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)

Anticonvulsant-induced alteration in C6 glioma cell adhesivity has been evaluated in two independent in vitro assay systems. A centrifugal shear assay was employed to determine drug-induced change in cell-substratum adhesivity. Valproate and clonazepam were found to significantly increase cell-substratum adhesivity when cells were cultured at concentrations which were within twice their therapeutic plasma level. A second assay evaluated change in affinity for concanavalin A lectin coated surfaces to determine change in cell surface glycoconjugate expression. Valproate and clonazepam and, to a lesser extent, diazepam significantly decreased drug-exposed C6 glioma cell affinity for concanavalin A lectin coated surfaces. Valproate and clonazepam had approximate IC50 values of 0.75 mM and 75 microM, respectively. These findings are compared and discussed in relation to those obtained with an anti-proliferative assay which has been suggested to predict teratogen potential.
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PMID:In vitro screening for anticonvulsant-induced teratogenesis: drug alteration of cell adhesivity. 180 54

Twenty consecutive patients with chronic partial seizures with onset before twenty years of age were investigated by means of 0.5 T MRI (20) and HM-PAO (19) in order to identify focal alterations amenable to surgical therapy. MRI evidentiated parenchymal lesions in 7 patients. Findings consistent with unilateral medial temporal sclerosis and cortico-subcortical parietal scars were found in two patients each. Small solid nodular lesions in the temporal lobe were observed in two patients. These and one additional patient with nodular partially cystic lesions in temporal lobe were administered a paramagnetic contrast agent (Gadolinium DPA) intravenously. In one case a contrast enhancement was observed. Histologic examination post surgery revealed a low grade glioma in one patient. HM-PAO SPECT examination showed area of abnormal captation in 9 of 19 patients. Aspects of EEG correlation with the MRI and SPECT findings are discussed. Our data supported the usefulness of magnetic resonance and SPECT imaging in the completion of pre-surgical assessment in this kind of patients.
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PMID:[MRI and HM-PAO SPECT in 20 patients with drug-resistant partial epilepsy]. 212 12

The effects of anticonvulsants on markers of growth, intracellular enzymes, and synaptic functions were evaluated using a rapidly dividing cholinergic neuroblastoma x glioma hybrid cell-line (NG108-15). Cell cultures were exposed for 4 days to phenobarbital, phenytoin, carbamazepine, or valproic acid. Anticonvulsant concentrations added to the media were selected to produce free levels in the cell media that were equivalent to free levels in humans ranging from therapeutic to very toxic. Free levels of anticonvulsants in the toxic range affected cell number, protein content, and neurochemical markers. However, only valproic acid and phenytoin reduced cell growth at therapeutic free drug concentrations. Valproic acid was the only medication to act as a differentiating agent, significantly increasing the activity of choline acetyltransferase, beta-galactosidase, and muscarinic cholinergic receptor binding. These results emphasize the importance of performing drug studies at appropriate free drug concentrations and suggest that valproic acid differs from other commonly prescribed anticonvulsants by having both a growth-suppressing and a differentiating effect.
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PMID:Effects of anticonvulsants on cell growth and enzymatic and receptor binding activity in a neuroblastoma x glioma hybrid cell culture. 310 72

Valproic acid (VPA) is a fatty acid antiepileptic with demonstrated antimanic properties, but the molecular mechanism or mechanisms underlying its therapeutic efficacy remain to be elucidated. In view of the increasing evidence demonstrating effects of the first-line antimanic drug, lithium, on protein kinase C (PKC), we investigated the effects of VPA on various aspects of this enzyme. Chronic exposure (6-7 days) of rat C6 glioma cells to "therapeutic" concentrations (0.6 mM) of VPA resulted in decreased PKC activity in both membrane and cytosolic fractions and increased the cytosol/membrane ratio of PKC activity. Western blot analysis revealed isozyme-selective decreases in the levels of PKC alpha and epsilon (but not delta or zeta) in both the membrane and cytosolic fractions after chronic VPA exposure; VPA added to reaction mixtures did not alter PKC activity or 3H-phorbol ester binding. Together, these data suggest that chronic VPA indirectly lowers the levels of specific isozymes of PKC in C6 cells. Given the pivotal role of PKC in regulating neuronal signal transduction and modulating intracellular cross-talk between neurotransmitter systems, the specific decreases in PKC alpha and epsilon may play a role in the antimanic effects of VPA.
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PMID:Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. 796 59

