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)

Recombinant tumor necrosis factor alpha (rTNF alpha; optimal dose 1000 U/ml) significantly increased the density of epidermal growth factor receptor (EGF-R) in three of four glioma cell lines in culture as determined by binding analysis of anti-EGF-R monoclonal antibody (mAb) 425. Since enhancement of EGF-R expression by rTNF-alpha was inhibited when cells were treated with the protein synthesis inhibitor cycloheximide, the effects of rTNF alpha may be protein-synthesis-dependent. The dose of rTNF alpha that was optimal for up-regulation of EGF-R on glioma cells did not inhibit the growth of these cells. 125I-labeled mAb 425 lysed glioma cells in culture following its internalization into the cells. After glioma cells had been treated with rTNF alpha, the growth-inhibitory effects of the mAb were significantly enhanced, probably a reflection of the increase in EGF-R density on the tumor cell surfaces. The rTNF alpha effects were specific to the EGF-R and did not affect unrelated glioma-associated antigens. In our previous clinical trials, 125I-labeled mAb 425 showed immunotherapeutic effects in glioma patients. The present study provides the basis for considerations of combined immunotherapy of glioma patients with 125I-labeled mAb 425 and rTNF alpha.
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PMID:Enhancement of epidermal growth factor receptor expression on glioma cells by recombinant tumor necrosis factor alpha. 156 13

Recombinant tumor necrosis factor alpha (TNF-alpha) significantly enhanced epidermal growth factor receptor (EGF-R) expression in U373-MG glioma cell line as determined by binding of anti-EGF-R monoclonal antibody (MAb) 425. The optimal dose of TNF-alpha was 1000 U/ml of media. When TNF-alpha was combined with recombinant interferon gamma (IFN-gamma), further upregulation of EGF-R was observed. However, IFN-gamma itself did not show any EGF-R enhancement in this cell line. Scatchard analysis of receptor binding revealed that this enhancement of EGF-R expression was due to an increase in the EGF-R density. TNF-alpha did not affect expression of other brain tumor-associated antigens defined by MAb ASHE2, ASHG4 and ASAY1. Cultured fibroblasts showed no upregulation of EGF-R by TNF-alpha, suggesting a differential effect of TNF-alpha on EGF-R expression on glioma cells and normal cells. We investigated whether TNF-alpha treatment of glioma cells increased the tumoricidal effects of radiolabeled MAb 425 which correlate with MAb density on tumor cell surfaces. Growth inhibition of glioma cells in culture by 125I-labeled MAb 425 was significantly enhanced after treatment of the cells with TNF-alpha. In previous clinical trials, 125I-labeled MAb 425 has shown immunotherapeutic effects in glioma patients. The present study provides the basis for considerations of combined immunotherapy of glioma patients with 125I-labeled MAb 425 and cytokines.
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PMID:[Enhancement of epidermal growth factor receptor (EGF-R) expression on glioma cells by cytokines]. 174 26

