Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biochemical, pharmacological and immunological characterization of cells derived from human neuroblastoma tumors recently acquired great interest, since these cells may be a putative donor source for transplantation in animal models of neurological disorders. We measured monoamine levels, tyrosine hydroxylase (TH) immunostaining, and the expression of major histocompatibility cell surface antigens (MHC) in 7 human neuroblastoma cell lines. Three cell lines (LAN5, NB69 and CHP126) had high levels of monoamines. TH immunostaining was strongly positive in CHP126 and LAN5, and NB69. MHC were not detected in any of the cells with high catecholamine levels. Treatment with neuroleptics increased the metabolism of dopamine in LAN5 but not in NB69. The implantation of LAN5 cells in immunocompetent, unilaterally 6-hydroxydopamine-lesioned rats decreased the apomorphine-induced contralateral rotation. The effect of the implant was greatest in animals in which LAN5 neuroblastoma cells, pretreated with dibutyryl cyclic adenosine monophosphate (DBcAMP) and prostaglandin E1 (PGE1, were implanted into the cerebral ventricle ipsilateral to the lesion, and then irrigated with DBcAMP administered through a totally implanted drug delivery system. The effect of the implant decreased after the second week. Neuroblastoma cells were found in approximately 50% of the implanted animals. TH immunostaining was weak or absent in the grafted animals. Inflammatory changes were present in the majority of the brains examined. Extensive tumor growth was present in one animal implanted with untreated cells. Grafting of cells treated with DBcAMP and PGE1 plus with mitomycin C and bromodeoxyuridine in animals immunosuppressed with cyclosporin A reduced the apomorphine-induced rotation to 40-60% of baseline levels and this reduction persisted beyond the period of infusion with DBcAMP. Intraventricular infusion of DBcAMP in animals injected with cell culture medium produced a transient reduction of rotation to 70% of baseline. The amphetamine-induced rotation was not significantly reduced during the 4 weeks follow up. Atypical cells, consistent with surviving neuroblastoma cells, were observed in the brain of all transplanted animals. TH immunostaining was weak or negative in most cases. Human neuroblastoma cells may be an alternative donor tissue for the study of the effects of transplantation in animal models of Parkinson's disease.
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PMID:Biochemical properties of monoamine-rich human neuroblastoma cells. 256 96

Little is known about the molecular events mediating neurotransmitter release, a crucial step in synaptic transmission. In this paper, the biosynthesis and release of L-beta-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine were analyzed in three heterologous cell lines after retroviral-mediated gene transfer of tyrosine hydroxylase (EC 1.14.16.2), the rate-limiting enzyme in catecholamine synthesis. A recombinant retrovirus encoding human tyrosine hydroxylase type I as well as neomycin-resistance gene was used to infect a fibroblast (NIH 3T3), a neuroblastoma (NS20 Y), and a neuroendocrine (AtT-20) cell line. After selection in the presence of neomycin and in tyrosine-free medium, high levels of exogenous tyrosine hydroxylase activity were detected in extracts of the three cell lines. High-performance liquid chromatography of cell extracts and culture supernatants confirmed that the three cell lines hydroxylated tyrosine to form L-DOPA and released this metabolite into the culture medium. Interestingly, the neuroendocrine cell line AtT-20 synthesized not only L-DOPA but also dopamine. Evoked secretion studies established that AtT-20 cells released the transmitter upon depolarization in a regulated, calcium-dependent way. We discuss the implication of this approach for the analyses of neurotransmitter release as well as in the context of degenerative disorders such as Parkinson disease.
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PMID:Retroviral transfer of a human tyrosine hydroxylase cDNA in various cell lines: regulated release of dopamine in mouse anterior pituitary AtT-20 cells. 257 Nov 52