Valproic acid (VPA) is an anticonvulsant drug with demonstrated efficacy in the treatment of mania. In the present study, we found that chronic exposure of rat C6 glioma cells to VPA induces a coordinate decrease in multiple components of the beta-adrenergic receptor- (beta-AR) coupled cyclic adenosine 3'-5'monophosphate (cAMP) generating system. Chronic VPA decreased the number of beta-ARs in a time- and concentration-dependent manner; the decrease of beta-ARs was largely beta 1-AR selective and affected beta-ARs in both the high- and low-affinity states. Chronic VPA also significantly attenuated receptor- and postreceptor-stimulated cAMP production, [3H]forskolin binding sites, immunolabeling of G alpha s 45, and cholera toxin catalyzed ADP-ribosylation of G alpha s 52 and 45. Although the precise underlying mechanisms remain to be elucidated, such profound long-term changes in the functioning of this key signaling pathway may help explain the antimanic effects of chronic VPA treatment and are worthy of further study.
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PMID:Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells. 887 10

The prediction that an anti-proliferative effect coupled with a pro-differentiative action will detect a neural tube teratogen has been validated by comparison of these in vitro endpoints with in vivo teratogenicity in a series of closely allied valproate structural analogues. The majority of the compounds significantly inhibited C6 glioma proliferation, the most potent compounds being ranked as octanoic acid > 2-propylhexanoic acid > or = 2-ethylhexanoic acid > or = valproic acid. The anti-proliferative potency of these compounds did not correlate strictly to their relative in vivo teratogenic potential. Valproic acid exhibited an anti-proliferative IC50 of 1.45 mM, whereas 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid were virtually indistinguishable, exhibiting significantly lower IC50 values of 2.5 and 2.55 mM, respectively. The concanavalin A lectin affinity assay was employed to establish whether an anti-proliferative action was coupled with an increased state of cell differentiation. In this lectin affinity assay, the most potent analogues to significantly attenuate the affinity of exposed C6 glioma cells for concanavalin A lectin-coated plastic included 2-butylhexanoic acid, 2-propyl-4-pentenoic acid, 2-propylhexanoic acid and 2-ethylhexanoic acid in a manner which can be related to their relative teratogenic potencies in vivo. All compounds screened positive in both the anti-proliferative and pro-differentiative assays exhibited in vivo exencephalic rates of 5-44%. These included valproic acid, 2-ethylhexanoic acid, 2-propylhexanoic acid and 2-butylhexanoic acid. It would appear that combined anti-proliferative and pro-differentiative screens provide a promising detection system for teratogenic status in a series of valproate analogues.
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PMID:Correlation of in vitro anti-proliferative potential with in vivo teratogenicity in a series of valproate analogues. 909 14

Valproic acid (VPA), a simple branched fatty acid anticonvulsant, has been demonstrated to have clinical efficacy in the treatment of manic-depressive illness (Bowden et al., 1994), but the mechanism(s) by which VPA produces its therapeutic effects remain to be elucidated. VPA's clinical antimanic action require a lag period for onset and are not immediately reversed upon discontinuation of treatment, effects that suggest alterations at the genomic level; we therefore investigated the effects of VPA on the modulation of the DNA binding activity of key transcription factors. DNA binding activities of activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB) were studied in acute (hours) and chronic (days) VPA-treated rat C6 glioma cells. VPA did not affect CREB DNA binding activity, but concentration- and time-dependently increased AP-1 DNA binding activity. The activity was raised at 2 hours (the shortest time examined) and remained high after 6 days (the longest time used) of continuing VPA treatment. VPA also enhanced AP-1 DNA binding activity in human neuroblastoma (SH-SY5Y) cells. Because the effects of VPA were markedly inhibited by cycloheximide, they appear to require new protein synthesis. Taken together, the data suggest that antimanic agents may affect gene expression by modulation of the activity of major transcription factors; in view of the key roles of these nuclear transcription regulatory factors in long-term neuronal plasticity and cellular responsiveness, these effects may play a major role in VPA's therapeutic efficacy and are worthy of further study.
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PMID:Increase in AP-1 transcription factor DNA binding activity by valproic acid. 913 40

