Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Glioblastoma multiforme is one of the most highly vascularized solid neoplasms, therefore treatments that target neovascularization process would be of great clinical importance. Studies of glioblastoma angiogenesis have revealed that expression of the vascular endothelial growth factor (VEGF) is up-regulated in these tumors. Previous reports have shown that down-regulation of VEGF correlates with modification in the glioma growth. To examine this phenomenon further, in this study we constructed two hammerhead ribozymes (RZI and RZII) to target the 5' common region of VEGF mRNA. Both ribozymes exhibited site-specific cleavage to a 318-nucleotide VEGF transcript and showed a high digestion efficiency in vitro (65-95%). After the transfection of glioma cells with two expression vectors carrying the ribozyme sequence, Northern blot analyses detected high levels of ribozyme expression. Treatment of the glioma cells with the ribozymes resulted in a reduction in VEGF mRNA in six of eight clones. Furthermore, the anti-VEGF effect was confirmed at protein level. Thus, enzyme-linked immunoabsorbent analyses (ELISA) showed a >70% reduction in the VEGF165 expression level. These results indicate that hammerhead ribozymes may be useful in down-regulating VEGF expression and suggest that anti-VEGF strategies may be used to potentiate other gene therapies targeting tumor suppressor genes.
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PMID:A novel approach to glioma gene therapy: down-regulation of the vascular endothelial growth factor in glioma cells using ribozymes. 959 5

Recent findings suggest that hepatocyte growth factor/scatter factor (HGF/SF) contributes to the malignant progression of human gliomas. We investigated the effect of HGF/SF on vascular endothelial growth factor (VEGF) expression of c-Met/HGF receptor-positive human glioma cell lines. Treatment of the glioma cells with various concentrations of HGF/SF resulted in an enhanced secretion of VEGF proteins accompanying increased transcription of VEGF mRNA in a dose-dependent fashion. Since malignant gliomas frequently co-express HGF/SF and its receptor, these results suggest that HGF/SF could act as an indirect angiogenic factor through autocrine induction of VEGF expression and secretion in malignant gliomas.
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PMID:Up-regulation of vascular endothelial growth factor induced by hepatocyte growth factor/scatter factor stimulation in human glioma cells. 970 34

Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, may be important as a mediator of brain tumour progression. However, it is still not clear whether VEGF plays a causative role in the early stage of glioma development. We investigated the relationship between VEGF protein expression (as assayed by immunohistochemistry) and different morphological parameters reflecting tumour progression (tumour diameter, vascular density and vascular diameter) in tumours at various stages. As a tumour model, ethylnitrosourea (ENU)-induced rat malignant astrocytoma was used. Tumours were classified by size and level of vascularity estimated by the von Willebrand factor (vWF) staining. Tumours less than 10 mm in diameter were designated early stage neoplastic lesions. All 34 early astroglial tumours were found to be VEGF positive. Increase in the VEGF immunopositive rate of tumour cells correlated significantly with increase in vascular density and vascular diameter. We suggest that VEGF induces angiogenesis and growth of microvessels, promoting growth of the early stage malignant astrocytoma.
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PMID:Changes in VEGF expression and in the vasculature during the growth of early-stage ethylnitrosourea-induced malignant astrocytomas in rats. 984 61

To evaluate the potential actions of vascular endothelial growth factor (VEGF) on capillary permeability and drug transport, tumorigenic human glioma cell lines were developed that expressed different levels of VEGF. Three human glioma cell lines (i.e. U373, SF126, SF188) were screened for VEGF under normoxic and hypoxic (i.e. induced by CoCl2) conditions by Western blot analysis. Subsequent to these results, sense and antisense VEGF164 cDNA transfections were conducted. It was found that parental SF188 (SF188/V-) and SF188/V+ (sense transfected) cells could serve as an appropriate in vivo model based on their divergent levels of VEGF expression. Media derived from SF188/V+ cells stimulated endothelial cell growth by 30-60%, and enhanced endothelial cell clonogenicity by 5-10-fold compared to SF188/V- or empty vector transfected cells. Nude rats implanted with either SF188/V- or SF188/V+ cells subcutaneously and intracerebrally formed tumors, with those derived from SF188/V+ cells growing at a faster rate. Immunohistochemistry analysis indicated that the expression of VEGF and number of capillaries (factor VIII assay) were approximately 3-fold greater in SF188/V+ tumors compared to SF188/V- tumors. Pharmacological assays, such as measurements of cytotoxicity and DNA adducts, in SF188/V- and SF188/V+ cells treated with carmustine or temozolomide were similar. Therefore, other than differences in VEGF expression and growth in vivo, SF188/V- and SF188/V+ cells possess a similar phenotype, and can serve as models to evaluate the influence of VEGF on drug transport.
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PMID:Modulation of angiogenesis by human glioma xenograft models that differentially express vascular endothelial growth factor. 987 3

