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)

Nitrous oxide irreversibly inactivates cob(I)alamin, which serves as a cofactor of the enzyme methionine synthase catalyzing the remethylation of homocysteine to methionine. In patients exposed to nitrous oxide, increase in plasma homocysteine is a responsive indicator of cob(I)alamin inactivation. In the present work, we measured the inactivation of methionine synthase and the concurrent homocysteine export rate of two murine and four human cell lines during nitrous oxide exposure. When cultured in a standard medium with high content (2.3 microM) of folic acid, the methionine synthase of all cell types was inactivated at an initial rate of 0.05 to 0.14 h-1. The inactivation curves leveled off, and a residual activity of 15 to 45% was observed after 48 h of nitrous oxide exposure. The rate and extent of the nitrous oxide-induced inactivation were markedly reduced when the cells were transferred and cultured (greater than 10 days) in a medium containing low concentration (10 nM) of 5-methyltetrahydrofolate. The methionine synthase inactivation increased in a dose-dependent manner when the 5-methyltetrahydrofolate content of the medium was increased from 3 nM to 2.3 microM. The inactivation of methionine synthase was associated with a marked enhancement of homocysteine export rate of murine fibroblasts and a moderate increase in export from two human glioma cell lines. In contrast, in three leukemic cell lines (murine T-lymphoma R 1.1 cells, human promyelocytic leukemia HL-60 cells and human acute myelogenous leukemia KG-1a cells), the homocysteine export rates were not increased during nitrous oxide exposure. In the responsive murine fibroblasts and the glioma cells, the homocysteine export rate varied inversely to the changes in methionine synthase activity induced by nitrous oxide exposure at different concentrations of folate in the medium. The enhancement of homocysteine export rate of some cell types during nitrous oxide exposure probably reflects inhibition of homocysteine remethylation in intact cells, and highlights the utility of extracellular homocysteine as an indicator of metabolic flux through the methionine synthase pathway. No enhancement of homocysteine export despite inactivation of methionine synthase in three leukemic cell lines questions the functional state of the enzyme in these cells.
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PMID:Homocysteine remethylation during nitrous oxide exposure of cells cultured in media containing various concentrations of folates. 160 76

Overproduction or aberrant catabolism of the predicted amyloid beta-protein precursor (APP) is suspected as the cause of amyloid deposition in Alzheimer's disease and Down's syndrome brains. For possible in vitro experiments of amyloid formation, we have examined the expression of APP in various cultured cells. We found two types of APP producing cell lines. PC12h (rat pheochromocytoma) and HL-60 (human acute promyelocytic leukemia) cells produce a secretory form that is released into the culture medium, while Bu-17 (human glioma) cells synthesize only a non-secretory form that accumulates at the cell surface. APP immunoreactivity on the latter cells was detected at the tips of cell processes or growth cones. These observations indicate that the nonsecretory form of APP may play a role in cell contact or adhesion.
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PMID:Amyloid beta-protein precursor (APP) of cultured cells: secretory and non-secretory forms of APP. 211 75

