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 (glioblastoma and anaplastic astrocytoma) remain incurable despite extensive resection, radiotherapy, chemotherapy and experimental therapies. Few studies have addressed either the costs of various treatments for malignant glioma or their cost effectiveness. The aims of this study were to identify direct hospital costs of treating patients with biopsy proven malignant glioma. The study was carried out within the setting of a dedicated neuro-oncology clinic at a university teaching hospital and included 236 patients treated between 1989 and 1995. The study used the unit costing of each item of treatment according to NHS National Costing Project. The cost of treatment was broken down into its various components: bed days, investigations, surgery, radiotherapy, chemotherapy and neuro-oncology out-patient follow-ups. The mean costs for each of the items based on 1995 figures for the 157 patients having surgery followed by radiotherapy were neuroradiological investigations (442 Pounds), neurosurgical bed days (2407 Pounds), neurosurgery (2068 Pounds), neuropathology (434 Pounds), radiotherapy (8832 Pounds), out-patients (1078 Pounds) and chemotherapy (440 Pounds). Total treatment costs per patient ranged from 1978 Pounds to 26,980 Pounds. Median costs of care decreased sequentially with worsening MRC Brain Tumour prognostic group. Management of patients with the best prognosis (MRC index score of 1-10) cost a median of 16,550 Pounds (range 4572-26,090 Pounds) whilst the median management cost of those in the worst prognostic group (MRC score 34-38) was 6514 Pounds (range 1978-18,360 Pounds). The median cost of each week of survival in the patients with the best outcome (MRC score 1-10) was < 150 Pounds compared to 232 Pounds for each week of survival for patients in the worst prognostic group (MRC score 34-38). This study made no attempt to collect costs of supportive or community-based care. Prospective studies are required to collect such data, as well as assessing the costs effectiveness of alternative treatment strategies.
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PMID:The costs of managing patients with malignant glioma at a neuro-oncology clinic. 1101 62

Ezrin belongs to the ezrin-radixin-moesin family proteins, which cross-link actin cytoskeleton and plasma membrane. Malignant glioma cells are paradigmatic for their strong migratory and invasive properties. Here, we report that the expression of dominant-negative ezrins inhibits clonogenicity, migration, and invasiveness of human malignant glioma cells. Furthermore, dominant-negative ezrins block hepatocyte growth factor (HGF)-mediated stimulation of clonogenicity and migration, without altering HGF-induced protein kinase B/Akt and focal adhesion kinase phosphorylation. Glioma cells expressing dominant-negative ezrins exhibit a shift of the BCL-2/BAX rheostat toward apoptosis, reduced alpha(V)beta(3) integrin expression and reduced matrix metalloproteinase (MMP) expression and activity. These changes are associated with a dramatic loss of transforming growth factor beta(2) (TGF-beta(2)) release. Exogenous supplementation of TGF-beta(2) overcomes the inhibitory effects of dominant-negative ezrins on migration and clonogenicity. A neutralizing TGF-beta(2) antibody mimics the effects of dominant-negative ezrins on clonogenicity and migration. Exogenous HGF markedly induces TGF-beta(2) protein levels, and a neutralizing TGF-beta(2) antibody abolishes the HGF-mediated increase in glioma cell motility. Finally, TGF-beta(2) does not modulate BCL-2 or BAX expression, but BCL-2 gene transfer increases the levels of latent and active TGF-beta(2). Intracranial xenografts of U87MG glioma cells transfected with the dominant-negative ezrins in athymic mice grow to significantly smaller volumes, and the median survival of these mice is 50 d compared with 28 d in the control group. These data define a novel pathway for HGF-induced glioma cell migration and invasion, which requires ezrin, changes in the BCL-2/BAX rheostat, and the induction of TGF-beta(2) expression in vitro, and underscore the important role of HGF signaling in vivo.
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PMID:Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2. 1133 65

