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 is a devastating brain tumor with no effective treatment. This randomised, controlled study involved 36 patients with operable primary or recurrent malignant glioma. Seventeen patients were randomized to receive AdvHSV-tk gene therapy (3 x 10(10) pfu) by local injection into the wound bed after tumor resection, followed by intravenous ganciclovir (GCV), 5 mg/kg twice daily for 14 days. The control group of 19 patients received standard care consisting of radical excision followed by radiotherapy in those patients with primary tumors. The primary end-point was survival as defined by death or surgery for recurrence. Secondary end-points were all-cause mortality and tumour progression as determined by MRI. Overall safety and quality of life were also assessed. Findings were also compared with historical controls (n = 36) from the same unit over 2 years preceding the study. AdvHSV-tk treatment produced a clinically and statistically significant increase in mean survival from 39.0 +/- 19.7 (SD) to 70.6 +/- 52.9 weeks (P = 0.0095, log-rank regression vs. randomized controls). The median survival time increased from 37.7 to 62.4 weeks. Six patients had increased anti-adenovirus antibody titers, without adverse effects. The treatment was well tolerated. It is concluded that AdvHSV-tk gene therapy with GCV is a potential new treatment for operable primary or recurrent high-grade glioma.
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PMID:AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. 1550 14

Malignant glioma is the major brain tumor in adults and has a poor prognosis. The failure to control invasive cell subpopulations may be the key reason for local glioma recurrence after radical tumor resection and may contribute substantially to the failure of the other treatment modalities such as radiation therapy and chemotherapy. As a model for this invasion, we have implanted spheroids from a human glioma cell line (U251) in three-dimensional collagen type I matrices, which these cells readily invade. We first observed that the Src family kinase-specific pharmacologic inhibitors PP2 and SU6656 significantly inhibited the invasion of the cells in this assay. We confirmed this result by showing that expression of two inhibitors of Src family function, dominant-negative-Src and CSK, also suppressed glioma cell invasion. To characterize this effect at the level of the cytoskeleton, we used fluorescent time-lapse microscopy on U251 cells stably expressing a YFP-actin construct and observed a rapid change in actin dynamics following addition of PP2 in both two-dimensional and three-dimensional cultures. In monolayer cultures, PP2 caused the disappearance of peripheral membrane ruffles within minutes. In three-dimensional cultures, PP2 induced the loss of actin bursting at the leading tip of the invadopodium. The inhibition of Src family activity is thus a potential therapeutic approach to treat highly invasive malignant glioma.
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PMID:SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions. 1556 76

Malignant glioma comprises the majority of primary human brain tumors with 16,800 new cases reported each year in the USA. Its prognosis remains dismal despite numerous attempts to improve conventional therapeutic modalities. Therefore, much effort is devoted to the exploration of alternative forms of treatment such as immunotherapy. The identification of potential target structures highly overexpressed in brain tumors is a crucial prerequisite for the activation of the immune defense against malignant glioma cells. By screening an expression database for genes highly expressed in glioblastoma multiforme (GBM), we identified the Pit-Oct-Unc (POU) cooperating transcription factor SOX11 that is known to be crucially involved in brain development. Analysis of the expression pattern of SOX11 in different normal adult and fetal tissues by multiple tissue dot blot and by a highly sensitive quantitative PCR assay confirmed the selective overexpression of SOX11 in fetal brain tissue. Examination of tissue specimens obtained from malignant gliomas and from normal brain by quantitative real-time PCR (Q-RT-PCR) revealed upregulation of SOX11 in almost all tumor samples (15/16) as compared to the pooled normal brain. Seventy-five percent of the tumor samples (12/16) showed a 5- to more than 600-fold overexpression. We conclude that, after downregulation of SOX11 in the adult brain, its expression is reactivated during tumorigenesis and that SOX11 therefore represents a promising novel molecular target for adjuvant therapy of malignant gliomas.
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PMID:Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas. 1558 15