Malignant cells were assayed for 1,25(OH)2D3 receptors and for the effects of 1,25(OH)2D3 on cell proliferation. The established lines studied were human promyelocytic leukemia (HL-60), T-cell lymphocytic leukemias (Molt-4, RPMI-8402, CEM), mouse leukemia (L1210), breast cancers (HT-39 and MCF-7) and a glioma (C-6) cultures. A TSK 3000 SW (0.75 X 60 cm) HPLC size exclusion column was used to characterize specific 1,25(OH)2D3 binding. We show for the first time that this column is capable of resolving the 3.2-3.5S 1,25(OH)2D3 mammalian receptor (Rs = 32 A) from the 5.5-6.0S form of the mammalian serum 25(OH)D3 transport receptor (Rs = 40 A). The molecular size of the 1,25(OH)2D3 receptors from these cancer cell lines was identical to that from rabbit intestine. HT-39, HL-60, MCF-7, Molt-4, C-6, RPMI-8402 and L1210 cells demonstrated specific 1,25(OH)2[3H]D3 binding (120, 90, 80, 45, 30 and 18 fmoles of sites/mg protein, respectively). Receptors were not detected in the CEM line. 1,25(OH)2D3 inhibited cell proliferation of HT-39, HL-60, MCF-7 and Molt-4 cells by 20% to 70%. In contrast, mouse leukemia (L1210) cells were stimulated to proliferate by this hormone. Proliferation of RPMI and CEM cells was not affected by 1,25(OH)2D3. We demonstrate that size-exclusion HPLC of 1,25(OH)2D3 binding proteins from mammalian intestine and cancer cells provided a rapid method for identification of specific 1,25(OH)2D3 receptors. Furthermore, in the cells studied, the presence and concentration of 1,25(OH)2D3 receptors qualitatively predicted the potency of this hormone to alter cell proliferation. We believe this assay will be useful for rapid analysis of human tumor receptor concentrations.
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PMID:High performance liquid chromatography analysis of 1,25-dihydroxyvitamin D3 receptor in malignant cells. Correlation of effects on cell proliferation and receptor concentration. 301 43

Normal human peripheral blood polymorphonuclear leukocytes (PMNs) and cells from a human acute promyelocytic leukemia line (HL-60) were tested for cytotoxic potential against two human glioma and one normal fibroblast line. Both the PMNs and HL-60 exhibited significant cytotoxicity against the tumor targets while sparing the normal fibroblasts. However, the two glioma cell lines were not equally susceptible to the effector cells. Addition of low levels of purified human lymphoblastoid interferon alpha (IFN) during the assay period significantly enhanced the tumoricidal effect against one of the glioma targets. HL-60 cells, partially differentiated to myelocytes and metamyelocytes by incubation with dimethylsulfoxide (DMSO), expressed reduced levels of cytotoxicity; IFN added during the assay was able to restore the cytotoxic activity against both glioma cell lines. Undifferentiated HL-60 cells were also able to lyse K562 targets in a six hour 51Cr release assay; this activity was also significantly enhanced by IFN. Separate incubation of both effectors and targets proved that the enhancement of cytotoxic activity demonstrated was due to an effect on the HL-60 effector cells. In contrast, the lysis of HSB-2, another NK sensitive target cell, was not enhanced by the addition of IFN to a mixture of HSB-2 and HL-60 cells. Pretreatment of effector and target cells separately with IFN demonstrated a dual effect: IFN both protected HSB-2 targets from lysis by the HL-60 effectors and induced significantly greater cytotoxicity by HL-60 cells.
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PMID:Tumoricidal activity of an acute promyelocytic leukemia cell line (HL-60) is augmented by human interferon alpha. 659 10

Using the technique of DD-PCR (differential display-polymerase chain reaction) we isolated a novel gene (D2-2) that is overexpressed in glioblastoma multiforme tissue (GMT) as compared to normal brain tissue (NBT). D2-2 is also highly expressed in recurrent glioma, colon tumor metastatic to brain, breast tumors, prostate tumors and a prostate tumor cell line (LNCaP). Northern blot analysis showed that D2-2 is highly expressed in several tumor cell lines (MOLT lymphoblastic leukemia, SW480 colorectal adrenocarcinoma, A549 lung carcinoma, HL-60 promyelocytic leukemia, S3 HeLa cells, K-562 chronic myelogeneous leukemia and G361 melanoma) as compared to NBT. Additionally, D2-2 is very highly expressed in cell lines derived from glioblastomas, grade IV astrocytomas, normal human fetal astrocytes (NHFA) and glioma. D2-2 is moderately expressed in neuroblastoma, neuroectodermal and medulloblastoma tumor cell lines. D2-2 expression is localized to the frontal lobe, occipital lobe and the cerebellum in the normal brain. Normal tissues such as thyroid, stomach, adrenal cortex, small intestine and pancreas show high expression of D2-2. We also show that D2-2 is expressed 28-fold higher in fetal brain (20 weeks) than in adult brain. Sequence analysis of a 2.0-kb fragment for D2-2 shows no homology to known sequences in the data base.
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PMID:Isolation and characterization of a novel gene from human glioblastoma multiforme tumor tissue. 917 9