The ultrastructural appearances of 7 primitive neuroepithelial tumours (PNETs) originating in soft tissues and bone are described. Three of the tumours represented primary soft tissue lesions, while locally recurrent tumour or pulmonary metastases were studied from the 4 skeletal tumours, all of which had been diagnosed previously as Ewing's sarcomas. Rosettes were present in one of the soft tissue lesions and although not seen in the primary skeletal neoplasms, they were identified by light microscopy (LM) in 2 of 3 pulmonary metastases, one of which had the morphology of a neuroepithelioma, with innumerable Homer Wright rosettes. Conventional TEM revealed cytoplasmic processes in all cases and rosettes in varying stages of development were also evident, but the appearances did not achieve the level of cellular organization seen in neuroblastoma: microtubules were few, while dense-core granules varied in number but were generally sparse and pleomorphic, resembling lysosomes. However, typical neurosecretory granules were found in one lung metastasis; the neoplastic cells comprising the same tumour also had epithelial markers in the form of well constructed desmosomes, while freeze-fracture analysis demonstrated elaborate tight junctions. In thin sections, junctions in the other tumours appeared rudimentary, but freeze-fracture of a further case revealed small collections of membrane particles suggesting extremely poorly developed desmosomes. Immunocytochemical study of 4 tumours (2 originating in soft tissue and 2 in bone) demonstrated weak to moderate immunostaining for neurone-specific enolase and with several monoclonal antibodies reactive with neuroblastomas, but there was no evidence of immunolabelling for tyrosine hydroxylase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Primitive neuroepithelial tumours of soft tissues and of bone: further ultrastructural and immunocytochemical clarification of 'Ewing's sarcoma', including freeze-fracture analysis. 264 32

Two clonal cell lines (the pheochromocytoma clone PC-12 and the neuroblastoma clone N1E-115) were used to compare direct and indirect drug effects on tyrosine hydroxylase and dopamine turnover. Both clones contain the cofactor of tyrosine hydroxylase, tetrahydrobiopterin, in sufficient concentrations. 2,4-Diamino-6-hydroxy-pyrimidine (DAO-Pyr), an inhibitor of GTP cyclohydrolase, which is the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, lowers DOPA production indicating that cofactor supply is a limiting factor for catecholamine synthesis. DOPA synthesis in the PC-12 cells can be stimulated by incubation with the natural cofactor tetrahydrobiopterin, but also by its possible precursors sepiapterin and dihydrobiopterin or the analogs methyl-tetrahydropterin and dihydropterin. The regulating enzyme for DOPA synthesis, tyrosine hydroxylase, can be inhibited by certain drugs either directly or indirectly by increasing dopamine concentrations in the cytoplasm after release from its vesicular stores. Using the neuroblastoma clone N1E-115 which lacks DOPA decarboxylase and thus contains only low levels of dopamine the site of action of certain drugs could be determined. Drugs affecting the tyrosine hydroxylase directly (alpha-methyl-para-tyrosine, apomorphine) decreased DOPA production in both clones, while drugs acting via interference with the vesicular stores (reserpine, amphetamine, nigericin) were effective only in the PC-12 cells. After total depletion of dopamine by nigericin at high concentrations or long-term incubation with 3-hydroxybenzyl-hydrazine (NSD 1015), DOPA production increased in the PC-12 cells indicating a usually occurring regulation of tyrosine hydroxylase by cytoplasmic dopamine. Dopamine concentration in the cytoplasm was calculated to be in the range of 1 X 10(-6) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of neurotropic drug actions on tyrosine hydroxylase activity and dopamine metabolism in clonal cell lines. 285 29

Two neuroblastoma cell lines were cultured in control (euthyroid) and hypothyroid media and examined for protein, RNA and DNA content, activity of the catecholaminergic enzymes tyrosine hydroxylase (TH, EC 1.14.16.2) and monoamine oxidase-A (MAO-A, EC 1.4.3.4), and for L-triiodothyronine (T3) nuclear receptors. In the hypothyroid condition, the rate of cell division and the levels of RNA and protein as well as the activities of TH and MAO were lower than in the euthyroid condition, the reduction being more marked in the E than in the A2(1) cell line. T3 nuclear receptors, unaltered in affinity, were increased in number in the hypothyroid medium, possibly as a regulatory response to hormonal deficiency. Examination of a possible relationship between T3 occupancy and TH activity in the E cells, most sensitive to thyroid hormone deficiency, revealed that induction of TH activity by T3 is dose-dependent and correlates with the number of nuclear sites occupied by the hormone. When neuroblastoma cells were induced to differentiate by the addition of sodium butyrate to the medium, parameters of cell growth (protein, RNA) and enzyme activity (TH and MAO-A) increased in both cell lines irrespective of the presence of thyroid hormones. These data indicate that thyroid hormones, through their nuclear receptors, directly affect the activity of catecholaminergic enzymes in cultured, immature (undifferentiated) neurons.
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PMID:Thyroid hormone binding and regulation of adrenergic enzymes in two neuroblastoma cell lines. 286 93

