UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of EGFR gene amplification in glioblastoma multiforme has prompted interest in experimental therapies to target the receptor on brain tumor cells. To develop an animal model for in vivo study of such strategies, we transfected C6 glioma cells with a plasmid containing the neomycin resistance gene and the human EGFR gene under the control of the glucocorticoid-inducible MMTV promoter. Following selection with G418, individual clones that expressed EGFR at high levels were selected. Kinetics of EGF binding fit a dual site model indicating the presence of both high (KA = 2.5 x 10(9) M-1) and low (KA = 3.3 x 10(7) M-1) affinity receptors. To assess growth in vivo, graded numbers of either wild-type or transfected cells were implanted into the brains of CD Fischer 344 rats. No differences in survival were observed between groups of animals injected with either wild-type or transfected cells at inocula of 10(3) or 10(4) respectively. In addition, one-third of animals (7/21) challenged with 10(5) or 10(6) transfected cells survived > 50 days compared to 0% of animals (0/12) challenged with 10(5) or 10(6) wild-type cells. Such an effect suggests greater immunogenicity of transfected cells, but only at the larger inocula. Since C6 glioma cells will grow in both outbred and inbred strains, our model should have a number of applications including the in vivo study of EGFR targeting for glioma therapy.
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PMID:The effect of epidermal growth factor receptor (EGFR) expression on in vivo growth of rat C6 glioma cells. 747

A concentration as high as 1 microgram/ml of non-radioactive epidermal growth factor, EGF/was necessary to inhibit effectively the binding of 125I-EGF in glioma U-343MGaC12:6 cells. This concentration blocked the available EGF receptors within 30 minutes in monolayers, while 24 hour treatments were required in spheroids. The effects on growth, incorporation of radioactive thymidine, cell density and on extracellular pH were analysed in spheroids after exposure to 1 microgram/ml EGF. The high EGF concentration did not significantly modify the growth curves for monolayers and small spheroids but increased the volume growth of large spheroids. The increase was partly due to lower cell density and partly to increased proliferation. The EGF treatment gave an increased incorporation of thymidine in spheroids, for at least up to 5 days after the administration, while no effect was seen in monolayers. The cell density decreased after the EGF treatment as seen from morphometric analysis in histological sections and by counting the number of cells per volume unit after trypsinization. The capacity to take up radiolabelled dextran increased, probably due to the decreased cell density. Other EGF-induced changes were also recognized, such as a reduction in extracellular pH by 0.1 units in the central regions of spheroids and an increase in intracellular pH by 0.47 units in analysed monolayer cells. The results showed that it is not possible to block the EGF-receptors without imposing changes in growth and metabolism.
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PMID:Effects of epidermal growth factor receptor blocking in cultured glioma spheroids. 751 45

Targeting with toxic EGF-based conjugates against tumour cells with amplified EGF-receptors might be a possible approach towards improved therapy of certain malignancies such as gliomas and squamous carcinomas. In this study, the penetration and binding of 125I delivered by EGF-dextran conjugates were analysed in cultured spheroids applied as a tumour nodule model. The spheroids consisted of human glioma cells, U-343MGaCl2:6, with large amounts of EGF-receptors. The penetration and binding patterns of 125I delivered by 125I-EGF and 125I-dextran were analysed for comparison. The EGF-dextran associated 125I-activity showed a rather slow penetration but after some hours significant amounts of radioactivity had reached the deeper regions and good penetration was obtained within 5 hours. The penetration seemed somewhat faster when the 125I-activity was delivered with EGF possibly dependent on the lower molecular weight allowing for faster diffusion. Furthermore, EGF-dextran associated 125I seemed to penetrate somewhat faster after the EGF-receptors were blocked with non-radioactive EGF, probably due to the lack of binding preventing free diffusion. After administration of 125I-EGF-dextran or 125I-EGF, the binding patterns were superimposed on the penetration patterns. In the penetration studies, the superimposed accumulations due to binding were removed by presaturation of the receptors with non-radioactive EGF. After a 1 hour incubation, binding of EGF-dextran associated 125I-activity could be seen only in an outer region, with an approximative thickness of 50 microns, of the viable cell layer. Extensive receptor specific binding in the deeper regions, at a depth of 100-200 microns, was seen after several hours incubation. In addition, low levels of non-specific binding in the central regions were seen when the 125I-activity was delivered with dextran without EGF. A similar low background binding was seen also in the centre of spheroids incubated with 125I-EGF-dextran or 125I-EGF after saturation of the receptors with non-radioactive EGF. However, the major amount of radioactivity delivered as 125I-EGF-dextran or 125I-EGF had a receptor specific binding and, also in inner regions, it could be displaced by non-radioactive EGF. Thus, EGF-dextran, which is a candidate compound for targeted therapy, allowed penetration of the applied radioactivity and binding could be observed, after some hours, also in the inner regions of the spheroids.
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PMID:Penetration and binding of epidermal growth factor-dextran conjugates in spheroids of human glioma origin. 752 98