Glioblastomas are particularly resistant to classical antitumor treatments. Retinoids, which proved effective in the treatment of promyelocytic leukemia, have been used for clinical assays on glioma tumors with only moderate effects; however in some cases they were active in combination with another therapy. These observations prompted us to analyse the efficacy of combining retinoic acid (RA) with a cytokine on a clonal human glioma cell line. On GL-15 cells, RA and tumor necrosis factor alpha (TNFalpha) both reduced the glial fibrillary acidic protein level and DNA synthesis and induced apoptotic pathways, but they were significantly more effective when used together. The up-regulation of the p55 TNF receptors observed during RA exposure might explain this cooperative effect.
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PMID:Effects of retinoic acid and tumor necrosis factor alpha on GL-15 glioblastoma cells. 1067 92

A number of thiosemicarbazones have been tested previously and herein are included three bis(thiosemicarbazones) for comparison to the previous derivatives. In general the uncomplexed thiosemicarbazones were more potent in the cytotoxic screens than the bis(thiosemicarbazone) except in the murine L1210 and the human colon SW480 screens. Mode of action studies have only demonstrated slight differences in the effects of the two types of compounds on nucleic acid metabolism. The symmetrical and unsymmetrical bis(thiosemicarbazones) complexes of copper, nickel, zinc, and cadmium have been examined to compare them to the heterocyclic N(4)-substituted thiosemicarbazones metal complexes. These new derivatives demonstrated excellent activity against the growth of suspended lymphomas and leukemias although it should be pointed out that generally they were not as active as the copper complexes of N(4)-substituted thiosemicarbazones. Nevertheless, selected bis(thiosemicarbazones) complexes were active against the growth of human lung MB9812, KB nasopharynx, epidermoid A431, glioma UM-86, colon SW480, ovary 1-A9, breast MCK-7, and osteosarcoma Saos-2. In human HL-60 promyelocytic leukemia cells the complexes preferentially inhibited DNA and purine syntheses over 60 min. The regulatory enzyme of the de novo purine pathway, IMP dehydrogenase, appeared to be a major target of the complexes. However, minor inhibition of the activities of DNA polymerase alpha, PRPP-amido transferase, ribonucleotide reductase, and nucleoside kinases occurred over the same time period. No doubt these effects of the complexes on nucleic acid metabolism were additive since the d[NTP] pool levels were reduced after 60 min as was DNA synthesis. The symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes did not cause as severe DNA fragmentation as the heterocyclic N(4)-substituted thiosemicarbazone metal complexes; furthermore, their metabolic effects in the tumor cell were more focused on a single synthetic pathway.
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PMID:The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells. 1096 96

Benzamide riboside, a recently discovered inhibitor of IMP dehydrogenase (IMPDH) exhibits oncolytic activity. IMPDH is the key enzyme of de novo guanylate biosynthesis and was shown to be linked with proliferation. Therefore, IMPDH is a very good target for antitumor therapy. In order to be active, benzamide riboside has to be converted to BAD, an NAD analogue that binds to the NAD site on IMPDH. Inhibition of the enzyme by benzamide riboside selectively inhibits tumor cell growth and induces apoptosis in various human tumor cell lines. In this manuscript we describe the induction of the CD71 transferrin receptor in human promyelocytic leukemia HL-60 cells following treatment with benzamide riboside. The results indicate a possible involvement of the iron metabolism in the action of this new compound. Benzamide riboside might be clinically used in the treatment of leukemia and solid tumors, alone or as part of combination therapy. Since transferrin receptors are overexpressed in certain cancers, such as glioma and colon cancer, a combination therapy that includes benzamide riboside in transferrin-coupled liposomes will not only target cancer cells but also leads to suicidal action because benzamide riboside will upregulate transferrin receptors on cancer cells thereby make it accessible to dose-intensive chemotherapy. We therefore believe that benzamide riboside itself or derivatives of benzamide riboside might become an important addition for the treatment to diseases that are otherwise fatal.
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PMID:Benzamide riboside, a recent inhibitor of inosine 5'-monophosphate dehydrogenase induces transferrin receptors in cancer cells. 1196 39

