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)

The effect of different hormones and growth factors was assayed on the in vitro growth and enzymatic activities of 2',3'-cyclic nucleotide 3'phosphohydrolase (CNP) and glutamine synthetase (GS) of rat glioma C6 cells at two different passages in culture. Young cultures (passage 26), mainly oligodendrocytic, and older cultures (passage 134), predominantly astrocytic, were treated with 10 microM dexamethasone, 20 ng/ml transforming growth factor alpha (TGF alpha), 10 ng/ml insulin, 20 ng/ml platelet-derived growth factor (PDGF), and 20 ng/ml, epidermal growth factor (EGF) in serum-free chemically defined media. In vitro growth rate was measured in terms of DNA content, by a fluorometric method of diaminobenzoic acid, and rate of DNA synthesis by 3H-thymidine incorporation. CNP activity (marker for in vitro oligodendrocytes) and GS activity (marker for astrocytes) were determined spectrophotometrically. Dexamethasone reversibly and significantly inhibited growth of C6 glioma in early and late passages. PDGF and insulin promoted in vitro growth only in late passage but not in early passage cells, whereas EGF and TGF alpha did not significantly affect growth. An increase in CNP activity was observed in early passage cells under the effect of PDGF and insulin. The increase in GS activity induced by insulin and dexamethasone suggests a differentiating role for these factors in C6 glioma cells. These results further present the C6 glioma cell line as a useful model for studies on glial cell properties and responsiveness in culture and support its use in experimental aging in vitro.
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PMID:Effect of growth factors on the in vitro growth and differentiation of early and late passage C6 glioma cells. 888 74

Dexamethasone is used frequently in brain tumor therapy of patients. In animal models it is known to inhibit the angiogenesis of solid tumors. We addressed the question, if this is also true in brain tumors. C6 malignant glioma and 9L gliosarcoma cells were implanted into rat-brains. Dexamethasone 3 mg/kg/d intraperitoneal increased the survival compared to saline treated controls. The tumors size and the vascular density were smaller in the dexamethasone groups in both models. In vitro dexamethasone inhibited the growth of the C6 cells but not of 9L cells. Thus the growth inhibition of brain tumors in vivo appeared to be mediated partly by direct growth inhibition of tumor cells in C6 cells but additionally by antiangiogenesis in both tumor models. Several in vitro models were used to address the mechanisms of antiangiogenesis. There was no effect of dexamethasone on the proliferation of central nervous endothelial cells and no effect on the formation of capillary like structures on matrigel. Dexamethasone inhibited, however, the formation of capillary like structures in a coculture model with glioma cells in vitro. Surprisingly, progesterone had the same effect in this model. The in vitro effect was mediated via glucocorticoid receptors since receptor antagonists could inhibit it. The primary target appeared to be the tumor cell because only this cell had the complete set of receptors. These data show, that antiangiogenic therapeutic effects are possible by influencing primarily the tumor cell. This way of targeting might be of value for future developments of new strategies.
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PMID:Dexamethasone inhibits glioma-induced formation of capillary like structures in vitro and angiogenesis in vivo. 929 62

Rodents with striatal C6 glioma were given carboplatin (65 mg kg(-1) in a 10 mg ml(-1) solution, i.v.) after pretreatment with the NO modulating agents 3-morpholinosydnonimine (SIN-1), NG-nitro-L-arginine methyl ester (L-NAME), bradykinin or dexamethasone, to determine whether platinum disposition in the glioma and normal brain was altered. There was no significant change in mean glioma platinum disposition after 3 days of dexamethasone (32+/-9.7 microg/g). Treatment with SIN-1 (45.1+/-14.2 microg/g), L-NAME (42.9+/-4.9 microg/g) and bradykinin (45.7+/-11.3 microg/g) all resulted in increased tumour platinum concentration compared with controls (29+/-5.5 microg/g) but these results were not statistically significant. Dexamethasone significantly (p < 0.05) reduced the platinum concentration in normal brain but the other agents had no effect. Although glioma platinum concentration could be increased by some agents that alter tissue NO levels, the patterns of response were unpredictable and the magnitude (approximately 50%) of the increased platinum disposition is unlikely to be biologically significant.
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PMID:Effects of nitric oxide manipulation on the disposition of platinum in an experimental glioma model. 950 52

