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

Eleven patients with intracranial tumors were investigated with MR imaging at different dose levels of gadolinium-DTPA to determine a safe and effective dose for imaging intracranial tumors. The patients were divided into two groups. Baseline spin-echo images were obtained with a repetition time of 800 msec and an echo time of 35 msec, and a total of 0.1 mmol of gadolinium-DTPA/kg (six patients) or 0.2 mmol gadolinium-DTPA/kg (five patients) was injected according to a fractionated incremental dose regime (0.025, 0.025, and 0.05 mmol/kg and 0.05, 0.05, and 0.1 mmol/kg, respectively). Postcontrast MR was performed after each injection. In group 1 the best visualization was achieved after the third injection in four cases. In one glioblastoma and in a pituitary adenoma tumor margins were well defined at lower dose levels. In group 2, with five patients, the total dose of 0.2 mmol of gadolinium-DTPA/kg (0.05, 0.05, and 0.1) significantly improved tumor visualization after the third injection in only one patient with multiple metastases. No short-term side effects were encountered. In a range of parameters measured in both serum and whole blood, slight transient elevation of serum iron levels was the only appreciable change. As a result of our investigation we conclude that 0.1 mmol of gadolinium-DTPA/kg is a safe and suitable dose for brain-tumor imaging. In selected cases of 0.2 mmol/kg may increase the diagnostic yield.
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PMID:Dose administration of gadolinium-DTPA in MR imaging of intracranial tumors. 282 88

A 56-year-old man had a right temporal lobe tumor with calcification, which was removed surgically and treated with irradiation. The histology of the tumor was mixed tumor of glioblastoma and fibrosarcoma, and in the sarcoma portion osteoid-chondral tissue was found. With stains for proteoglycan and enzyme digestion tests, hyaluronic acid and chondroitin sulfate were demonstrated in the cartilage matrix. The positive reactivity of the proteoglycans to high iron diamine staining in the first surgical specimens changed to negative in the second and autopsy specimens. It is likely that the osteoid-chondral tissue derived from metaplastic change in sarcoma cells and in the later stage pleomorphism appeared.
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PMID:Mixed glioblastoma and sarcoma with osteoid-chondral tissue. 311 59

The 59Fe-iron(II) chelates of 2-formylpyridine thiosemicarbazone (I), 5-dimethylamino-2-formylpyridine thiosemicarbazone (II), and 5-hydroxy-2-formylpyridine thiosemicarbazone (III) were prepared and their biodistribution determined in normal rats. Early accumulation of these complexes occurred in the liver, muscle and pelt with lesser amounts in the blood, kidneys and other organs. The tissue levels decreased with a 1 to 2-h half-life with the exception of the liver and intestines. The liver level tended to remain constant over the 2-h period. Accumulation in the gut resulting from hepatobiliary excretion increased over the first 60 min and then leveled off. In rats bearing a subcutaneous glioblastoma the uptake of compound I increased during the first 24 h after administration, and tumor to normal tissue ratios of 2 to 3.3 were obtained.
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PMID:Biodistribution of 59Fe-thiosemicarbazones. 710 27

The major cytotoxic component of hemin was identified as metal free protoporphyrin IX in an epithelioid sarcoma cell line (VA-ES-BJ) and a glioblastoma cell line (U-373 MG) by exposing the cell lines to the iron chelator deferoxamine, tin-protoporphyrin IX, and protoporphyrin IX. The contribution of lipid peroxidation and free radical generation to toxicity was examined using DL-buthionine-[S,R]-sulfoximine (BSO), and 21-aminosteroid (lazaroid, U74500A). Hemin caused significantly greater toxicity in VA-ES-BJ than in U-373 MG. While exogenous PpIX was more toxic than hemin in both cell lines, this toxicity was not due to iron depletion following intracellular heme formation since ferric citrate did not reverse PpIX toxicity. Pre-treatment with BSO enhanced hemin toxicity in the VA-ES-BJ cell line but not in U-373 MG, suggesting different modes of toxicity in the two cell lines. Exposure to lazaroid protected only VA-ES-BJ from protoporphyrin-induced toxicity implicating a specific sensitivity to lipid peroxidation and/or free radical generation by this cell line. These characteristics of the VA-ES-BJ cell line distinguish it from the glioblastoma and emphasize its utility for exploring cytotoxic effects of hemin and its precursors.
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PMID:Hemin toxicity in a human epithelioid sarcoma cell line. 857 85

Agents that modulate cellular iron availability have been studied for their antitumor activity. Based on encouraging in vitro studies, the iron chelator deferoxamine (DFO) has been used in clinical studies to treat cancer patients. The observation that DFO induced macular edema in several cancer patients led to the present investigation of vascular endothelial growth factor (VEGF) as a possible mediator of the encountered side effects. Both normal and malignant cell lines were incubated with DFO and a variety of other iron chelators. DFO, at concentrations achievable in humans, induced a 3-5-fold increase in VEGF mRNA expression in all cell lines studied. This increased VEGF mRNA expression was dose and time dependent. A panel of structurally different iron chelators induced an even more potent increase in VEGF mRNA expression. The DFO-induced increase in VEGF mRNA expression translated into 6- and 4-fold increases in VEGF protein secretion in conditioned media of retinal pigment epithelial and C6 glioblastoma cells, respectively. These findings suggest that VEGF may act as a mediator of the side effects induced by iron chelation therapy. In addition, because VEGF is an important regulator of angiogenesis, iron chelators should be given with caution to cancer patients.
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PMID:Up-regulation of vascular endothelial growth factor production by iron chelators. 870 19