Lysis of tumor cells by activated cytotoxic lymphocytes requires their recognition of antigens associated with major histocompatibility complex molecules. The authors studied the constitutive expression of Class I and Class II major histocompatibility complex antigens on mouse brain-tumor cells and the capacity of different cytokines and cytokine combinations to alter this expression in vitro. Cells from the murine glioma 26 (GL26), glioma 261 (GL261), and ependymoblastoma A (EpA) cell lines were established in monolayer culture and treated for 48 hours with either alpha interferon, gamma interferon, tumor necrosis factor alpha, tumor necrosis factor alpha plus gamma interferon, or interleukin-2. They were then analyzed by flow cytometry for baseline and cytokine-altered major histocompatibility complex expression. All cell lines had a similar constitutive major histocompatibility complex pattern with low Class I antigen expression and no detectable Class II antigen expression. Alpha interferon substantially induced and up-regulated Class I antigen expression, but had no effect on Class II antigen expression. Gamma interferon also stimulated up-regulation of Class I antigen expression, generally doubling the anti-Class I antigen fluorescence of treated cells. Its effect on Class II antigen expression was more extensive. In the GL26 and GL261 cell lines the expression of Class II antigen determinants increased to 12 x and 14 x control values and as many as 75% of cells that had no detectable constitutive expression of Class II antigen expressed this antigen after priming with gamma interferon. The addition of tumor necrosis factor alpha to gamma interferon further increased Class II antigen expression on EpA tumor cells only. Interleukin-2 and tumor necrosis factor alpha alone had no effect on Class I or Class II antigen expression of any cell lines. It is concluded that Class I and Class II antigen expression in mouse glioma cell lines is induced and enhanced after treatment with certain cytokines in vitro. Use of these cell lines to create in situ primary brain tumors in C57BL/6 mice should provide an excellent animal system to study major histocompatibility complex modulation in brain tumor cells and to examine the potential impact of major histocompatibility complex up-regulation on the response of brain tumors to immunotherapy.
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PMID:Expression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro. 158 18

Cytokines exert receptor-mediated control over glia. Up-regulation of receptor expression of cytokine production corresponds with the acquisition of a neoplastic phenotype. A modified radial dish assay was used to determine whether in vitro locomotion of glioma cells is modified by the epidermal growth factor, the basic fibroblast growth factor, the bb dimer of platelet-derived growth factor, the nerve growth factor, or the tumor necrosis factor alpha. Human glioma cells were plated in the center of a petri dish with one of these cytokines in 0.5 ml agar (50 ng/ml if the cytokine was distributed evenly throughout the dish) at one edge, and 0.5 ml plain agar at the opposite edge. After 24 hours, a central zone of cells was established; the agar was gelatinized. Feeding medium was added to the dish, and slow elution from the agar established a cytokine gradient. Cell counts were performed daily over 6 to 10 days at predetermined distances on both sides of the central zone to assess directional cellular movement with respect to the cytokine gradient and the plain agar. The epidermal growth factor caused continuous chemoattraction, whereas the tumor necrosis factor alpha caused slight chemorepulsion for 24 to 48 hours, followed by strong chemoattraction. The bb dimer of platelet-derived growth factor, the basic fibroblast growth factor, and the nerve growth factor all maintained chemorepulsion over the entire 6 to 10 days. Therefore, the cytokines did affect glioma cell motility in vitro, and the modified radial dish assay used in this study provided a useful in vitro model for assessing the impact of the cytokines on glioma cell locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modification of human glioma locomotion in vitro by cytokines EGF, bFGF, PDGFbb, NGF, and TNF alpha. 764 98

We have found that the small stress protein, hsp27, exists in extracts of U251 MG human glioma cells in two forms: a large or aggregated form (L-hsp27, 300-400 kDa) and a small or dissociated form (S-hsp27, < 70 kDa), as indicated by centrifugation on sucrose density gradients. Dissociation of L-hsp27 to S-hsp27 was enhanced by incubation of cells with phorbol 12-myristate-13 acetate, interleukin-1 alpha, tumor necrosis factor alpha, or okadaic acid, all of which are known to enhance or mimic the effects of phosphorylation of hsp27 without stimulation of its synthesis. Exposure of cells to chemical stressors, namely, NaAsO2 and CdCl2, also enhanced the dissociation of L-hsp27. hsp27 that had been labeled with [32P]H3PO4 in U251 MG cells was detected mostly in fractions that contained S-hsp27, and the incorporation of radioactivity to S-hsp27 was enhanced under conditions that stimulated the dissociation of L-hsp27. L-hsp27 present in the (NH4)2SO4 fraction (0-50% saturation) of cell extracts were dissociated to 32P-labeled hsp27 when incubated in the presence of [gamma-32P]ATP and Mg2+. These results indicate that the molecular configuration of hsp27 in cells is determined in part by phosphorylation and dephosphorylation of this protein by protein kinase(s) and phosphatase(s) and, moreover, that the rapid dissociation of the aggregated form of hsp27 by phosphorylation might be involved in a cellular defense mechanism for protection against stress.
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PMID:Dissociation as a result of phosphorylation of an aggregated form of the small stress protein, hsp27. 815 58