Dexamethasone (DEX)-mediated inhibition of drug-induced, but not CD95 ligand-induced, apoptosis in malignant glioma cells correlates with wild-type p53 status. Here, we examined mechanisms underlying DEX-mediated protection from apoptosis. DEX did not induce p53 expression in two p53 wild-type cell lines (U87MG, LN-229) and did not alter drug-induced p53 accumulation. Forced expression of temperature-sensitive p53val135 in mutant conformation failed to prevent accumulation of endogenous wild-type p53 but acted in a transdominant negative manner to inhibit p53-mediated, camptothecin-induced p21WAF1/CIP1 expression. p53val135-transfected cells retained responsiveness to DEX at restrictive temperature, suggesting that p53 activity is not required for cytoprotection. Forced expression of wild-type p53val135 abrogated the protective effect of DEX, suggesting redundant cytoprotective effects of DEX and p53. Indeed, DEX induced moderate accumulation of p21WAF1/CIP1 in U87MG, LN-229 and p53 mutant LN-18 cells, but not in p53 mutant LN-308 or T98G cells. LN-18 is also the p53 mutant cell line with the best cytoprotective response to DEX. p21WAF1/CIP1 accumulation occurred in the absence of changes in p21WAF1/CIP1 mRNA expression. Wild-type p53 was not required for this DEX effect since DEX induced p21WAF1/CIP1 accumulation in p53val135-transfected LN-229 cells, too. DEX failed to induce p21WAF1/CIP1 expression or cytoprotection in untransformed rat astrocytes. The same lack of modulation of p21WAF1/CIP1 expression and drug toxicity was observed in p21(+/+), p21(+/-) and p21(-/-) human colon carcinoma cells. Paradoxically, while only p21(+/+) and p21(+/-) mouse embryonic fibroblasts showed enhance p21WAF1/CIP1 levels after exposure to DEX, only p21(-/-) fibroblasts were protected from drug toxicity by DEX. The present study links DEX-mediated protection from cancer chemotherapy to a p53-independent pathway of regulating p21WAF1/CIP1 expression in glioma cells but this effect appears to cell type-specific.
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PMID:Dexamethasone-mediated protection from drug cytotoxicity: association with p21WAF1/CIP1 protein accumulation? 979 34

Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-beta or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.
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PMID:Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-beta, dexamethasone, and p53 gene transfer. 981 63

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

Glucocorticoids are known to influence the ability of cells to undergo apoptosis, directly inducing apoptosis in thymocytes while inhibiting it in hepatoma and carcinoma cells. Dexamethasone, a synthetic glucocorticoid, is reported to induce partial resistance to certain anticancer drugs in glioma cell lines. In the present study, the effect of dexamethasone on apoptosis of glioma and astrocytoma cell lines was investigated. Exposure of D384 human astrocytoma and C6 rat glioma cells to staurosporine induced apoptosis as judged by the formation of condensed nuclei and caspase activation. Pre-treatment of cells with dexamethasone caused a reduction in staurosporine-induced apoptosis. In addition, dexamethasone also conferred protection against the induction of apoptosis by anticancer agents including camptothecin and etoposide. The protective effect of dexamethasone was dose and time dependent, with maximal protection obtained with concentrations equal to or greater than 100 nM and a pre-incubation period of at least 24h. The earliest significant inhibition was seen with a pre-incubation period of 8h. Co-treatment with the glucocorticoid receptor antagonist RU38486 abolished the effect of dexamethasone, indicating that the protection due to dexamethasone is mediated via this receptor. Dexamethasone was found to induce a time-dependent up-regulation of Bcl-x(L) protein expression. However, the ability of cytochrome c/dATP to activate the caspase cascade in cytosolic extracts of D384 cells was unaffected by prior exposure of the cells to dexamethasone (1 microM) for 48 h. In conclusion, dexamethasone inhibits the induction of apoptosis in astrocytoma cells, probably via an up-regulation of Bcl-x(L), which could prevent cytochrome c release from mitochondria and subsequent caspase activation. Since glucocorticoids are often used in the treatment of gliomas to relieve cerebral oedema, the inhibition of apoptosis by these compounds could potentially interfere with the efficacy of chemotherapeutic drugs.
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PMID:Dexamethasone pre-treatment interferes with apoptotic death in glioma cells. 1068 82

