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)

Malignant glioma cells are generally resistant or only weakly sensitive to tumor necrosis factor family of cell death-inducing ligands, including TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. The chemopreventive activity of polyphenolic compounds present in plant-derived food products has been well recognized in epidemiological studies; however, the mechanism of chemoprevention by these dietary constituents largely remains unknown. Curcumin, the yellow pigment in the spice turmeric, has profound anti-inflammatory activity and exhibits chemopreventive and tumor growth inhibitory activity. In the present study, we investigated whether curcumin sensitizes malignant glioma cell lines U251MG and U87MG to TRAIL-induced apoptosis. Treatment with low concentrations (5-20 microM) of curcumin alone had no effect on the viability of either cell line. At low concentration (5 ng/ml) TRAIL induced cytotoxicity in U251MG cells but not in U87MG cells. Whereas curcumin at subtoxic concentration sensitized U87MG cells to TRAIL-induced cytotoxicity, it had no effect on TRAIL-mediated cytotoxicity in U251MG cells. The combined curcumin and TRAIL treatment enhanced accumulation of hypo-diploid U87MG cells in sub G1 cell cycle phase and induced the cleavage of procaspases-3, -8, -9 and release of cytochrome c from mitochondria. These data indicate that curcumin differentially sensitizes glioma cells to TRAIL-induced apoptosis through the activation of both extrinsic (receptor-mediated) and intrinsic (chemical-induced) pathways of apoptosis. These results define a potential use of curcumin to sensitize glioma cells for TRAIL-mediated immunotherapy.
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PMID:Curcumin differentially sensitizes malignant glioma cells to TRAIL/Apo2L-mediated apoptosis through activation of procaspases and release of cytochrome c from mitochondria. 1641

A 30-year-old man presented with a supratentorial malignant glioma manifesting as isolated progressive left oculomotor nerve paresis. Computed tomography and magnetic resonance imaging showed an intra-axial tumor in the left temporal lobe, extending to the basal and prepontine cisterns, and compressing the brainstem. The tumor was removed subtotally. The histological diagnosis was anaplastic astrocytoma. Malignant glioma with exophytic growth in the temporal lobe should be considered in the differential diagnosis of isolated oculomotor nerve paresis.
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PMID:Isolated oculomotor nerve paresis in anaplastic astrocytoma with exophytic invasion. 1663 12

The current chemotherapeutic treatment of glioblastoma patients has minor success. Little is known about the molecular and cellular mechanisms of the resistance of gliomas towards current therapies. This study investigated both suppressive cellular effects and regulation of extracellular matrix remodeling proteins with pro-invasive activity in surviving human glioblastoma cells under clinically relevant treatments. All cellular and molecular biological investigations were performed on the genetically well-defined and clinically relevant p53-wild type U87Mg glioma cells. Malignant glioma cells underwent either radiation or temozolomide treatments alone, or combined chemo/radio treatment. Protein expression patterns were investigated by two-dimensional polyacrylamide gel electrophoresis followed by protein spot identification using tandem mass spectrometry analysis. Specific expression levels were quantified by Western-blotting. Extracellular gelatinase activities for both metalloproteinases MMP-2 and MMP-9 were determined by zymogramms. Survival curves indicated no effective suppression of glioma cells under all treatment conditions tested. Morphological changes demonstrated sub-lethal effect of both temozolomide and combined treatment. Expression of MMP-2, MMP-9, and membrane type 1 matrix metalloproteinases (MT1-MMP) was differentially up-regulated by increasing cellular density and treatment conditions. A significantly enhanced extracellular degrading activity under all treatment conditions tested was demonstrated for MMP-2 only. Being a marker for brain tumour progression and angiogenesis, lysozyme c was highly up-regulated under the combined chemo/radio treatment. The activation of proteins with pro-invasive activity indicates an increasing malignancy grade of surviving glioma cells under treatment conditions tested correlating well with more aggressive tumour phenotypes observed clinically in recurrences of treated glioblastomas.
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PMID:Pro-invasive gene regulating effect of irradiation and combined temozolomide-radiation treatment on surviving human malignant glioma cells. 1680 66