Significant angiogenesis occurs only after injury in the adult mammalian brain; capillaries proliferate and astrocytes are activated by presently unresolved cellular mechanisms. Because of the intimate relationship between astrocytes and brain capillaries we examined the expression of the specific endothelial mitogen vascular endothelial growth factor (VEGF) in reactive astrocytes following CNS trauma models: neural grafting, stab wounds, and glioma implantation. In situ hybridization was combined with GFAP immunohistochemistry to delineate VEGF mRNA expression in reactive astrocytes. In addition, VEGF and its receptor flt-1 protein expression were detected immunohistochemically. In all three models we found unexpectedly that only reactive astrocytes, not endothelium, expressed the VEGF receptor flt-1, VEGF mRNA, and VEGF protein in a spatiotemporal manner, suggesting that activated astroglia may have a direct role in the induction of angiogenesis or permeability in mature brain. In addition, secreted VEGF may play a part in astroglial signalling by the induction of its own receptor in reactive astroglia following injury. These findings may have significant implications with regard to growth and reparative mechanisms of the adult cerebrovasculature.
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PMID:VEGF mRNA and its receptor flt-1 are expressed in reactive astrocytes following neural grafting and tumor cell implantation in the adult CNS. 987 68

Presently, there is no effective treatment for glioblastoma, the most malignant and common brain tumor. Angiogenic factors are potentially optimal targets for therapeutic strategies because they are essential for tumor growth and progression. In this study, we sought a strategy for efficiently delivering an antisense cDNA molecule of the vascular endothelial growth factor (VEGF) to glioma cells. The recombinant adenoviral vector Ad5CMV-alphaVEGF carried the coding sequence of wild-type VEGF165 cDNA in an antisense orientation. Infection of U-87 MG malignant glioma cells with the Ad5CMV-alphaVEGF resulted in reduction of the level of the endogenous VEGF mRNA and drastically decreased the production of the targeted secretory form of the VEGF protein. Treatment of s.c. human glioma tumors established in nude mice with intralesional injection of Ad5CMV-alphaVEGF inhibited tumor growth. Taken together, these findings indicate that the efficient down-regulation of the VEGF produced by tumoral cells using antisense strategies has an antitumor effect in vivo. This is the first time that an adenoviral vector is used to transfer antisense VEGF sequence into glioma cells in an animal model, and our results suggest that this system may have clinical and therapeutic utility.
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PMID:Antiangiogenesis treatment for gliomas: transfer of antisense-vascular endothelial growth factor inhibits tumor growth in vivo. 1002 81

Oxygen deprivation is an important biological feature of tumor growth. We previously showed that in glioma, anoxia increases expression of IL-8, a chemokine and angiogenic factor. Here, we analysed for the first time the biochemical mechanisms inducing the IL-8 gene upon anoxia in glioma cells, and showed that they differ from those inducing the VEGF gene. Both genes are induced in biologically and genetically heterogenous glioblastoma cell lines (LN-229, LN-Z308, U87MG, T98G), whereas, in gliosarcoma cells (D247MG), only the VEGF gene is induced. The kinetics of IL-8 and VEGF mRNA inductions differ in these cells and reoxygenation experiments showed that the induction is due to the anoxic stress per se. Furthermore, in LN-229 and LN-Z308 cell lines actinomycin D, DRB and nuclear run-on experiments showed that anoxia stimulates increased transcription of both genes. Electromobility shift assays show increased protein binding to the AP-1 site on the IL-8 promoter following anoxia treatment. Finally, in situ hybridization on glioblastoma sections shows that the in vivo expression patterns of IL-8 and VEGF genes overlap, but are not identical. Since intratumoral augmentation of IL-8 and VEGF secretion, following microenvironmental decreases in oxygen pressure, may promote angiogenesis, further definition of these pathways is essential to appropriately target them for antitumoral therapy.
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PMID:Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. 1005 Aug 81

