumor progression in vitro and in vivo; antisense-MMP-9 stably transfected clones were less invasive than untransfected parental cells and did not form tumors in nude mice. In this study, we examined the role of ERK-1 in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which ERK1 is constitutively activated. SNB19 cells were stably transfected with mt-ERK, a vector encoding ERK-1 cDNA in which the conserved lysine at codon 71 was changed to arginine, thus impairing the catalytic efficiency of this enzyme. Gelatin zymography showed reduced levels of MMP-9 in the mt-ERK-transfected cell lines relative to those in vector-transfected and parental control cells. Reductions in MMP-9 protein mRNA levels were also detected in the mt-ERK-transfected cells by Western and Northern blotting. The mt-ERK-transfected cells were much less invasive than parental or vector control cells in a Matrigel invasion assay and in a spheroid coculture assay. Thus an ERK-dependent signaling pathway seems to regulate MMP-9 mediated glioma invasion in SNB19 cells; interfering with this pathway could be developed into a therapeutic approach, which aims at a reduction of cancer cell invasion.
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PMID:Downregulation of MMP-9 in ERK-mutated stable transfectants inhibits glioma invasion in vitro. 1216 59

A polypeptide with 33 amino acid residues was designed and synthesized. Its C terminal was composed of multiple lysine residues, which played as a DNA condensing agent, whereas the N terminal was the receptor binding domain of Epidermal Growth Factor(N32-K48). Through a spontaneous self-assembly process with electrostatic interaction, the synthetic peptide combined with a luciferase expression vector, pEBluc, to form an EGF receptor targeting nucleic acid complex. Significant luciferase activity was detected 48 hours after adding this complex directly to the culture medium of the A431 cells. This synthetic peptide could be used to construct a gene transfer system mediated by the endocytosis via EGF receptor. It promoted a very possibility of the gene therapy for the cancers such as glioma, melanoma and squamous carcinoma which are known of epidermal growth factor receptor overexpression.
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PMID:[A novel gene delivery system targeting to epidermal growth factor receptor overexpressing cancer cells]. 1251 70

An important criterion in design of acylation agents for the radioiodination of internalizing monoclonal antibodies (mAbs) is to maximize the retention of radioiodine in the tumor following mAb intracellular processing. We have previously shown that labeling methods that generate positively charged catabolites have enhanced tumor retention. Herein we have extended this strategy to investigate the potential utility of labeling internalizing mAbs with an acylation agent that yielded labeled catabolites that would be negatively charged at lysosomal pH. The negatively charged acylation agent, N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), was prepared from its tin precursor, N-succinimidyl 4-di-tert-butylphosphonomethyl-3-trimethylstannylbenzoate (tBu-SPMTB), in 40% radiochemical yield. The free acid, 3-[(131)I]iodo-4-phosphonomethylbenzoic acid ([(131)I]IPMBA), was also prepared from the corresponding precursor, 4-di-tert-butylphosphonomethyl-3-trimethylstannylbenzoic acid (tBu-PMTBA), in 80% radiochemical yield. The rapidly internalizing mAb L8A4 was conjugated to [(131)I]SIPMB in 25-40% yield with preservation of its immunoreactivity. Internalization and processing in the U87DeltaEGFR glioma cell line was studied in a paired label format with L8A4 labeled with (125)I using the Iodogen method. Retention of initially bound radioactivity in these cells at 24 h from [(131)I]SIPMB-labeled mAb was approximately 6-fold higher than that for directly labeled mAb. Catabolite analysis demonstrated that this difference reflected an order of magnitude higher retention of low molecular weight species in these cells. The [(131)I]SIPMB-L8A4 conjugate was intact over the first 2 h; thereafter, lysine-[(131)I]SIPMB was the predominant catabolite. In contrast, L8A4 labeled using Iodogen rapidly gave rise to mono-[(125)I]iodotyrosine within 2 h, which then cleared rapidly from the cells. These results suggest that SIPMB could be a potent candidate for labeling internalizing mAbs and warrant further study.
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PMID:N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), a negatively charged substituent-bearing acylation agent for the radioiodination of peptides and mAbs. 1264 43