Malignant glioma is the most common central nervous system tumor of adults and is associated with a significant degree of morbidity and mortality. Gliomas are highly invasive and respond poorly to conventional treatments. Gliomas, like other tumor types, arise from a complex and poorly understood sequence of genetic and epigenetic alterations. Epigenetic alterations leading to gene silencing, in the form of aberrant CpG island promoter hypermethylation and histone deacetylation, have not been thoroughly investigated in brain tumors, and elucidating such changes is likely to enhance our understanding of their etiology and provide new treatment options. We used a combined approach of pharmacologic inhibition of DNA methylation and histone deacetylation, coupled with expression microarrays, to identify novel targets of epigenetic silencing in glioma cell lines. From this analysis, we identified >160 genes up-regulated by 5-aza-2'-deoxycytidine and trichostatin A treatment. Further characterization of 10 of these genes, including the putative metastasis suppressor CST6, the apoptosis-inducer BIK, and TSPYL5, whose function is unknown, revealed that they are frequent targets of epigenetic silencing in glioma cell lines and primary tumors and suppress glioma cell growth in culture. Furthermore, we show that other members of the TSPYL gene family are epigenetically silenced in gliomas and dissect the contribution of individual DNA methyltransferases to the aberrant promoter hypermethylation events. These studies, therefore, lay the foundation for a comprehensive understanding of the full extent of epigenetic changes in gliomas and how they may be exploited for therapeutic purposes.
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PMID:Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma. 1688 46

Management of Malignant Gliomas continues to be a challenge. We prospectively studied the role of adding weekly Paclitaxel to Fractionated Stereotactic Radiation Therapy (FSRT) in the treatment of Malignant Gliomas. Twenty-three Glioblastoma Multiforme and two Anaplastic Astrocytoma were studied. Patients received 46 Gy at 2 Gy/fraction followed by a boost utilizing FSRT at a fraction of 2.5 Gy for 8 fractions. Paclitaxel is delivered concomitantly at 150 mg/m(2) weekly for six cycles. Eighteen patients had pharmacokinetic assays of Paclitaxel levels. All patients were followed until death or for a maximum of 36 months. The overall survival of the whole group was 14 months. The median survival for RPA prognostic classes III, IV, V, and VI were 20, 14, 12, and 11 months. Higher survival (14 months) was noted in the subtherapeutic phenytoin level group compared to 10 months in the therapeutic group (P=0.271). No grade 4 CTCAE (version 3.0) toxicities were observed. Enhanced survival was demonstrated with gross tumor resection (20.8 months), KPS > or =80 (18.7 months) and age < or =60 years (27 months) as compared to subtotal resection or biopsy (12.1 months, P< 0.005), KPS < or =70 (10.8 months, P=0. 005) and older age > 60 (10.46 months, P=0.006), respectively. Our study suggests that: i) the use of weekly Paclitaxel and FSRT in Gliomas is well tolerated with a survival of 14 months; ii) the regimen resulted in improvement of survival of RPA classes IV, V, VI; and iii) the use of FSRT boost may be studied with other chemotherapeutic agents to see if superior results can be attained.
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PMID:Fractionated stereotactic radiotherapy boost and weekly paclitaxel in malignant gliomas clinical and pharmacokinetics results. 1753 24

Malignant glioma represents one of the most lethal and angiogenic cancers. Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Although several molecular mechanisms contribute to tumor angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway appears particularly important and has been a prominent therapeutic target in cancer treatment. Several preclinical studies have demonstrated efficacy of antiangiogenic agents in both subcutaneous and orthotopic malignant glioma xenograft models. Recently, a phase II clinical trial of bevacizumab, a neutralizing monoclonal antibody to VEGF, in combination with irinotecan has demonstrated promising radiographic response and survival benefit in patients with recurrent malignant glioma. Several other antiangiogenic agents such as inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors (FGFs), angiopoietins/Tie-2 system, protein kinase C and integrins are currently in preclinical and clinical development. Despite the encouraging results of antiangiogenic therapies in malignant glioma, there are several challenges to be overcome to achieve optimal clinical benefit. Identification of biomarkers to predict response or resistance and to monitor antiangiogenic effects is important to enrich for patients who are likely to respond to therapy and to define the optimal biological dose. At present, antiangiogenic therapies remain palliative suggesting that overcoming antiangiogenic resistance may require multi-targeted agents, combination of agents targeting different angiogenic pathways or multi-modality combination with radiation, chemotherapy, other targeted therapeutics or immunotherapy. In this review, we will discuss the current development, promise and challenge of antiangiogenic therapy in malignant glioma.
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PMID:Antiangiogenic therapy in malignant glioma: promise and challenge. 1822 Jul 91