Valproic acid (VPA) is a potent broad spectrum anticonvulsant with demonstrated efficacy in the treatment of Bipolar Affective Disorder, but the biochemical basis for VPA's antimanic or mood-stabilizing actions have not been fully elucidated. It has been demonstrated that VPA, at therapeutically relevant concentrations, increases AP-1 DNA binding activity in cultured cells in vitro. These findings raise the possibility that VPA may produce its mood-stabilizing effects by regulating the expression of subsets of genes via its effects on the AP-1 family of transcription factors. To determine if VPA does, in fact, enhance AP-1 mediated gene expression, the effects of VPA on the expression of a luciferase reporter gene were studied in transiently transfected rat C6 glioma and human SH-SY5Y neuroblastoma cells using the pGL2-control vector. The luciferase gene in the vector is driven by an SV40 promoter which contains well characterized AP-1 sites. VPA produced a greater than doubling of luciferase activity in a time- and concentration-dependent manner in both cell lines. Furthermore, mutations of the AP-1 sites in the SV40 promoter markedly attenuated the VPA-induced increases in luciferase activity. These effects of VPA on AP-1 mediated gene expression are very similar to the effects observed with lithium, and suggest that the temporal regulation of AP-1 mediated gene expression in critical neuronal circuits may play a role in the long-term therapeutic efficacy of these agents.
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PMID:Valproate robustly enhances AP-1 mediated gene expression. 988 18

Despite surgery and adjuvant cytotoxic therapy anaplastic astrocytoma, glioblastoma and diffuse intrinsic brain stem glioma continue to have dismal prognosis. Differentiation induction is a new approach taking into account that malignant glioma cells share many features with immature glial progenitor cells that are capable of terminal differentiation. The concept of differentiation therapy is currently evaluated for several pediatric malignancies with or without multimodal standard therapy. Valproic acid (VPA) is a branched chain fatty acid that is able to inhibit proliferation of neuroectodermal cells and to induce these cells along neuronal or glial lineage. Preclinical studies have shown that VPA inhibits growth of human and rodent glial tumor cells in vitro and induces a distinct mature glial phenotype. In addition, growth of human neuroblastoma cells is inhibited in vitro and in vivo and exhibits marked evidence of differentiation. Treatment of neuroblastoma and glioma cells with VPA was accompanied by changes of surface molecule expression that enhance immunogenicity and reduce their capability to metastasize. The antitumoral effects observed in preclinical studies were reached at concentrations that are readily achieved in patients treated with VPA for epilepsy. Epilepsy patients receiving VPA have significantly enhanced hemoglobin F levels, supporting the hypothesis that nontoxic levels of VPA can induce cellular differentiation. Broad clinical experience with VPA and its low toxicity encourage the evaluation of VPA in patients that have been submitted to postoperative combined chemo- and radiotherapy for pediatric malignant glioma.
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PMID:Valproic acid for the treatment of pediatric malignant glioma. 1047 71

Valproic acid (VPA) has been considered as a possible treatment agent for malignant gliomas. In order to characterise the possibilities of VPA, we investigated the effects on cell migration and proliferation. Human cell lines T98G, A172, 85HG66 and 86HG39 were treated with VPA or left untreated, afterwards Boyden chamber assay was used for measuring vertical migration. In a second assay cells were stimulated to create spheroids and spheroid migration was measured. Proliferation was assessed using a cell counter. VPA decreased proliferation of 86HG39 > A172 > 85HG66 cells, whereas T98G remained uninfluenced. The influence of VPA on migration was different; whereas VPA dose-dependently stimulated migration of 86HG39 cells, migration of T98G and 85HG66 decreased, whereas A172 cells remained uninfluenced. Only 86HG39 and A172 cells created spheroids. In both cell lines Boyden-chamber-findings were confirmed by analysing the influence of VPA on spheroid migration. These non-uniform data demonstrate that the benefit of VPA in glioma treatment is not clear and needs further investigation.
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PMID:Different effects of valproic acid on proliferation and migration of malignant glioma cells in vitro. 1129 60


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