Malignant glioma cells secrete thrombospondin-1 (TSP-1) which participates in the motility of glioma cells, and binds to cell surface alphavbeta3 and alpha3beta1 integrins, and syndecan-1. This study evaluated the amount of TSP-1 secretion from malignant glioma cells, and the expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1. The amounts of TSP-1 in the supernatants from 10 malignant glioma cell lines and eight non-glioma malignant tumor cell lines were measured by enzyme-linked immunosorbent assay. Expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1 were examined by flow cytometry. The amounts of TSP-1 secreted by malignant glioma cells were 43 to 2431 ng/l x 10(6) cells/24 h (mean +/- SD = 626 +/- 792). Seven of 10 glioma cell lines secreted more than 100 ng of TSP-1 and three of these cell lines secreted more than 1 microg. Seven of eight non-glioma cell lines secreted less than 100 ng of TSP-1. All glioma cell lines expressed alpha3beta1 integrin and syndecan-1, and seven of 10 glioma cell lines expressed alphavbeta3 integrin. Treatment of the glioma cell lines with TGF-beta2 did not change the expression of alphavbeta3 integrin. These results suggest that malignant glioma cells secrete high levels of TSP-1, which may be important in the migration of glioma cells via interactions with alphavbeta3 and alpha3beta1 integrins, and syndecan-1.
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PMID:Quantification of thrombospondin-1 secretion and expression of alphavbeta3 and alpha3beta1 integrins and syndecan-1 as cell-surface receptors for thrombospondin-1 in malignant glioma cells. 1566 72

Malignant glioma of the CNS is a tumor with a very bad prognosis. Development of adjuvant immunotherapy is hampered by interindividual and intratumoral antigenic heterogeneity of gliomas. To evaluate feasibility of tumor vaccination with (autologous) tumor cells, we have studied uptake of tumor cell lysates by dendritic cells (DCs), and the T-cell stimulatory capacity of the loaded DCs. DCs are professional antigen-presenting cells, which have already been used as natural adjuvants to initiate immune responses in human cancer. An efficacious uptake of tumor cell proteins, followed by processing and presentation of tumor-associated antigens by the DCs, is indeed one of the prerequisites for a potent and specific stimulation of T lymphocytes. Human monocytes were differentiated in vitro to immature DCs, and these were loaded with FITC-labeled tumor cell proteins. Uptake of the tumor cell proteins and presentation of antigens in the context of both MHC class I and II could be demonstrated using FACS analysis and confocal microscopy. After further maturation, the loaded DCs had the capacity to induce specific T-cell cytotoxic activity against tumor cells. We conclude that DCs loaded with crude tumor lysate are efficacious antigen-presenting cells able to initiate a T-cell response against malignant glioma tumor cells.
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PMID:Uptake and presentation of malignant glioma tumor cell lysates by monocyte-derived dendritic cells. 1569 47

Malignant glioma invasion into the surrounding brain tissue is still a major problem for any therapeutical methods. Matrix metalloproteinases (MMPs) have been implicated as important factors in this pathological process. In this study, one of the non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin was employed to investigate the effect of inhibition of cell invasion mediated by MMP-2 and MMP-9 in human malignant glioma cell lines, A172, U87MG, U251MG, and U373MG in vitro. MTT assay was firstly examined to determine non-cytotoxic dose range, then gelatin zymography, matrigel invasion assay, migration assay and MMP-2 activity assay for 24 h exposure in indomethacin were employed to assess the inhibitory effect of indomethacin. MTT assay revealed that dose with 0, 50, and 500 microM/ml were non-cytotoxic. Zymography demonstrated: (a) expression of MMP-2 and MMP-9 activity was downregulated along with elevated dose of indomethacin. (b) MMP-2 activity that changed from pro-MMP-2 to active form of MMP-2 in supernatants of cell lines could not be inhibited by indomethacin. Invasion assay disclosed that the number of invading cells through the matrigel were significantly decreased in a dose dependent manner. Migration assay indicated indomethacin did not affect cells migration. MMP-2 activity assay showed the total and active MMP-2 secretion was suppressed by 500 microM/ml of indomethacin. Our present study is the first report on inhibitive effect of indomethacin mediated by MMP-2 and MMP-9 in invasion assay of glioma cell lines. The current study suggested that non-cytotoxic level of indomethacin was able to reduce the cell invasion of malignant gliomas mediated by MMP-2 and MMP-9, but it did not affected on cell motility. It also lowered down the activity of MMP-2 and MMP-9, and could reduce of MMP-2 secretion of cell lines. Thus, high concentration of indomethacin within non-cytotoxic dose might offer a new therapeutic strategy to impair cell invasion of gliomas.
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PMID:Inhibition of cell invasion by indomethacin on glioma cell lines: in vitro study. 1580 68