The goal of our study was to assess whether the human immunodeficiency virus (HIV) coat protein gp120 induces functional alterations in astrocytes and microglia, known for their reactivity and involvement in most types of brain pathology. We hypothesized that gp120-induced anomalies in glial functions, if present, might be mediated by changes in the levels of intracellular messengers important for signal transduction, such as cAMP. Acute (10 min) exposure of cultured rat cortical astrocytes or microglia to 100 pM gp120 caused only a modest (50-60%), though statistically significant, elevation in cAMP levels, which was antagonized by the beta-adrenergic receptor antagonist propranolol. More importantly, the protein substantially depressed [by 30% (astrocytes) and 50% (microglia)] the large increase in cAMP induced by the beta-adrenergic agonist isoproterenol (10 nM), without affecting that induced by direct adenylate cyclase stimulation by forskolin. Qualitatively similar results were obtained using a glial fibrillary acidic protein (GFAP)-positive human glioma cell line. The depression of the beta-adrenergic response had functional consequences in both astrocytes and microglia. In astrocytes we studied the phosphorylation of the two major cytoskeletal proteins, vimentin and GFAP, which is normally stimulated by isoproterenol, and found that gp120 partially (40-50%) prevented such stimulation. In microglial cells, which are the major producers of inflammatory cytokines within the brain, gp120 partially antagonized the negative beta-adrenergic modulation of lipopolysaccharide (10 ng/ml)-induced production of tumor necrosis factor alpha. Our results suggest that, by interfering with the beta-adrenergic regulation of astrocytes and microglia, gp120 may alter astroglial "reactivity" and upset the delicate cytokine network responsible for the defense against viral and opportunistic infections.
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PMID:Human immunodeficiency virus coat protein gp120 inhibits the beta-adrenergic regulation of astroglial and microglial functions. 838 71

The expression of vascular endothelial growth factor (VEGF) has been implicated in brain tumor angiogenesis, and the promoter region for the VEGF gene contains several SP-1 and AP-1 (c-Fos and c-Jun) binding motifs. Among eight human glioma cell lines, cellular mRNA levels of transcription factors SP-1 and AP-1 (c-Fos and c-Jun) were found to be closely correlated with those of VEGF. VEGF expression appears to be highly susceptible to hypoxia or exogenous cytokines and growth factors. Of various cytokines and growth factors, basic fibroblast growth factor (bFGF), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 most potently enhanced VEGF mRNA levels of a glioma cell line, U251. Incubation of the glioma cells with bFGF or TNF-alpha increased both VEGF and SP-1 mRNA at 30 min and c-Fos mRNA at 1-3 h, over 5-fold. Nuclear run-on assays showed an apparent increase of the transcription of the VEGF gene as well as the SP-1 gene by bFGF or TNF-alpha. Gel mobility shift assays demonstrated that only SP-1 binding activity was increased 1 h after exposure to bFGF or TNF-alpha, and also that AP-1, but not SP-1, activity was significantly activated by hypoxia. Mithramycin, an inhibitor of SP-1, at 1-10 nM inhibited activation of the VEGF gene by bFGF or TNF-alpha but not that by hypoxia. Western blot analysis also demonstrated an increase in cellular amounts of VEGF by TNF-alpha and a decrease by co-administration with mithramycin. The promoter activity of the VEGF gene, which contains five SP-1 binding sites and one AP-1 binding site but not hypoxia regulatory elements, was enhanced by bFGF or TNF-alpha but not by hypoxia. The chloramphenicol acetyltransferase assay with VEGF promoter deletion constructs demonstrated that four clusterized SP-1 binding sites in the proximal promoter were essential for the basal transcription and the TNF-alpha-dependent activation. These data indicated that the expression of the VEGF gene enhanced by bFGF or TNF-alpha appeared to be mediated in part through the transcription factor SP-1, suggesting a different mechanism from that for hypoxia-induced activation of the VEGF gene.
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PMID:Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. 891 Apr 39

Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with a chronic neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraperesis (HAM/TSP). Although the pathogenesis of this disease remains to be elucidated, the evidence suggests that immunopathological mechanisms are involved. Since HTLV-1 tax mRNA was colocalized with glial acidic fibrillary protein, a marker for astrocytes, we developed an in vitro model to assess whether HTLV-1 infection activates astrocytes to secrete cytokines or present viral immunodominant epitopes to virus-specific T cells. Two human astrocytic glioma cell lines, U251 and U373, were transfected with the 3' portion of the HTLV-1 genome and with the HTLV-1 tax gene under astrocyte-specific promoter control. In this study, we report that Tax-expressing astrocytic glioma transfectants activate the expression of tumor necrosis factor alpha mRNA in vitro. Furthermore, these Tax-expressing glioma transfectants can serve as immunological targets for HTLV-1-specific cytotoxic T lymphocytes (CTL). We propose that these events could contribute to the neuropathology of HAM/TSP, since infected astrocytes can become a source for inflammatory cytokines upon HTLV-1 infection and serve as targets for HTLV-1-specific CTL, resulting in parenchymal damage by direct lysis and/or cytokine release.
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PMID:Astrocyte-specific expression of human T-cell lymphotropic virus type 1 (HTLV-1) Tax: induction of tumor necrosis factor alpha and susceptibility to lysis by CD8+ HTLV-1-specific cytotoxic T cells. 937 71

Numerous in vivo methodologies have documented the invasive behavior of glioma cells through normal brain parenchyma. Glioma cell locomotion has also been assessed with a number of in vitro assays including the Boyden chamber and other chemotaxis assays, colloidal gold cell tracking, analysis of migration of cells tumor cells from spheroids, confrontation cultures of glioma cells with aggregates of non-neoplastic tissue, time-lapse video microscopy, electron microscopic examination of the cytomorphologic correlates of cell motility, the radial dish assay, and quantitative enzyme immunoassay of proteins associated with invasion (e.g. laminin). Several of these techniques have been specifically modified to assess the effects of cytokines on glioma cell motility in vitro. Cytokines studied utilizing these methods include: epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), the bb dimer of platelet-derived growth factor (PDGFbb), nerve growth factor (NGF), interleukin 2 (IL-2), transforming growth factors alpha and beta 1 (TGF alpha and TGFstraat1), and tumor necrosis factor alpha (TNF alpha). This review summarizes the investigational methods used to evaluate random and directional glioma cell motility and invasion in vivo and in vitro. The roles of specific mitogens as motogens, as evaluated with these methods are then presented.
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PMID:Mitogens as motogens. 944 23

Glioblastomas are particularly resistant to classical antitumor treatments. Retinoids, which proved effective in the treatment of promyelocytic leukemia, have been used for clinical assays on glioma tumors with only moderate effects; however in some cases they were active in combination with another therapy. These observations prompted us to analyse the efficacy of combining retinoic acid (RA) with a cytokine on a clonal human glioma cell line. On GL-15 cells, RA and tumor necrosis factor alpha (TNFalpha) both reduced the glial fibrillary acidic protein level and DNA synthesis and induced apoptotic pathways, but they were significantly more effective when used together. The up-regulation of the p55 TNF receptors observed during RA exposure might explain this cooperative effect.
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PMID:Effects of retinoic acid and tumor necrosis factor alpha on GL-15 glioblastoma cells. 1067 92


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