Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour levels of O6-alkylguanine-DNA-alkyltransferase (O6 AT) and glutathione content (GSH) were correlated with 1, 3-Bis (2-chloroethyl)-1-nitrosourea (BCNU) sensitivity in two human ovarian cancer xenografts (HOC8 and HOC18) and in two human glioblastoma xenografts (HG12 and HG15). HOC8 and HOC18, which were not responsive to BCNU treatment, showed O6 AT levels 14 and 23-fold higher than HG12 that was moderately sensitive to the same BCNU treatment. HG15, which was more sensitive to BCNU than HG12, showed significantly lower O6 AT levels. GSH levels were similar in all tumor xenografts. These data further stress the importance of O6 AT level as a relevant parameter for nitrosourea response in human tumours.
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PMID:Tumour levels of O6-alkylguanine-DNA-alkyltransferase and sensitivity to BCNU of human xenografts. 129 58

Glioblastoma multiforme is one of the most resistant of human tumors to radiation whether used alone or in combination with surgery and/or chemotherapy. This resistance may be caused by one or more of several different factors. These include inherent cellular radiation sensitivity, an efficient repair of radiation damage, an increased number of clonogens per unit of volume, a high hypoxic fraction, high [GSH] concentration, and rapid proliferation between fractions. In the present study, we evaluate the intrinsic radiation sensitivity (surviving fraction at 2 Gy or mean inactivation dose) of malignant human glioma cells in vitro. The in vitro radiation sensitivity of 21 malignant glioma cell lines (early and long term passages) has been measured using colony formation as the end-point of cell viability. The survival curve parameters (SF2 measured and calculated, alpha, beta, D0, n and MID) have been determined for single dose irradiations of exponential phase cells (18-24 hr after plating) under aerobic conditions and growing on plastic. The mean SF2 of the 21 cell lines is 0.51 +/- 0.14 (with a range of 0.19 to 0.76). This value may be compared to the mean SF2 of 0.43-0.47 for SCC, 0.43 for melanoma, and 0.52 for glioblastoma as reported from other authors when using colony formation of cells in exponential phase on plastic. Although glioblastoma is almost invariably fatal, our data demonstrate a very wide range of intrinsic radiosensitivities. These broadly overlap the radiation sensitivities of cell lines from tumors that are often treated successfully. We conclude that standard in vitro measurements of cellular radiation sensitivity (SF2) do not yield values that track in a simple manner with local control probability at the clinical level and that, for at least some of the tumors, other parameters and/or physiological factors are more important.
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PMID:In vitro intrinsic radiation sensitivity of glioblastoma multiforme. 131 13

Glutathione (GSH) and Glutathione S-transferase (GST) plays an important role in the protection of cells against damage from free radicals and also influences cytotoxicity to some kinds of chemotherapeutic agents. GST comprises a group of abundant and widely distributed catalytic and binding proteins that facilitate the conjugation of GSH with the electrophilic center of a large spectrum of hydrophilic molecules. Multiple GST isozymes in mammalian tissues arise from dimeric combination of a number of distinct subunits grouped into three major classes: alpha (alpha), mu (mu), and pi (p). We report the total GST, GST-p activity and GSH content of human brain tumors, C6 rat glioma cells and drug resistant C6 cells. The values of total GST activity in 42 normal brain and brain tumors were quantitatively analyzed. Total GST activity was 92.6 +/- 25.1 units (mean +/- standard deviation) in 8 samples of normal brain tissues, 126 +/- 58.8 units in five grade II or III astrocytomas (154 +/- 63.3 units in grade II astrocytomas, 84.4 +/- 2.7 units in 2 grade III astrocytoma), 66.2 +/- 29.3 in 5 glioblastoma cases, 94.7 +/- 47.7 units in 3 metastatic tumors, 302 +/- 114 unit in 8 meningiomas and 213 +/- 90.4 units in 3 neurinomas. Differences of GST activity between glioblastomas and meningiomas, grade II or III astrocytomas and meningioma, in normal brain tissues and meningioma were statistically significant (p < 0.01). The difference between normal brain tissues and benign tumors (meningiomas and neurinomas), gliomas and benign tumors were also statistically significant (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Quantitative analysis of glutathione and glutathione S-transferase in human brain tumors, C6 rat glioma cells and drug resistant C6 cells]. 140 41