Because of the outstanding importance of the glucocorticoid Dexamethasone (DEX) as supportive therapy in the management of brain tumours, the direct effect of DEX on tumour cell proliferation is of particular interest. Previous in vitro studies led to contradictory results. To characterise more precisely the influence of DEX, we investigated the glioblastoma multiforme (GM) cell lines A172, T98G and 86HG39. Cells were treated with DEX concentrations ranging from 5 x 10(-9) to 5 x 10(-5) M from 24 to 240h under different treatment conditions. Influence of DEX on glioma cell viability was assessed daily for 5 days by MTT-assay: (I) with continuous DEX incubation (acute treatment), (II) in a recultivation period without DEX after 5 days of DEX pre-incubation (pre-treatment), (III) with continuous DEX incubation after 5 days of DEX pre-incubation (combination treatment). DEX acute treatment led to strongly decreased proliferation of A172 cells, whereas T98G and 86HG39 cells remained uninfluenced. In opposite, a time-delayed inhibition of cell proliferation was observed in all three cell lines after DEX pre-treatment. Combination treatment induced a significant increase of the inhibitory effect in A172 and T98G cells. These data show a variable, partial time-dependent inhibitory effect of DEX on the proliferation of GM cells and may open new treatment strategies for malignant brain tumours.
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PMID:Time-dependent inhibition of glioblastoma cell proliferation by dexamethasone. 1138 6

Accumulating evidence suggests that dexamethasone might decrease permeability of the blood-brain tumor barrier, further limiting the delivery of agents into brain tumors. The bradykinin B2 receptor agonist, Cereport (RMP-7), selectively increases permeability of the vasculature supplying brain tumors in both animal models and humans. The present study was conducted to characterize the effects of dexamethasone on the blood-brain tumor barrier and its potential interaction with Cereport's ability to enhance penetration of radiolabeled carboplatin. Dexamethasone (1.5 mg/kg/day, twice a day) was given to RG2 glioma-bearing rats via oral gavage for 3 consecutive days. After treatment, animals received a 15-min intracarotid infusion of Cereport (4.5 micrograms/kg) and a bolus of [14C]carboplatin. The levels of [14C]carboplatin (nCi/g) in the tumor and nontumor regions were determined at 1, 14, or 24 h after the last dose of dexamethasone. Dexamethasone, alone, significantly decreased the levels of radiolabeled carboplatin permeating the tumor (19%), although there were no significant differences between any of the time points examined. Cereport administration significantly increased levels of carboplatin in the tumor, independent of whether or not dexamethasone was given (46% with and 49% without). Although the relative effects of Cereport on tumor carboplatin levels were not affected by dexamethasone, the absolute levels achieved with Cereport were modestly reduced (44 nCi/g versus 55.5 nCi/g of [14C]carboplatin, with and without dexamethasone, respectively). Thus, while the data support the use of Cereport as adjunctive therapy in the treatment of glioma patients, they also warn that the use of dexamethasone may reduce delivery of chemotherapeutic agents to brain tumors, even when special pharmacologic measures are employed to enhance delivery.
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PMID:Cereport (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone. 1155 Mar 18

Meaningful palliation is possible for selected patients with recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic mixed oligoastrocytoma) using aggressive treatment. Although long-term disease-free survival occurs in fewer than 10% of patients, most who achieve such survival have been treated for multiple recurrences. Surgical resection with the placement of lomustine-releasing wafers is the only therapy proven in randomized trials to be beneficial for recurrent malignant gliomas. Reoperation is indicated when local mass effect limits the quality of life. Reoperation may make other treatments more effective by removing treatment-resistant hypoxic cells and thereby prolonging high-quality survival. Combination chemotherapy (including procarbazine and a nitrosourea) provides dramatic benefit for many recurrent anaplastic or aggressively behaving oligodendrogliomas and anaplastic mixed oligoastrocytomas. For other recurrent malignant gliomas, single-agent cytotoxic chemotherapy (eg, intravenous lomustine or platinums, oral carmustine, temozolomide, or procarbazine) appears to provide equivalent results and better quality of life at a lower cost than do the combinations of cytotoxic drugs. A randomized phase II trial demonstrates that temozolomide provides longer progression-free survival and better quality of life than standard-dose procarbazine in patients with recurrent glioblastoma multiforme. Because benefits of available cytotoxic chemotherapy for anaplastic astrocytoma and glioblastoma are small, participation in clinical trials is appropriate for most patients. Reirradiation (using stereotactic or three-dimensional conformal techniques with or without concomitant cytotoxic chemotherapy) as radiation sensitization can prolong high-quality survival in selected patients. Specific examples include radiosurgery with the gamma knife or with linear accelerators, intracavitary radiation with the newly US Food and Drug Administration-approved GliaSite (Proxima Therapeutics, Alpharetta, GA) radiation therapy system, low dose rate permanent-seed brachytherapy, and high dose rate stereotactic brachytherapy. Dexamethasone (used for the shortest time in the lowest effective doses) can provide symptomatic benefits. Osmotic diuretics such as mannitol reduce cytotoxic edema more rapidly.
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PMID:Recurrent malignant glioma in adults. 1239 40


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