Heightened monoamine oxidase (MAO) and inducible nitric oxide synthase (iNOS) activity can contribute to oxidative stress, the formation of active neurotoxins, and associated neurodegenerative diseases of the brain. Although these enzymes co-exist within astrocytes, there has been little research examining the correlation between the two during inflammation. In this study, C6 glioma cells were stimulated with lipopolysaccharide (LPS):Escherichia coli 0111:B4 (6 micro g/mL):rat interferon-gamma (IFN-gamma) (100U/mL). In LPS/IFN-gamma-treated cells, the MAO substrates dopamine (DA) and tyramine caused a concentration-dependent attenuation of NO(2)(-) and NO(3)(-). In contrast, treatment with an MAO-A inhibitor (clorgyline) or an MAO-B inhibitor ((-)-deprenyl) did not reverse these effects. MAO activity was inhibited effectively by clorgyline and deprenyl; however, neither MAO inhibitor had an effect on NO(2)(-) in stimulated cells. Inversely, increasing concentrations of LPS/IFN-gamma resulted in heightened iNOS protein expression and NO(2)(-); however, these events did not correlate with any distinctive change in MAO enzyme activity. Moreover, a selective iNOS inhibitor, N(6)-(1-iminoethyl)-L-lysine, in LPS/IFN-gamma-stimulated cells caused a concentration-dependent attenuation of NO(2)(-) with no effects on MAO activity or iNOS protein expression. The attenuating effects of DA on iNOS were blocked completely by ICI 118-551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride], indicating a role for the beta(2)-adrenergic receptor. In conclusion, these data indicate that activity or expression of iNOS does not influence MAO activity in activated rat glioma cells. Moreover, DA exerts an inhibitory effect on glial iNOS through a receptor-mediated cascade.
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PMID:Inflammation and inducible nitric oxide synthase have no effect on monoamine oxidase activity in glioma cells. 1275 8

The concentrations of endogenous amino acids and choline in the extracellular fluid of human cerebral gliomas have been measured, for the first time, by in vivo microdialysis. Glioblastoma growth was associated with increased concentrations of choline, GABA, isoleucine, leucine, lysine, phenylalanine, taurine, tyrosine, and valine. There was no difference between grade III and grade IV tumors in the concentrations of phenylalanine, isoleucine, tyrosine, valine, and lysine, whereas the concentrations of choline, aspartate, taurine, GABA, leucine, and glutamate were significantly different in the two tumor-grade subgroups. In contrast to the other compounds, the concentration of glutamate was decreased in glioma. The parenchyma adjacent to the tumor showed significant changes only in the extracellular concentration of glutamate, isoleucine, and valine. The concentrations of choline and the amino acids, glutamate, leucine, taurine, and tyrosine showed significant positive correlations with the degree of cell proliferation. Epilepsy, which is relatively common in subjects with gliomas, was shown to be a significant confounding variable when the extracellular concentrations of aspartate, glutamate and GABA were considered.
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PMID:Extracellular levels of amino acids and choline in human high grade gliomas: an intraoperative microdialysis study. 1499 93

Brain tumors are highly angiogenesis dependent. The cell adhesion receptor integrin alpha(v)beta(3) is overexpressed in glioma and activated endothelial cells and plays an important role in brain tumor growth, spread and angiogenesis. Suitably labeled alpha(v)beta(3)-integrin antagonists may therefore be useful for imaging brain tumor associated angiogenesis. Cyclic RGD peptide c(RGDyK) was labeled with (18)F via N-succinimidyl-4-[(18)F]fluorobenzoate through the side-chain epsilon-amino group of the lysine residue. The radiotracer was evaluated in vivo for its tumor targeting efficacy and pharmacokinetics in subcutaneously implanted U87MG and orthotopically implanted U251T glioblastoma nude mouse models by means of microPET, quantitative autoradiography and direct tissue sampling. The N-4-[(18)F]fluorobenzoyl-RGD ([(18)F]FB-RGD) was produced in less than 2 h with 20-25% decay-corrected yields and specific activity of 230 GBq/micromol at end of synthesis. The tracer showed very rapid blood clearance and both hepatobiliary and renal excretion. Tumor-to-muscle uptake ratio at 30 min was approximately 5 in the subcutaneous U87MG tumor model. MicroPET imaging with the orthotopic U251T brain tumor model revealed very high tumor-to-brain ratio, with virtually no uptake in the normal brain. Successful blocking of tumor uptake of [(18)F]FB-RGD in the presence of excess amount of c(RGDyK) revealed receptor specific activity accumulation. Hence, N-4-[(18)F]fluorobenzoyl labeled cyclic RGD peptide [(18)F]FB-RGD is a potential tracer for imaging alpha(v)beta(3)-integrin positive tumors in brain and other anatomic locations.
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PMID:18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis. 1501 83

