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)

The human TAX-1 gene encodes a Mr 135,000 glycoprotein that is transiently expressed on the surface of a subset of neurons during development and is involved in neurite outgrowth. The TAX-1 gene has been mapped to a region on chromosome 1 that has been implicated in microcephaly and the Van der Woude syndrome. Using restriction landmark genome scanning to search for amplified genes in gliomas, we found TAX-1 to be amplified in 2 high-grade gliomas among a group of 26 gliomas investigated. Real-time reverse transcription-quantitative PCR analysis detected high levels of TAX-1 mRNA in glial tumors, even in the absence of TAX-1 gene amplification. Immunohistochemical analysis revealed abundant levels of TAX-1 in neoplastic glial cells of glioblastoma multiforme tumors. Because glial tumors are highly invasive and in view of the role of TAX-1 in neurite outgrowth, we investigated the potential role of TAX-1 in glioma cell migration. Using an in vitro assay, we found that the migration of glioma tumor cells is profoundly reduced in the presence of either an anti-TAX-1 antibody or a TAX-1 antisense oligonucleotide. Our findings suggest that TAX-1 plays a role in glial tumorigenesis and may provide a potential target for therapeutic intervention.
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PMID:The gene for the axonal cell adhesion molecule TAX-1 is amplified and aberrantly expressed in malignant gliomas. 1128 Jul 81

The susceptibility of the C6 rat glioma cell line (ATCC; CCL-107) to rabies virus was characterized. The kinetics of infection performed with a fixed and a wild strain (from an infected cow) of rabies virus was monitored by direct immunofluorescence. Fluorescent cytoplasmic bodies were readily observed by UV microscopy from 24 hours post-infection (hpi) onwards. The ability of C6 to produce rabies infective virion particles was confirmed by determining the viral titres present in the supernatants of infected cultures, by both BHK-21 cell infection and mice inoculation. C6 cells produced similar viral titres to those produced by BHK-21 for both strains used. In addition, the yield of rabies glycoprotein was assessed by ELISA. In general, BHK-21 and C6 cells infected either by PV or with the wild rabies strain produced similar amounts of rabies glycoprotein. At 96 hpi, however, when the glycoprotein production peaked, BHK-21 infected with the wild strain produced significantly higher amounts of glycoprotein than C6. Subsequently, the optimal conditions for isolation of wild rabies virus strains from C6 cells were established and these proved to be as sensitive as NA cells in detecting 10 wild rabies samples. Due to the high sensitivity exhibited, C6 rat glioma cells present a new and useful system for rabies virus investigation.
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PMID:Isolation and replication of rabies virus in C6 rat glioma cells (clone CCL-107). 1158 Feb 11

We evaluated the interaction between oncolytic, replication-competent adenoviral vectors and the herpes simplex virus-1 thymidine kinase (HSV1-tk) gene/ganciclovir (GCV) suicide system for the treatment of malignant gliomas. We constructed a panel of replication-competent adenoviral vectors in which the luciferase (IG.Ad5E1(+). E3Luc) or HSV1-tk gene (IG.Ad5E1(+).E3TK) replace the M(r) 19,000 glycoprotein (gp19K) coding sequence in the E3 region. IG.Ad5E1. IG.Ad5.ClipLuc and IG.AdApt.TK are E1-deleted viruses that contain the luciferase or the HSV1-tk gene in the former E1 region driven by the human cytomegalovirus promoter. IG.Ad5. Sarcoma 1800HSA.E3Luc contains an irrelevant gene in the E1 region, whereas the gp19K coding sequence in the E3 region is replaced by the luciferase gene as in the replicating virus IG.Ad5E1(+).E3Luc. For in vitro experiments, we used a panel of human glioma cell lines (U87 MG, T98G, A172, LW5, and U251), a rat gliosarcoma cell line (9 L), and human lung (A549) and prostate carcinoma (P3) cell lines. In vitro, GCV sensitivity (10 microg/ml) was studied in U87 MG cells after infection at a multiplicity of infection of 1 and 10. A s.c. U87 MG glioma xenograft model was established in NIH-bg-nu-xid mice. Tumors of 100-150 mm(3) were treated with a single injection of adenovirus 10(9) IU suspended in 100 microl of PBS, and GCV 100 mg/kg was administered i.p. twice daily for 7 days. The cytopathic effect of all three replication-competent adenoviral vectors was similar to the cytopathic effect of wild-type adenovirus 5 on all human cell lines tested, indicating that deletion of the E3 gp19K sequences did not affect the oncolytic effect of the vectors. In vitro, luciferase expression was the same for both E1-deleted vectors (IG.Ad5.ClipLuc and IG.Ad5. Sarcoma 1800HSA.E3Luc), demonstrating the strength of the internal E3 promoter even in the absence of E1A. However, in vitro expression levels obtained with replication-competent IG.Ad5E1(+). E3Luc were 3 log higher (allowing infection with a 2-3-log lower multiplicity of infection) in the human cell lines. In U87 MG glioma cells, the oncolytic effect of replication-competent IG.Ad5E1(+).E3TK was significantly enhanced by the addition of GCV and greatly exceeded the cytotoxicity of replication-incompetent IG.AdApt.TK combined with GCV. In established s.c. U87 MG glioma xenografts, a single injection of IG.Ad5E1(+).E3TK resulted in a significant slowing of tumor growth and prolonged survival compared with injection of IG.AdApt.TK. Addition of GCV slowed tumor growth, further adding to survival. In conclusion, the oncolytic effect of replicating adenoviral vectors and HSV1-tk/GCV have potent antitumor effects in gliomas. When combined, these two approaches are complementary, resulting in a significantly improved treatment outcome. In addition, replication-competent adenoviral vectors missing the E3 gp19K coding sequences, have oncolytic efficacy comparable with wild type. In combination with high expression levels obtained with the natural E3 promoter, such vectors are promising new anticancer agents.
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PMID:Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. 1175 94