Malignant glioma tumor cells in situ exhibit on their surfaces the interleukin 13 (IL-13) receptor designated IL13Ralpha2. To target herpes simplex virus 1 to this receptor, we constructed a recombinant virus (R5111) in which the known heparan sulfate binding sites in glycoproteins B and C were deleted and IL-13 was inserted into both glycoproteins C and D. We also transduced a baby hamster kidney cell line lacking the known viral receptors (J1-1) and Vero cells with a plasmid encoding IL13Ralpha2. The J1-1 derivative (J-13R) cell line is susceptible to and replicates the R5111 recombinant virus but not the wild-type parent virus. We report the following. (i) Expression of IL13Ralpha2 was rapidly lost from the surface of transduced cells grown in culture. The loss appeared to be related to ligands present in fetal bovine serum in the medium. None of the malignant glioma cell lines cultivated in vitro and tested to date exhibited the IL13Ralpha2 receptor. (ii) Soluble IL-13 but not IL-4 or IL-2 blocked the replication of R5111 recombinant virus in J-13R cells. (iii) The endocytosis inhibitor PD98059 blocked the replication in J1-1 cells of a mutant lacking glycoprotein D (gD-/-) but not the replication of R5111 in the J-13R cells. We conclude that R5111 enters cells via its interaction with the IL13Ralpha2 receptor in a manner that cannot be differentiated from the interaction of wild-type virus with its receptors.
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PMID:Characterization of a recombinant herpes simplex virus 1 designed to enter cells via the IL13Ralpha2 receptor of malignant glioma cells. 1582 41

Malignant glioma are especially difficult to model in vivo. Here we review the most recent strategies for designing relevant models of glioma. These should greatly contribute to identification of new tumor regulating molecules and facilitate testing of inhibitors to be used in therapeutical trials as well as the drug resistance that they might confer.
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PMID:[Understanding in treating gliomas: an adequate experimental model for each question]. 1612 1

Frequent loss of heterozygosity (LOH) and mutations of the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) have been found in sporadic gliomas. The most documented regions of allelic losses include 9p21, 10q23-25 and 17p1 3 whereas PTEN aberrations are preferentially found in glioblastoma multiformes. This research aimed to detect the incidence of allelic losses on chromosomes 10q, 9p, 17p and 13q and mutations on exons 5, 6 and 8 of PTEN in malignant gliomas. Malignant glioma specimens obtained were classified histopathologically according to the WHO criteria. Each tumor was then subjected to polymerase chain reaction (PCR)-LOH analysis using microsatellite markers and single-stranded conformational polymorphism (SSCP) analysis. Twelve of 23 (52%) malignant glioma cases showed allelic losses whereas 7 of 23 (30%) samples showed aberrant band patterns and mutations of PTEN. Four of these cases showed LOH in 10q23 and mutations of PTEN. The data on LOH indicated the involvement of different genes in the genesis of glioma whereas mutations of PTEN indicated the role of PTEN tumor suppressor gene in the progression of glioma in Malay population.
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PMID:Malignant glioma: the involvement of loss of allelic heterozygosity and PTEN mutations in a group of Malay patients. 1612 50

Invasion of tumor cells into the surrounding normal brain tissues is a prominent feature of malignant gliomas. Malignant glioma cells secrete thrombospondin-1 which participates in the motility of glioma cells and binds cell surface heparan sulfate proteoglycan. To clarify the invasion mechanism of tumor cells, expression of the syndecans (syndecan-1, -2, -3, and -4), a major cell surface heparan sulfate proteoglycan family, was analyzed in malignant gliomas. Involvement of nuclear factor-kappaB (NF-kappaB) on syndecan-1 expression was also investigated. Using reverse transcription-PCR, the authors analyzed the expression of syndecan-1, -2, -3, and -4 in 10 malignant glioma cell lines, 2 glioblastoma specimens, and 2 normal brain specimens. All malignant glioma cell lines and glioblastoma specimens expressed all types of syndecan mRNA, except in one glioma cell line that lacked syndecan-3 expression. On the other hand, normal brain specimens expressed syndecan-2, -3, and -4 mRNA, but did not syndecan-1 mRNA. Syndecan-1 protein was localized in the cell surface of all malignant glioma cell lines by flow cytometry. Various levels of active nuclear factor-kappa B (NF-kappaB) was detected in all malignant glioma cell lines using immunoblotting. The expression of active NF-kappaB and syndecan-1 increased in U251 glioma cells after tumor necrosis factor-alpha or interleukin-1beta treatment, which can activate NF-kappaB. The amplification of active NF-kappaB and syndecan-1 by tumor necrosis factor-alpha or interleukin-1beta was suppressed by an inhibitor of NF-kappaB activation (emodin). Emodin also downregulated the expression of syndecan-1 mRNA in U251 cells. These results indicate that malignant glioma cells express all types of syndecans and suggest that NF-kappaB participates in the upregulation of the syndecan-1 expression at the transcriptional level, and increased expression of syndecan-1 could associate with extracellular matrices including thrombospondin-1.
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PMID:Expression of syndecans, a heparan sulfate proteoglycan, in malignant gliomas: participation of nuclear factor-kappaB in upregulation of syndecan-1 expression. 1613 27


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