Iron and transferrin are required for DNA synthesis and cell division. Cellular iron uptake is mediated by transferrin receptors. In order to investigate whether iron uptake in brain tumors is associated with their histological grade, we studied 24 patients (5 astrocytoma, 11 glioblastoma, 8 meningioma) using positron emission tomography and 52Fe-citrate. Tracer uptake from blood into brain and tumor tissue was assessed 1. using multiple time graphical analysis yielding a measure for unidirectional net tracer uptake (Ki) and 2.) testing a one- and two-tissue kinetic compartment model, where K1 denotes tracer uptake from blood into tissue, k2 efflux from tissue into plasma, and k3 specific tracer binding. In the plasma, 52Fe was bound to a 80 kD protein (transferrin). Ki (in units of 10(-5)/min) was higher in glioblastomas (Ki mean +/- SD 13.6 +/- 6.1) compared with astrocytomas (4.8 +/- 3.5, Mann Whitney p = 0.015) and contralateral brain (2.2 +/- 0.9, Mann Whitney p = 0.009). Highest values were found in meningiomas (no blood-brain barrier (BBB); Ki 33.4 +/- 16.5, Mann Whitney p = 0.008 compared with glioblastomas). Among the compartment models, fitting with K1 and regional plasma volume explained the data best (one-tissue model), data fits were not significantly improved by addition of a k2 or k3 parameter. K1 and Ki values were significantly correlated (Spearman Rank, p = 0.0006). We conclude that 52Fe accumulation in tumors is governed by tracer uptake at the BBB, and does not reflect number of transferrin receptors at the level of tumor cells.
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PMID:Brain tumor iron uptake measured with positron emission tomography and 52Fe-citrate. 885 21

We investigated the effect of deferoxamine mesylate (DFO), an iron chelator, to test whether ascorbate-induced cytotoxicity is due to iron-catalyzed oxidation. Exposing human promyelocytic leukemic HL-60 cells to either sodium ascorbate or ascorbic acid for 1 h resulted in the progressive production of apoptotic cells characterized by cell shrinkage, as well as nuclear and internucleosomal DNA fragmentation. The addition of micromolar to millimolar concentrations of DFO during the 1-h exposure did not inhibit, but rather enhanced the ascorbate-induced apoptosis in both regular and serum-free RPMI1640 medium. However, a higher concentration of serum significantly inhibited the ascorbate-induced cytotoxicity. In contrast, the cytotoxic activity of ascorbate against T98G human glioblastoma cells was enhanced or reduced by micromolar and millimolar concentrations of DFO, respectively. Ascorbate significantly increased the oxidation potential in the culture medium, and the pro-oxidant action of ascorbate was further augmented by the presence of the cells. DFO did not significantly affect the ascorbyl radical intensity and only slightly reduced the ascorbate-elevated oxidation potential. These data demonstrated that ascorbate can induce cytotoxicity even in iron-deficient medium.
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PMID:Effect on an iron-chelator on ascorbate-induced cytotoxicity. 919 88

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

Heme oxygenase is a rate-limiting enzyme in heme catabolism that cleaves heme to form biliverdin, carbon monoxide, and iron. Heme oxygenase-1 is an inducible isozyme and is expressed in many types of cells and tissues. Large amounts of these heme degradation products may be noxious to the host, especially in the brain. We therefore searched for the factors that suppress the expression of heme oxygenase-1. Northern blot analysis showed that treatment with interferon-gamma and with interleukin-1beta for 24 h decreased the expression levels of heme oxygenase-1 mRNA to approximately 20 and approximately 50% of the control levels, respectively, in a human glioblastoma cell line, T98G. Treatment with a combination of these two cytokines additively decreased the expression levels of heme oxygenase-1 mRNA. Western blot analysis showed that the expression level of heme oxygenase-1 protein was also decreased by treatment with interferon-gamma, but not with interleukin-1beta. Moreover, pretreatment with interferon-gamma partially suppressed the induction of heme oxygenase-1 mRNA expression caused by either sodium nitroprusside, cadmium, or hemin. These findings raise the possibility that the expression of heme oxygenase-1 is down-regulated by interferon-gamma in the nervous system.
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PMID:Suppression of heme oxygenase-1 mRNA expression by interferon-gamma in human glioblastoma cells. 1034 44

This study was initiated to investigate the mechanism of ceruloplasmin (CP)-mediated iron release from brain cells using BT325 cells (a glioblastoma cell line); however, negative results were obtained. The BT325 cells were preloaded with 1 microM 59Fe2+ in sucrose (pH 5.8) for 60 min, and then with CP (0-300 microg/ml) for 30 min at 37 degrees C. The addition of CP, either at low (25 microg/ml) or high (300 microg/ml) concentrations, did not lead to a significant change in iron release from iron-loaded BT325 cells. No significant difference in total iron of cells was found between all CP treated groups and the control (P>0.05). Although apotransferrin (apoTf) was shown to have a role in iron release from the cells, the effect of apoTf was not significantly affected by the addition of different concentrations of CP. When the cells were incubated with 1 microM 59Fe2+ in the presence of varying amounts of CP for 30 min at 37 degrees C, it was found that CP increased iron uptake. The total iron uptake by BT325 cells in CP treatment groups (25, 75, 150, 300 microg/ml) was significantly higher than that in the control (no CP addition) (all P<0.01). Furthermore, in contrast to our expectation, CP was shown to promote significantly iron uptake in not only iron-sufficient but also iron-deficient cells. These results showed that CP had a role in iron uptake rather than release in BT325 cells.
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PMID:Ceruloplasmin promotes iron uptake rather than release in BT325 cells. 1168 12


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