Malignant glioma cells secrete transforming growth factor-beta (TGF-beta) and can activate latent TGF-beta. However, the mechanism of the latent TGF-beta activation has not yet been determined. This study examined whether thrombospondin-1 (TSP-1) secreted by malignant glioma cell lines participates in the activation of latent TGF-beta secreted by the glioma cells. Western blot analysis revealed that TSP-1 was present in both the cell lysates and the culture supernatants of all three malignant glioma cell lines (T98G, A172, and U251). A bioassay for TGF-beta activity revealed that all malignant glioma cell lines used in this study could activate latent TGF-beta by themselves. Latent TGF-beta 1 activation, evaluated by enzyme-linked immunosorbent assay, was inhibited by more than 50% by the addition of neutralizing anti-TSP-1 monoclonal antibody or anti-TSP-1 polyclonal antibody. These results indicate that TSP-1 has a predominant role in the activation of latent TGF-beta in malignant glioma cells.
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PMID:Participation of thrombospondin-1 in the activation of latent transforming growth factor-beta in malignant glioma cells. 1139 5

Cell invasion is a nature of malignant gliomas, demeriting to many efforts of the treatment. Matrix metalloproteinase (MMP) is acknowledged as a key factor in this complicated process. The aim of this study was to investigate whether inhibition of MMP activity in malignant glioma cells could be achieved by a novel agent, BE16627B (BE). Malignant glioma cell lines, U87MG, U251MG, and U373MG, were employed to evaluate inhibitory effect on zymogram, type IV collagenolysis assay, and haptoinvasion assay for 24 h exposure of BE, following preliminar
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PMID:Suppression of matrix metalloproteinase-2 and -9 mediated invasiveness by a novel matrix metalloproteinase inhibitor, BE16627B. 1145 Nov 98

Kupffer cells play an important role in controlling the growth and development of liver metastases. However, the pathway of Kupffer cells against tumor metastases is not clear. In the present study, we set up an experimental model to investigate the mechanisms on how Kupffer cells kill tumor cells which metastasize to the liver. Malignant glioma cells were cocultured with Kupffer cells or treated with culture medium collected from lipopolysaccharide (LPS)-activated Kupffer cells. The results showed that the interaction between Kupffer cells and malignant glioma cells significantly stimulated the generation of tumor necrosis factoralpha (TNFalpha). TNFalpha was mainly produced by Kupffer cells, as its level in culture medium obtained from LPS-treated Kupffer cells was not significantly different from that of malignant glioma cells treated with the same medium. Both Kupffer cells and LPS/Kupffer cell-conditioned supernatants induced expression of Fas and Fas ligand on malignant glioma cells. Subsequently a significant proportion of malignant glioma cells became apoptotic, as evidenced by positive staining of annexin V and propidium iodine and an increase in cellular DNA fragmentation. Therefore, this study supports a novel pathway of Kupffer cells against liver metastases, in which tumor cells were apoptotic via the Fas-Fas ligand system induced by TNFalpha released from Kupffer cells.
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PMID:Induction of Fas and Fas ligand expression on malignant glioma cells by Kupffer cells, a potential pathway of antiliver metastases. 1167 53

Experimental evidence suggests that the transcription factor nuclear factor-Kappa B (NF-kappa B) plays an important role in tumor cell invasion, apoptosis suppression and growth. Malignant glioma is one of the most intractable tumors because of its invasiveness to surrounding brain tissue. Our study investigated the role of neomycin on NF-kappa B activity in glioma cell cultures. We performed immunocytochemical analysis of cells with the antibody NF-kappa Bp65 which results show that neomycin decreases significantly the activation of NF-kappa B when added to glioma cultures for 30 min. This finding supports an important role for neomycin in glioma invasion, apoptosis and growth. Collectively, these data suggest a rationale for clinical trials with neomycin in the treatment of gliomas.
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PMID:Glioma cell-associated sustained activation of the transcription factor, nuclear factor-kappa B, was inhibited by neomycin. 1273 36

Malignant glioma (MG) cells up-regulate angiogenic factor expression in response to different extracellular signals such as hypoxia and cytokines. This up-regulation in turn promotes angiogenesis and tumor progression. Posttranscriptional gene regulation has been implicated as one mechanism for this tumor response, and we have previously shown that HuR, a protein associated with RNA stabilization, is overexpressed in MGs (L. B. Nabors et al., Cancer Res., 61: 2154-2161, 2001). Here, we demonstrate a marked up-regulation (RNA and protein) of tumor necrosis factor alpha (TNF-alpha), interleukin 8, and, to a lesser extent, vascular endothelial growth factor in U251 glioma cells after stimulation with TNF-alpha. RNA kinetic studies indicated that TNF-alpha induced the stabilization of all three transcripts. Using a luciferase reporter assay, we demonstrate that the AU-rich elements (AREs) in the 3'-untranslated region of these genes significantly contribute to this posttranscriptional regulation. UV cross-linking and immunoprecipitation with glioma extracts indicate that HuR binds to all three AREs. When HuR is overexpressed in glioma cells, there is enhanced RNA stabilization of all three angiogenic factor transcripts with a concomitant increase in mRNA and protein expression (up to 7-fold). These findings indicate that TNF-alpha up-regulates angiogenic factor expression in MG cells and that RNA stabilization, via the AREs in the 3'-untranslated region, contributes to this up-regulation.
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PMID:Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR. 1287 24