Specific accumulation of [(14C)]agmatine in six human intestinal tumor cell lines and in the glioma cell line SK-MG-1 was inhibited by phentolamine, idazoxan, clonidine, 1,3-di-(2-tolyl)guanidine, histamine, putrescine, spermine and spermidine. Corticosterone, desipramine, O-methylisoprenaline, cirazoline, moxonidine, l-arginine, l-lysine, verapamil, nifedipine, CdCl(2), ondansetron, and l-carnitine failed to inhibit specific [(14)C]agmatine accumulation, thus excluding that it is mediated by amino acid or monoamine carriers, by the putrescine carrier, by 5-HT(3) receptor channels, by Ca(2+) channels or by the organic cation transporters OCT1, OCT2, OCT3, OCTN1, or OCTN2. This conclusion is supported by the finding that transfection of HEK293 cells with cDNA encoding either hOCT1, hOCT2, or hOCT3 did not enhance specific [(14)C]agmatine accumulation compared to nontransfected cells. The data suggest that agmatine is accumulated by a specific agmatine transporter. Since incubation with exogenous agmatine for 24 hours increased intracellular agmatine content in all cell lines by a multiple of the basal endogenous content, the agmatine uptake system may be relevant for the regulation of the intra- and extracellular concentration of agmatine in humans.
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PMID:Identification and pharmacological characterization of a specific agmatine transport system in human tumor cell lines. 1502 72

Optical spectroscopic techniques such as CD, Raman scattering, and fluorescence imaging allowed us to analyze the complex formation and vectorization of a single-stranded 20-mer phosphorothioate oligodeoxynucleotide with a 15-mer amphipathic peptide at molecular and cellular levels. Different solvent mixtures (methanol and water) and molecular ratios of peptide/oligodeoxynucleotide complexes were tested in order to overcome the problems related to solubility. Optimal conditions for both spectroscopic and cellular experiments were obtained with the molecular ratio peptide/oligodeoxynucleotide equal to 21:4, corresponding to a 7:5 ratio for their respective +/- charge ratio. At the molecular level, CD and Raman spectra were consistent with a alpha-helix conformation of the peptide in water or in a methanol-water mixture. The presence of methanol increased considerably the solubility of the peptide without altering its alpha-helix conformation, as evidenced by CD and Raman spectroscopies. UV absorption melting profile of the oligodeoxynucleotide gave rise to a flat melting profile, corresponding to its random structure in solution. Raman spectra of oligodeoxynucleotide/peptide complexes could only be studied in methanol/water mixture solutions. Drastic changes observed in Raman spectra have undoubtedly shown: (a) the perturbation occurred in the peptide secondary structure, and (b) possible interaction between the lysine residues of the peptide and the oligodeoxynucleotide. At the cellular level, the complex was prepared in a mixture of 10% methanol and 90% cell medium. Cellular uptake in optimal conditions for the oligodeoxynucleotide delivery with low cytotoxicity was controlled by fluorescence imaging allowing to specifically locate the compacted oligonucleotide labeled with fluorescein at its 5'-terminus with the peptide into human glioma cells after 1 h of incubation at 37 degrees C.
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PMID:Complex formation and vectorization of a phosphorothioate oligonucleotide with an amphipathic leucine- and lysine-rich peptide: study at molecular and cellular levels. 1504 76


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