Reduced glutathione (gamma-glutamylcysteinylglycine, GSH) plays an important role in the protection of cells against damage from free radicals and other electrophils and also influences cellular radiosensitivity, cellular response to hyperthermia, and cytotoxicity to some kinds of chemotherapeutic agents. The concentrations of GSH in 40 primary and metastatic brain tumors were quantitatively analyzed, and GSH was localized in these tumors by a novel o-phthalaldehyde histofluorescence method. The level of GSH was 195.2 +/- 57.1 micrograms/gm (mean +/- standard deviation) in glioblastomas multiforme, 444.1 +/- 105.1 micrograms/gm in normal brain tissues, and 614.4 +/- 237.4 micrograms/gm in meningiomas. The differences in GSH levels between glioblastomas and normal brain tissues and between glioblastomas and meningiomas were statistically significant (p less than 0.01). The mean GSH level in astrocytoma grades II and III was 321.9 +/- 11.8 micrograms/gm. The difference in the GSH level between glioblastomas and astrocytomas was statistically significant (p less than 0.05). Radiosensitive tumors, such as multiple myeloma, germinoma, and small-cell carcinoma, showed low GSH levels. These data suggest the possibility that the GSH may be a predictor for the efficacy of radiation therapy. The cytochemical study showed GSH localized in the cytoplasm; although it stained well in meningioma tissue, GSH was not well stained in sections of multiple myeloma. The endothelial proliferation did not stain well in glioblastoma, which seems to imply that this area is vulnerable to attack by free radicals from irradiation and/or chemotherapy.
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PMID:Quantitative analysis of glutathione in human brain tumors. 169 Jul 92

Antioxidants and reactive oxygen species are considered to play an important role in experimental in vivo carcinogenesis studies. We attempted in this study to evaluate the repercussions on the antioxidant and lipid peroxide status of the growth of human malignant tumors xenografted into athymic mice. We selected three tumor models: two urothelial carcinomas (bladder tumors stage 3) and one brain tumor (glioblastoma stage 4). All these tumors exhibited a fast growth pattern when xenografted into athymic mice. Tumoral tissue was implanted subcutaneously. After growth establishment each tumor size was measured at regular intervals: every 2 d for bladder tumor and twice a week for glioblastoma. The period of observation was 3 wk for bladder tumors and 5 wk for glioblastoma. At the end of the observation period, all mice were sacrificed; tumoral tissue was taken and blood collected. Superoxide dismutase activity (SOD), glutathione peroxidase activity (GSH-Px), zinc (Zn), selenium (Se), and thiobarbituric acid reactive substances (TBARS) were measured in blood. TBARS alone were measured into tumoral tissue. A modification of the antioxidant blood status was observed in mice xenografted with bladder tumors with decrease in Se status and GSH-Px activities, and increase in TBARS. Such an effect was absent in mice xenografted with glioblastoma. It would appear that an oxygen-mediated stress exists in the animal bearing an implanted tumor compared with the control group, and that tumoral tissue itself is able to induce an oxidative stress into its host. All this leads to a disturbance of the antioxidant defense system.
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PMID:Antioxidant status and lipid peroxidation in athymic mice xenografted with two types of human tumors. 777 35