Malignant glioma is the most common primary brain tumor, and its ability to invade the surrounding brain parenchyma is a leading cause of tumor recurrence and treatment failure. Whereas the molecular mechanisms of glioma invasion are incompletely understood, there is growing evidence that cytoskeletal-matrix interactions contribute to this process. Fascin, an actin-bundling protein, induces parallel actin bundles in cell protrusions and increases cell motility in multiple human malignancies. The role of fascin in glioma invasion remains unclear. We demonstrate that fascin is expressed in a panel of human malignant glioma cell lines, and downregulation of fascin expression in glioma cell lines by small interfering RNA (siRNA) is associated with decreased cellular attachment to extracellular matrix (ECM) and reduced migration. Using immunofluorescence analysis, we show that fascin depletion results in a reduced number of filopodia as well as altered glioma cell shape. In vitro invasiveness of U251, U87, and SNB19 glioma cells was inhibited by fascin siRNA treatment by 52.2%, 40.3%, and 23.8% respectively. Finally, we show a decreased invasiveness of U251-GFP cells by fascin knockdown in an ex vivo rat brain slice model system. This is the first study to demonstrate a role for fascin in glioma cell morphology, motility, and invasiveness.
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PMID:The role of fascin in the migration and invasiveness of malignant glioma cells. 1828 37

Malignant glioma is a consistently fatal brain cancer. The tumor invades the surrounding tissue, limiting complete surgical removal and thereby initiating recurrence. Identifying molecules critical for glioma invasion is essential to develop targeted, effective therapies. The expression of astrocyte elevated gene-1 (AEG-1) increases in malignant glioma and AEG-1 regulates in vitro invasion and migration of malignant glioma cells by activating the nuclear factor-kappaB (NF-kappaB) signaling pathway. The present studies elucidate the domains of AEG-1 important for mediating its function. Serial NH(2)-terminal and COOH-terminal deletion mutants were constructed and functional analysis revealed that the NH(2)-terminal 71 amino acids were essential for invasion, migration, and NF-kappaB-activating properties of AEG-1. The p65-interaction domain was identified between amino acids 101 to 205, indicating that p65 interaction alone is not sufficient to mediate AEG-1 function. Coimmunoprecipitation assays revealed that AEG-1 interacts with cyclic AMP-responsive element binding protein-binding protein (CBP), indicating that it might act as a bridging factor between NF-kappaB, CBP, and the basal transcription machinery. Chromatin immunoprecipitation assays showed that AEG-1 is associated with the NF-kappaB binding element in the interleukin-8 promoter. Thus, AEG-1 might function as a coactivator for NF-kappaB, consequently augmenting expression of genes necessary for invasion of glioma cells. In these contexts, AEG-1 represents a viable potential target for the therapy of malignant glioma.
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PMID:Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. 1831 12

The immune system of patients with malignant gliomas is profoundly suppressed. The suppression involves both the cellular and humoral immunity and it is mainly attributable to selective depletion and malfunction of helper T cells. Malignant glioma cells express potent immunosuppressive factors such as transforming growth factor-beta(2), inteleukin-10 and prostaglandin E(2). Malignant glioma cells also produce chemoattractants and immunostimulatory cytokines which may activate the immune cells. However, the production of these stimulatory cytokines is not self-destructive to glioma cells because of the immunosuppression. Rather, the tumour cells use them to gain a growth advantage. Indeed the cytokines may act as a growth stimulator of the tumour cells themselves (autocrine mechanism), they may act as angiogenic factors to endothelial cells (paracrine mechanism) or induce the attracted immune cells to secrete angiogenic factors. Some cytokines produced by malignant glioma cells are known to be growth inhibitory to normal astrocytes. Recent studies on tumour suppressor genes suggest a close link between the aberrant genes and the immunobiologic features of malignant glioma cells.
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PMID:Immunobiology of malignant gliomas. 1863 50

Malignant glioma, in particular glioblastoma multiforme (GBM), represents one of the most devastating cancers currently known and existing treatment regimens do little to change patient prognosis. Conditionally replicating adenoviral vectors (CRAds) represent attractive experimental anti-cancer agents with potential for clinical application. However, early protein products of the wild type adenovirus backbone--such as E1A--limit CRAds' replicative specificity. In this study, we evaluated the oncolytic potency and specificity of CRAds in which p300/CPB and/or pRb binding capacities of E1A were ablated to reduce non-specific replicative cytolysis. In vitro cytopathic assays, quantitative PCR analysis, Western blot, and flow cytometry studies demonstrate the superior anti-glioma efficacy of a double-mutated CRAd, Ad2/24CMV, which harbors mutations that reduce E1A binding to p300/CPB and pRb. When compared to its single-mutated and wild type counterparts, Ad2/24CMV demonstrated attenuated replication and cytotoxicity in representative normal human brain while displaying enhanced replicative cytotoxicity in malignant glioma. These results have implications for the development of double-mutated CRAd vectors for enhanced GBM therapy.
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PMID:Evaluation of E1A double mutant oncolytic adenovectors in anti-glioma gene therapy. 1864 43


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