SY5Y neuroblastoma cells were treated with retinoic acid to induce differentiation of neuroblast-like cells and with aphidicolin (an inhibitor of DNA polymerase) to eliminate the flat cells present in the long-term cultures and masking some of the biochemical developmental changes. Catecholaminergic enzyme (tyrosine hydroxylase and monoamine oxidase-A) activity was consistently increased with development and the increase was significantly greater after aphidicolin-induced elimination of dividing, non-neuronal cells.
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PMID:Tyrosine hydroxylase and monoamine oxidase-A activity increases in differentiating human neuroblastoma after elimination of dividing cells. 287 18

The results of an immunocytochemical evaluation of tyrosine hydroxylase (TH) immunoreactivity in 30 neuroblastic tumors of infancy are reported. Although no correlations could be found between the immunoreactive pattern and the site of origin or the staging of the tumor, a positive relationship between the urinary catecholamine output and the density of TH-immunoreactive cells could be established. TH was mostly localized on the cytoplasm of the differentiating neuroblasts, whereas immature elements were rarely positive. Moreover, 2 stage IVS cases did not contain any TH immunoreactivity. The possible significance of this finding in the investigation of this form of neuroblastoma, which has a peculiar biological behavior, is considered.
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PMID:Correlation between tyrosine hydroxylase immunoreactive cells in tumors and urinary catecholamine output in neuroblastoma patients. 287 74

Tyrosine hydroxylase and tryptophan hydroxylase are widely held to be rate-limiting for the synthesis of the catecholamines and serotonin, respectively. Both enzymes are oxygen-requiring and kinetic properties suggest that oxygen availability may limit synthesis of these neurotransmitters in the brain. Using pheochromocytoma cells as a cell culture model for catecholamine synthesis, and neuroblastoma cells as a model for serotonin synthesis, enzyme activity was measured under control and hypoxic conditions. Both tyrosine hydroxylase and tryptophan hydroxylase activity increased substantially with chronic exposure but not with acute exposure. In the case of tyrosine hydroxylase, increased enzyme content with hypoxia accounts for increased activity. This suggests a mechanism for the maintenance of neurotransmitter synthesis with chronic hypoxia. Measurement of intracellular metabolites revealed no change in dopamine or norepinephrine in hypoxic pheochromocytoma cells, consistent with a simple adaptive mechanism. However, in neuroblastoma cells, hypoxia was associated with an increase in serotonin concentration. The reasons for this are still unclear.
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PMID:Adaptations of neurotransmitter synthesis to chronic hypoxia in cell culture. 288 82

Differentiation of N1E-115 neuroblastoma cells into neuron-like cells, with extension of neurites and acquisition of excitable membranes, can be induced by dimethyl sulfoxide (DMSO). We have found this differentiation to be accompanied by an increase in tyrosine hydroxylase (TH) mRNA, an increase disproportionate to changes in mRNAs for other measured, non-neuron-specific genes. The mRNA increases slowly over several days and falls gradually after removal of DMSO. Nuclear run-on studies suggest that a change in the rate of transcription cannot explain the increase in steady-state mRNA levels. TH mRNA half-life does, however, increase. This suggests that regulation is exerted in this case not at the level of transcription but rather at that of mRNA stability.
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PMID:Regulation of tyrosine hydroxylase gene expression during differentiation of neuroblastoma cells. 288 36

Three human neuroblastoma cell lines were shown to have markedly different contents of catecholamines and serotonin. Two of the cell lines (CHP-134 and IMR-5) have higher levels of dopamine and its metabolites, while CHP-404 cells have higher levels of serotonin and its metabolites. Each cell line responded to the addition of D,L-2-amino-5-phosphonovalerate, an agent which increases plasma membrane permeability to Ca2+ (Pastuszko and Wilson, 1988; with striking changes in the metabolism of the neurotransmitters. These changes were dependent on the extracellular calcium concentration and include activation of dopamine synthesis (tyrosine hydroxylase), increased levels of dihydroxyphenylacetic acid and increased formation of N-methylated dopamine derivatives. Catabolism of serotonin to 5-hydroxyindole acetic acid was inhibited while that to 5-hydroxytryptophol was stimulated. These data clearly identify several important sites for regulation of neurotransmitter metabolism by calcium. The mechanisms, direct or indirect, by which the enzyme activities are modulated by calcium remain to be established.
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PMID:Calcium dependent regulation of catecholamine and serotonin metabolism in human neuroblastoma cells. 290 75


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