Malignant glioma is characterised by extensive neovascularisation, principally influenced by vascular endothelial growth factor (VEGF). ZD6474 is a potent inhibitor of VEGF-R2 tyrosine kinase activity, but with additional inhibitory effects on other growth factors. In this study, we have investigated the effects of ZD6474 with regard to tumour growth, neovascularisation, proliferation and apoptosis in the intracerebral rat glioma model, BT4C. ZD6474 (50 and 100 mg kg(-1)) was given as a daily oral gavage. Animals were killed on day 19 and tumour volume was measured. Sections were stained for factor VIII, Ki-67 and for apoptosis. The ability of ZD6474 to inhibit cell growth directly was examined in vitro, using the glioma cell line BT4C and the transformed rat brain endothelial cell line RBE4. Cell growth was analysed with fluorometric microculture cytotoxicity assay to quantify the cytotoxic effects. ZD6474 significantly decreased tumour volume compared to controls. Microvascular density increased after treatment with ZD6474, and tumour cell proliferation index was reduced. There was also an increase in tumour cell apoptosis. In vitro, the growth of both cell lines was significantly reduced. The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities.
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PMID:The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model. 1530 85

Malignant glioma is a fatal human cancer in which surgery, chemo- and radiation therapies are ineffective. Therapeutic gene transfer used in combination with current treatment methods may augment their effectiveness with improved clinical outcome. We have shown that NUREL-C2, a replication-defective multigene HSV-based vector, is effective in treating animal models of glioma. Here, we report safety and biodistribution studies of NUREL-C2 using rhesus macaques as a model host. Increasing total doses (1 x 10(7) to 1 x 10(9) plaque forming units (PFU)) of NUREL-C2 were delivered into the cortex with concomitant delivery of ganciclovir (GCV). The animals were evaluated for changes in behavior, alterations in blood cell counts and chemistry. The results showed that animal behavior was generally unchanged, although the chronic intermediate dose animal became slightly ataxic on day 12 postinjection, a condition resolved by treatment with aspirin. The blood chemistries were unremarkable for all doses. At 4 days following vector injections, magnetic resonance imaging showed inflammatory changes at sites of vector injections concomitant with HSV-TK and TNFalpha expression. The inflammatory response was reduced at 14 days, resolving by 1 month postinjection, a time point when transgene expression also became undetectable. Immunohistochemical staining following animal killing showed the presence of a diffuse low-grade gliosis with infiltrating macrophages localized to the injection site, which also resolved by 1 month postinoculation. Viral antigens were not detected and injected animals did not develop HSV-neutralizing antibodies. Biodistribution studies revealed that vector genomes remained at the site of injection and were not detected in other tissues including contralateral brain. We concluded that intracranial delivery of 1 x 10(9) PFU NUREL-C2, the highest anticipated patient dose, was well tolerated and should be suitable for safety testing in humans.
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PMID:Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates. 1530 39

Malignant glioma patients have a dismal prognosis with an urgent need of new treatment modalities. Previously developed gene therapies for brain tumors showed promising results in experimental animal models, but failed in clinical trials due to low transfection rates and insufficient expression of the transgene in tumor cells, as well as low bystander killing effects. We have previously shown that the histone deacetylase inhibitor 4-phenylbutyrate (4-PB) enhances gap junction communication between glioma cells in culture. In this study, we demonstrate an activation of recombinant HSV-tk gene expression, and a dramatic enhancement of gap junction-mediated bystander killing effect by administration of the HSV-tk prodrug ganciclovir together with 4-PB. These findings that 4-PB potentiates "suicide gene" expression as well as enhances gap junctional communication and bystander killing of tumor cells justify further testing of this paradigm as an adjunct to suicide gene therapy of malignant gliomas.
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PMID:HDACi phenylbutyrate increases bystander killing of HSV-tk transfected glioma cells. 1546 75


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