Conjugates based on transforming growth factor alpha, TGF alpha, or epidermal growth factor, EGF, are candidates for targeted radiotherapy against EGF-receptor rich tumours such as gliomas or squamous carcinomas. In this study, binding, internalization and excretion of radiolabelled TGF alpha and TGF alpha-dextran conjugates was analysed in an EGF-receptor rich human glioma cell line. The binding of 125I-TGF alpha was EGF-receptor specific and the binding pattern was similar to that of 125I-EGF. The TGF alpha-dextran conjugate also bound specifically but gave maximum binding for a longer time during continuous incubation compared to when only TGF alpha was used. The excretion pattern of internalized radioactivity was somewhat slower for 125I-TGF alpha-dextran, with 125I-labelling on the TGF alpha part, as compared to 125I-TGF alpha although most of the radioactivity in both cases was excreted within 4 hours. The fate of the dextran part of the conjugate, as followed by means of 125I-labelling of the dextran, was different since all radioactivity in that case remained cell-associated for at least up to 22 hours. Furthermore, by comparison with previously published results, it was seen that the radioactivity delivered through the TGF alpha part of TGF alpha-dextran was retained for a shorter period of time by the cells than when delivered by EGF in EGF-dextran conjugates. However, when the radioactivity was delivered by the dextran part of the conjugates, the radioactivity seemed to be retained equally well or even better when TGF alpha-dextran was applied. It is concluded that TGF alpha-dextran, as well as EGF-dextran, have interesting properties for targeting against EGF-receptors and that the dextran part is well retained in the cells and therefore might be a suitable carrier for toxic agents such as radionuclides. It is of high interest to continue with toxicological and pharmacological in vivo studies of the conjugates.
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PMID:Binding, internalization and excretion of TGF alpha-dextran associated radioactivity in cultured human glioma cells. 752 99

External beam irradiation has been shown to enhance accumulation of monoclonal antibodies (MAb) in tumors in vivo. This effect is mainly attributed to an unspecific damage of vascular endothelial cells resulting in an increased vascular leakage. The aim of our studies was to determine the effects of external beam radiation on the expression and function of the epidermal growth factor receptor (EGF-R) in vivo. Expression and internalization of EGF-R was tested in vivo, employing 125I-MAb 425 that binds specifically to the human EGF-R. Irradiation of human high-grade glioma cell lines U87-MG and A1207 with increasing doses (0-3600 Rad) of 240 kVp X-rays, markedly enhanced the binding of 125I-MAb 425 to the cell surface. This effect could only be observed for a few days following irradiation. No correlation of the radiation dose and overexpression of EGF-R were found. At the same time, irradiation stimulated significant and dose-dependent internalization of 125I-MAb. Internalization and intranuclear accumulation of 125I-MAb are necessary to explain the radiocytotoxic effects of 125I. The combination of external beam irradiation and labeled MAb 425 showed at least additive effects on tumor cell survival, when the interval between irradiation and MAb treatment was short. Our data support the clinical observations in the adjuvant treatment of high grade gliomas with 125I-MAb 425 following surgery and external beam radiation.
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PMID:Enhancement of monoclonal antibody efficacy: the effect of external beam radiation. 759 Jul 68

Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca2+ ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca2+]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGF-mediated [Ca2+]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.
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PMID:Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. 768 Feb 47

The epidermal growth factor receptor (EGFR) gene is amplified in over 40% of primary human glioblastomas and overexpressed in the majority. The authors' investigations demonstrate that the function of the EGFR in glioblastomas is distinct from that in other human cancers because it does not appear to mediate the primary growth-promoting effect of EGF. Findings show that the level of EGFR expression does not directly predict the growth response to EGF, with growth stimulated in some cells but inhibited in others when cells were cultured in plastic dishes. On the other hand, when human glioblastoma cells were placed in soft agar cultures, the cell line expressing the highest levels of the EGFR demonstrated considerable colony formation in response to EGF treatment. In addition, cell lines with the highest EGFR levels were also more resistant to the growth-suppressive effects of retinoic acid when maintained in soft agar. These observations suggest that even though the overexpression of the EGFR did not confer a distinct growth advantage to glioma cells cultured on flat culture dishes, the ability of these cells to maintain anchorage-independent growth in soft agar especially in response to EGF and retinoic acid is facilitated. Because anchorage-independent growth is the best in vitro correlate to tumorigenicity, amplification and overexpression of the EGFR in human glioblastoma cells may be in part responsible for the tumorigenic potential of these cells.
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PMID:The role of the epidermal growth factor receptor in human gliomas: I. The control of cell growth. 771 11