Lymphocytic choriomeningitis virus (LCMV) is a noncytopathic arenavirus shown to infect a broad range of different cell types. Here, we combined the beneficial characteristics of the LCMV glycoprotein (LCMV-GP) and those of retroviral vectors to generate a new, safe, and efficient gene transfer system. These LCMV-GP pseudotypes were systematically compared with vectors containing the widely used amphotropic murine leukemia virus envelope (A-MLVenv) or the vesicular stomatitis virus G protein (VSV-G). Production of LCMV-GP-pseudotyped oncoretroviral and lentiviral vectors by transient transfection resulted in vector titers similar to those with A-MLVenv or VSV-G. In contrast to A-MLVenv particles, LCMV-GP pseudotypes could be efficiently concentrated by ultracentrifugation without loss of vector titer. Unlike the cell-toxic VSV-G, a stable retroviral packaging cell line constitutively expressing LCMV-GP could be established. Vectors pseudotyped with LCMV-GP efficiently transduced many cell lines from different species and tissues relevant for gene therapy. Transduction of human glioma cells was studied in detail. These cells are a major target for cancer gene therapy and were transduced more efficiently with LCMV-GP-pseudotyped vectors than with the generally used A-MLVenv particles. The high stability, low toxicity, and broad host range make LCMV-GP-pseudotyped vectors attractive for gene transfer applications. The recombinant LCMV-GP-pseudotyped vectors will also allow functional characterization of naturally occurring and recombinant LCMV-GP variants.
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PMID:Oncoretrovirus and lentivirus vectors pseudotyped with lymphocytic choriomeningitis virus glycoprotein: generation, concentration, and broad host range. 1177 21

In the first stage of engineering a herpes simplex virus (HSV)-1 that specifically targets human malignant glioma cells, we constructed a recombinant virus designated R5111 in which we have ablated the binding sites for sulfated proteoglycans in glycoproteins B and C, replaced the amino-terminal 148 aa in glycoprotein C by IL-13 flanked at its amino terminus with a signal peptide, and inserted a second copy of IL-13 after the amino acid 24 of glycoprotein D. In the process, the binding site for HveA, a viral entry receptor, was disrupted. We have also transformed a cell line (J1.1) lacking HSV-1 receptors to express IL13Ralpha2 receptor (J13R cells). We report the following: the R5111 recombinant virus replicates as well as wild-type virus in a variety of cell lines including cell lines derived from brain tumors. R5111 failed to replicate in the parent J1.1 cell line but multiplied to titers similar to those obtained in other cell lines in the J13R cell line. On the basis of the evidence that R5111 can use the IL13Ralpha2 receptor for entry, we conclude that HSV-1 can use receptors other than HveA or nectins, provided it can bind to them. The domains of gD that interact with HveA and nectin receptors are independent of each other. Lastly, the fusogenic activities of the glycoproteins in the viral envelope are not dependent on a set of unique interactions between glycoprotein D and its receptor. The construction of R5111 opens the way for construction of viruses totally dependent on selected receptors for entry or imaging of targeted cells.
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PMID:Engineered herpes simplex virus 1 is dependent on IL13Ralpha 2 receptor for cell entry and independent of glycoprotein D receptor interaction. 1241 44

Little is known about the expression of mitogens and other tumour-related substances in the cerebrospinal fluid (CSF) of glioma patients. The aim of the current study was to determine the presence of aberrant proteins in the CSF of patients with low-grade gliomas. Lumbar puncture was performed in 8 adult patients with supratentorial low-grade gliomas at the time of diagnosis and in 7 controls. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry were used to detect and quantify deviant proteins in the CSF. Two isoforms of alpha(2)-Heremans-Schmid glycoprotein (AHSG) were identified and demonstrated in higher levels in patients with low-grade gliomas compared with the control group consisting of patients with mixed neurological diagnoses (p = 0.001 and p = 0.04, respectively). In 1 patient, the level of AHSG was significantly reduced after gross total resection of the tumour. AHSG appears in the present proteome screening as a novel substance in glioma research. This glycoprotein is expressed in the fetal human brain and is believed to be involved in the embryonic development of the neocortex. Further analyses are planned to determine the significance of the increased levels of AHSG in the CSF of patients with low-grade gliomas.
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PMID:Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas. 1285 4