Malignant gliomas are often treated with cisplatin (cis-diamminedichloroplatinum(II), CDDP) and radiation but results remain unsatisfactory. To investigate whether CDDP induces radioresistance in glioma, T98G human glioblastoma cells were pretreated 5 times with 10(-6)M CDDP for 24 hours and then the sensitivity of wild type (wt) and pretreated cells towards radiation (9Gy 60Co) and CDDP was tested in a colorimetric assay (MIT). The growth rates of wt and pretreated cells were 1.8 +/-0.2 and 3.1 +/- 0.2 respectively (p = 0.000155) 216 hours post radiation. Pretreated cells also developed resistance to CDDP (resistance factor 2.35). Glutathione (GSH) which potentially mediates resistance to both treatments was measured. Incubation for 6 hours with 10(-5) M CDDP increased GSH levels by a factor of 2.28 (p < 0.0001). However, neither basal nor increased levels differed between wt and pretreated cells. These data show that CDDP pretreatment can induce resistance against radiation and CDDP independently of GSH.
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PMID:Cisplatin induces radioprotection in human T98G glioma cells. 913 60

The human lung adenocarcinoma cell line A-427 is significantly more sensitive to cytotoxic lipid peroxidation products of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than the human lung adenocarcinoma cell line SK-LU-1, and the glioblastoma cell lines A-172 and U-87 MG. The cytotoxic effect as well as lipid peroxidation were abolished by vitamin E. The differential sensitivities of the cell lines were not correlated to the levels of lipid peroxidation products (measured as the end product malondialdehyde), indicating differences in sensitivities to products of lipid peroxidation. The high sensitivity of A-427 is apparently due to a low level of selenium-dependent glutathione peroxidase (GSH-Px), because pretreatment with sodium selenite (250 nM) increased the GSH-Px activity 3- to 4-fold and protected the cells almost completely against the growth inhibitory effect of DHA. Furthermore, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) a seleno-organic GSH-Px mimic, suppressed the cytotoxic action of DHA to A-427 in a dose dependent manner. Northern analysis demonstrated that pretreatment with sodium selenite (250 nM) was accompanied by an increased level of GSH-Px mRNA (1.8-fold) in A-427 cells, while the level remained unchanged under the same conditions in DHA/EPA-resistant A-172 cells. In addition, the level of selenophosphate synthetase mRNA (SelD), a key intermediate in tRNA(Sec) formation, increased 1.2- to 1.7-fold in A-427 and A-172 cells after pretreatment with sodium selenite. These results indicate that upregulation of GSH-Px activity by sodium selenite in the EPA/DHA sensitive cell line A-427 may be due to an increase in mRNAs for GSH-Px and a precursor important for formation of tRNA(Sec) which is required for incorporation of selenocysteine in GSH-Px during translation. These results demonstrate an important role for GSH-Px in the cellular defence against cytotoxic lipid peroxidation products. Furthermore, measurement of GSH-Px activities in tumour cells may be one useful biochemical predictor for their sensitivities to polyunsaturated fatty acids.
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PMID:Evidence that changes in Se-glutathione peroxidase levels affect the sensitivity of human tumour cell lines to n-3 fatty acids. 936 97

The aim of the present study was to assess the toxic potential of drugs of abuse and other neuropharmacological agents in the pathogenesis of AIDS dementia complex (ADC), the neurological complication of AIDS. Neuroblastoma and glioblastoma cell lines expressing the dopamine transporter, as well as primary macrophages exposed to human immunodeficiency virus-1 (HIV-1), were used to investigate the possibility of any synergistic effect between the mode of toxicity of such substances and virus exposure. The drugs of abuse used in our experiments were cocaine and morphine, which exert their action, among others, on the dopaminergic system. Effects were compared to treatment with dopamine itself and a typical dopaminergic drug used pharmaceutically, selegiline. In macrophage cultures, glutathione (GSH) was upregulated strongly after treatment with dopamine, morphine or selegiline, and this effect was enhanced when cells were pre-exposed to virus. This upregulation is discussed as a compensatory reaction to an oxidative signal. When hydrogen peroxide plus iron sulfate was used as a strong oxidant in macrophages, GSH concentrations decreased as a result of cell injury. Cell numbers remained constant in all treatment groups. In contrast, in both neuroblastoma and glioblastoma cell lines, the modulation of GSH concentrations by neurotropic substances was accompanied by significant cell loss, which was exacerbated by HIV-1 pretreatment. Selegiline did not change cell numbers when incubated alone. However, when incubated following treatment with HIV-1 cell death was highly significant. Ascorbic acid (AA), included as antioxidant, totally restored cell loss in cultures treated with dopamine. However, no effect was observed in combined treatment of AA and morphine or selegiline. The results demonstrate a synergistic role in cellular toxicity due to neurotropic substances and HIV-1, and suggest that neuropharmacological agents may contribute to the pathogenesis of ADC.
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PMID:Regulation of glutathione and cell toxicity following exposure to neurotropic substances and human immunodeficiency virus-1 in vitro. 937 55