Previously, we induced vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) secretion in glioma cell lines by using physiologic concentrations of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), or platelet-derived growth factor-BB (PDGF-BB). We hypothesized that VEGF/VPF might enhance the blood supply required for the unregulated growth of tumors, and that it acts as the central mediator of tumor angiogenesis. The objective of this study was to determine whether the expression of VEGF/VPF by meningiomas is regulated by growth factors or sex hormones. By means of an enzyme-linked immunosorbent assay of CH-157MN meningioma cell supernatants, we demonstrated that EGF and bFGF similarly induce VEGF secretion by CH-157MN meningioma cells. At the maximum concentrations of EGF (50 ng/mL) and bFGF (50 ng/mL) used in this study, VEGF secretion was induced to 140% to 160% above baseline constitutive secretion. PDGF-BB homodimer did not enhance VEGF secretion significantly. Estradiol (up to 10(-7) mol/L), progesterone (up to 10(-5) mol/L), or testosterone (up to 10(-5) mol/L) did not stimulate or inhibit VEGF secretion in CH-157MN meningioma cells (p > 0.05). Furthermore, we demonstrated that dexamethasone decreased VEGF secretion to 32% of baseline constitutive secretion. This might explain the effect of corticosteroids in alleviating peritumoral brain edema in meningiomas. These results suggest that VEGF secretion in CH-157MN meningioma cells is mainly regulated by growth factors and corticosteroids, but not by sex hormones. Understanding the regulation of VEGF/VPF secretion in meningiomas might contribute to the development of a new therapeutic strategy.
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PMID:Regulation of vascular endothelial growth factor secretion in human meningioma cells. 1008 66

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a mitogen and chemotactic factor for endothelial cells in vitro and an angiogenesis and vascular permeability factor in vivo. Due to its properties, VEGF is a candidate for both angiogenesis and vascular permeability/oedema induction which typically occur in glioblastomas. In this study we test the hypothesis that the antioedema effect of dexamethasone is mediated by downregulation of VEGF or VEGF receptor expression. VEGF mRNA and protein levels of two rat glioma cells lines, C6 and GS-9L, were determined after incubation with dexamethasone under normoxic and hypoxic conditions. In normoxic C6 and GS9L cells, we observed 50-60% downregulation of VEGF mRNA by dexamethasone (P=0.015 and P=0. 01, respectively). This effect was dependent on glucocorticoid-receptor (GR) function. The inhibitory effect of dexamethasone on VEGF gene expression by tumour cells was markedly reduced by hypoxia which suggests that the upregulation of VEGF driven by hypoxia overcomes the effect of the dexamethasone. Dexamethasone did not alter VEGFR-2 mRNA levels in human umbilical endothelial cells. In a subcutaneous glioma tumour model, we observed only a 15% decrease in VEGF mRNA expression in dexamethasone treated animals (n = 12) compared with controls animals (P = 0.24). We conclude that dexamethasone may decrease brain tumour-associated oedema by reduction of VEGF expression in tumour cells. However, the highly reduced activity on hypoxic tumour cells suggests that dexamethasone efficacy may be limited by hypoxia in rapidly growing tumours.
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PMID:Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. 1021 98

Malignant gliomas are associated with a dysfunctional blood-tumor barrier (BTB) that causes substantial morbidity. Scatter factor/hepatocyte growth factor (SF/HGF) is a multifunctional growth factor that correlates with glioma malignancy and has several biological properties that suggest a role in enhancing blood-glioma barrier permeability. In this study, we examined the effects of glioma cell SF/HGF expression on BTB permeability to horseradish peroxidase (HRP). Fischer 344 rats bearing intrastriatal 9L tumors engineered to secrete SF/HGF (9L-SF) and SF/HGF-negative control tumors (9L-neo) received intracardiac injections of HRP and were rapidly decapitated. Densitometric analysis of brain sections reacted with diaminobenzidine showed significantly greater extravascular HRP surrounding SF/HGF-secreting tumors than 9L-neo tumors of comparable size (p<0.05). HRP enzymatic activity associated with striata containing SF/HGF-expressing tumors was 1. 6-fold greater than that of striata containing control tumors (p<0. 05). Northern analysis showed that expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) did not differ between 9L-neo and 9L-SF tumors. These data demonstrate that SF/HGF expression by intracerebral glial tumors can enhance BTB permeability independent of changes in VEGF/VPF expression.
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PMID:Scatter factor/hepatocyte growth factor gene transfer increases rat blood-glioma barrier permeability. 1037 92


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