Our earlier investigations of the biology of the epidermal growth factor receptor (EGFR) in human gliomas demonstrated that the level of EGFR expression did not directly predict the glioma growth response to EGF, suggesting that the function of the EGFR in glioblastomas might not be limited to mediating the growth effects of EGF. We conducted the current studies to investigate the function(s) of the EGFR not related to growth control in human gliomas. These investigations show that the EGFR mediates the stimulative effects of EGF on glial process extension and glial fibrillary acidic protein (GFAP) expression. In addition, the level of EGFR expression correlates inversely with glioma cell responsiveness to differentiation promoting agents (for example, nerve growth factor and transforming growth factor-beta) that act through transmembrane tyrosine kinase receptors. Thus, glioma lines with a high level of EGFR expression (for example, T-98G cells) responded to fewer differentiation promoting factors than lines with a low level of EGFR expression (such as U-373MG cells). Our results suggest that the EGFR in gliomas may participate in mediating the process extension and GFAP stimulative effects of both EGF and other differentiation promoting agents. These properties represent components of the differentiated state in glia because their expression is stimulated by dibutyryl cyclic adenosine monophosphate in normal astrocytes. The involvement of the EGFR in the expression of these glial specific properties suggests that the EGFR may play an important role in glial differentiation.
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PMID:The role of the epidermal growth factor receptor in human gliomas: II. The control of glial process extension and the expression of glial fibrillary acidic protein. 771 12

Alterations of cell surface expression of HLA (class I, class II DR, DP and DQ) and EGF-receptor on two malignant glioma cell lines (U-343MG and U-563MG) induced with cytokines (IFN-gamma, TNF-alpha, IL-1 alpha) and differentiation promoters (all-trans retinoic acid, phorbol ester TPA) were analyzed with the aid of flow cytometry. IFN-gamma induced a 10-15fold increase of HLA class I. TNF-alpha alone induced a two- to fivefold increase of HLA class I cell surface density and increased the IFN-gamma induced upregulation of HLA class I to approximately 20-24 times the antigen density of uninduced cells. TNF-alpha was able to increase HLA class II DR and DP cell surface expression on glioma lines, but it enhanced only the IFN-gamma-induced HLA class II DR upregulation. All-trans retinoic acid and TPA regulated in the opposite way the EGF-receptor cell surface expression on U-563MG cells.
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PMID:Modulation of cell surface EGF receptor and HLA expression on glioma cell lines induced with cytokines and differentiation promoters. 789 57

The blood-brain barrier GLUT1 glucose transporter is localized in brain to the capillary endothelium, which makes up the blood-brain barrier (BBB) in vivo. However, its expression is markedly downregulated in cultured bovine brain capillary endothelium (ECL cells), possibly due to the absence of brain-derived or astrocyte trophic factors in the tissue culture medium. To examine this hypothesis, we studied the effect of a bovine brain homogenate (BBH), and conditioned media and plasma membranes obtained from the rat C6 glioma cell line, on the abundance of the GLUT1 transcript in ECL cells. BBH induced a significant increase in the abundance of both GLUT1 and actin mRNAs, and this effect was dose and time dependent. The increase in the GLUT1 mRNA levels correlated with an increase in the transcriptional rate of this gene measured by nuclear run-on experiments. C6 conditioned media and C6 plasma membranes had no effect on the abundance of either GLUT1 or actin mRNA. To determine whether known growth factors cause BBH-like induction of GLUT1 and actin mRNAs, a series of growth factors was also tested. EGF and PDGF had no effect on the levels of these mRNAs. Basic FGF had a moderate effect and TNF alpha partially mimicked the effect of BBH on both GLUT1 and actin transcripts. The present data suggests that brain-derived trophic factors present in BBH stimulate BBB-GLUT1 glucose transporter gene expression in ECL cells through a transcriptional mechanism. Although this effect was partially mimicked by TNF alpha, C6 cell membranes or C6 conditioned media were unable to induce changes in the abundance of GLUT1 mRNA. Therefore, BBH may be a useful model to study the characterization of soluble brain-derived trophic factors involved in the induction of BBB-GLUT1 gene expression.
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PMID:Enhanced expression of the blood-brain barrier GLUT1 glucose transporter gene by brain-derived factors. 801 84

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