The relation between the intracellular glutathione (GSH) concentration and hydrogen-peroxide(H2O2)-induced cytotoxicity was investigated. The intracellular GSH concentration in human glioblastoma (T98G, U87MG) and glioma (KG1C) cell lines was one or two orders of magnitude higher than that in a human myelogenous leukemic cell line (HL-60), which showed higher sensitivity to H2O2. Pretreatment of these cell lines with L-buthionine-[S,R]-sulfoximine, which significantly reduced the intracellular GSH concentration, increased their sensitivity against H2O2, whereas pretreatment with N-acetyl-L-cysteine, which did not significantly change the intracellular GSH concentration, only marginally protected the cells from the cytotoxic effect of H2O2. The results suggest that drug sensitivity of tumor cells can be modified by glutathione-modulating compounds.
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PMID:Effect of glutathione-modulating compounds on hydrogen-peroxide-induced cytotoxicity in human glioblastoma and glioma cell lines. 962 Feb 20

Glioblastoma is one of the most malignant of all neoplasms, and often shows resistance to chemotherapy and radiation therapy. Ionizing radiation activates transcriptional factors, such as nuclear factor kappa-B (NF-kappa B). Previously we found that glutathione (GSH) synthesis is induced by cytokines mediated by NF-kappa B (Urata et al. J. Biol. Chem., 1996). Here, we present direct evidence that NF-kappa B activated by ionizing radiation induces the expression of gamma-glutamylcysteine synthetase (gamma-GCS), the rate limiting enzyme of GSH synthesis, using T98G human glioblastoma cells. T98G cells have approximately 14-times the level of intracellular GSH of NB9 cells, radiation-sensitive neuroblastoma cells. In T98G cells, 30-Gy of ionizing radiation was required for the activation of NF-kappa B on an electrophoretic mobility shift assay and the induction of gamma-GCS mRNA on Northern blots and a nuclear run-on assay. However, when T98G cells were treated with buthionine sulfoximine, 3-Gy of ionizing radiation stimulated the DNA-binding activity of NF-kappa B and the expression of gamma-GCS. We constructed chimeric genes containing various regions of gamma-GCS promoter gene and the coding region for Luciferase. T98G cells transiently transfected with a plasmid containing the gamma-GCS promoter-luciferase construct showed increased luciferase activity when treated with ionizing radiation. The luciferase activity stimulated by ionizing radiation was found in the gamma-GCS promoter containing the NF-kappa B binding site, whereas not in that containing its mutated site. These results suggest that GSH synthesis is upregulated by ionizing radiation mediated by NF-kappa B and a high concentration of GSH in T98G cells causes downregulation of the NF-kappa B-DNA binding activity in response to ionizing radiation. The irresponsiveness of the intracellular signal transduction cascade to irradiation may be a factor in the resistance of T98G cells to radiation therapy.
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PMID:Nuclear factor kappa B dependent induction of gamma glutamylcysteine synthetase by ionizing radiation in T98G human glioblastoma cells. 962 82


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