Recent clinical studies have demonstrated that As2O3 is an effective drug in the treatment of acute promyelocytic leukemia (APL) by inducing apoptosis and inhibiting the proliferation of leukemia cells both in vitro and in vivo. As a novel anticancer agent for the treatment of solid cancer, As2O3 is promising, but no experimental investigations of its efficacy on glioblastoma have been conducted at concentrations that may be achieved clinically. In addition, the cell proliferation and cell cycle regulating mechanism of As2O3 has not yet to be clarified, especially in solid cancers. We investigated the effect of As2O3 on proliferation and cell cycle regulation with change in cyclins in two human glioblastoma cell lines differing in p53 status (U87MG-wt; T98G-mutated). Sensitivity to As2O3 varied depending on the dose with the IC50 of the U87MG and T98G cells being 1.78 and 3.55 microM, respectively. Analysis by laser scanning cytometry (LSC) indicated that As2O3 inhibited the proliferation of the two cell lines via cell cycle arrest both at the G1 and G2 phases. To address the mechanism of the antiproliferative effect of As2O3, we examined its effect on cell cycle-related proteins by means of LSC, confocal microscopy and Western blot analysis. As2O3 induced an increase in p53 level and a decrease in level of cyclin B1 combined with cell arrest at G2/M in both cell lines. Cell arrest in G1, however, was associated with a decline in cyclin D1 expression only in the wt U87MG cells. As2O3 also induced apoptosis of U87MG cells as evidenced by the presence of cells with fractional DNA content ( cell populations). The present evidence that As2O3 at relatively low concentration effectively inhibited proliferation of U87MG and T98G cells in vitro, suggests that the drug may be considered for in vivo testing on animal models and possibly clinical trials on glioma patients.
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PMID:Effect of As2O3 on cell cycle progression and cyclins D1 and B1 expression in two glioblastoma cell lines differing in p53 status. 1206 49

Recent clinical data shows that arsenic trioxide (As(2)O(3)) causes remission in patients with acute promyelocytic leukemia and multiple myeloma without severe side effects. Laboratory data suggest that As(2)O(3) induces apoptosis or cell differentiation of hematopoietic or solid tumor cells. To date, there has been no study on the effects of As(2)O(3) on glioma cells. In this study, we investigated the in vitro effect of As(2)O(3) on cell growth inhibition and cell death mechanisms in human glioma cells. As(2)O(3) significantly inhibited the proliferation of all six of the glioma cell lines (U373, U87, U251, GB1, A-172, and T98G) tested in this study in a dose-dependent manner. The IC(50) of As(2)O(3) for all of the tumor cell lines was <2 micro M. Previous studies have shown that this is a clinically safe concentration. Treatment with 2 micro M As(2)O(3) induced G(2)/M arrest in all of the glioma cell lines. Autophagy (programmed cell death type II), but not apoptosis (programmed cell death type I), was detected by electron microscopy in U-373-MG cells treated with 2 micro M As(2)O(3). Caspase inhibitors did not halt As(2)O(3)-induced cell death. Furthermore, combination of As(2)O(3) with bafilomycin A1 autophagy inhibitor enhanced the antitumor effect of As(2)O(3) through induction of apoptosis. These findings suggest that As(2)O(3) at a clinically safe concentration may be an effective chemotherapeutic agent for malignant gliomas.
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PMID:Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. 1272 26


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