In the last two decades radioimmunotherapy has been used as an additional treatment option for malignant glioma in several centers. More than 400 patients have been reported, who were treated in the framework of different studies. Most of them received labelled antibodies to tenascin, an extracellular matrix-glycoprotein, which is expressed in high amounts in malignant gliomas. We report side effects and survival time of 46 patients, treated after surgical resection and conventional radiotherapy with intralesionally injected labelled (131-Iodine) antibodies to tenascin. Despite the fact, that many treatments have been performed, little is known about the distribution properties of labelled antibodies after injection in the tumour cavity. For an optimal effect labelled antibodies should be able to reach tumour cells, which have migrated into the surrounding tissue. We investigated the propagation velocity and area of distribution of labelled antibodies and their considerably smaller fragments after the injection in C6-gliomas of Wistar rats. Propagation increased with time and was significantly greater after injection of labelled fragments than after injection of labelled antibodies. According to our results labelled fragments might be better able to reach distant tumour cells in the peritumoural tissue of malignant gliomas than labelled antibodies.
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PMID:Intralesional radioimmunotherapy in the treatment of malignant glioma: clinical and experimental findings. 1453 64

Human glioma cell line U-373 MG expresses CMP-NeuAc : Galbeta1,3GlcNAc alpha2,3-sialyltransferase [EC No. 2.4.99.6] (alpha2,3ST), UDP-GlcNAc : beta-d-mannoside beta1,6-N-acetylglucosaminyltransferase V [EC 2.4.1.155] (GnT-V) and UDP-GlcNAc3: beta-d-mannoside beta1,4-N-acetylglucosaminyltransferase III [EC 2.4.1.144] (GnT-III) but not CMP-NeuAc : Galbeta1,4GlcNAc alpha2,6-sialyltransferase [EC 2.4.99.1] (alpha2,6ST) under normal culture conditions. We have previously shown that transfection of the alpha2,6ST gene into U-373 cells replaced alpha2,3-linked sialic acids with alpha2,6 sialic acids, resulting in a marked inhibition of glioma cell invasivity and a significant reduction in adhesivity. We now show that U-373 cells, which are typically highly resistant to cell death induced by chemotherapeutic agents (< 10% death in 18 h), become more sensitive to apoptosis following overexpression of these four glycoprotein glycosyltransferases. U-373 cell viability showed a three-fold decrease (from 20 to 60% cell death) following treatment with staurosporine, C2-ceramide or etoposide, when either alpha2,6ST and GnT-V genes were stably overexpressed. Even glycosyltransferases typically raised in cancer cells, such as alpha2,3ST and GnT-III, were able to decrease viability two-fold (from 20 to 40% cell death) following stable overexpression. The increased susceptibility of glycosyltransferase-transfected U-373 cells to pro-apoptotic drugs was associated with increased ceramide levels in Rafts, increased caspase-3 activity and increased DNA fragmentation. In contrast, the same glycosyltransferase overexpression protected U-373 cells against a different class of apoptotic drugs, namely the phosphatidylinositol 3-kinase inhibitor LY294002. Thus altered surface protein glycosylation of a human glioblastoma cell line can lead to lowered resistance to chemotherapeutic agents.
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PMID:Transfection of 2,6 and 2,3-sialyltransferase genes and GlcNAc-transferase genes into human glioma cell line U-373 MG affects glycoconjugate expression and enhances cell death. 1518 46

Malignant gliomas are the most frequent primary brain tumors and have a dismal prognosis due to their infiltrative growth. Gene therapy using viral vectors represents an attractive alternative to conventional cancer therapies. In a previous study, we established lentiviral vectors pseudotyped with lymphocytic choriomeningitis virus (LCMV) glycoproteins (GPs) and demonstrated transduction of human malignant glioma cells in culture. In the current approach, we compared the transduction efficacy of LCMV-GP- and vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped lentiviral vectors for malignant glioma cells and normal brain cells in vitro and in vivo. LCMV-GP pseudotypes transduced almost exclusively astrocytes, whereas VSV-G pseudotypes infected neurons as well as astrocytes. LCMV-GP pseudotypes showed an efficient transduction of solid glioma parts and specific transduction of infiltrating tumor cells. In contrast, VSV-G-pseudotyped lentiviral vectors transduced only a few tumor cells in solid tumor parts and infected mostly normal brain cells in infiltrating tumor areas. In conclusion, lentiviral vectors pseudotyped with LCMV glycoproteins represent an attractive option for gene therapy of malignant glioma.
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PMID:Selective transduction of malignant glioma by lentiviral vectors pseudotyped with lymphocytic choriomeningitis virus glycoproteins. 1561 Jun 9

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.
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PMID:Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases. 1721 7


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