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)

A two-year-old boy with a malignant tumor of the brain (medulloblastoma) excreted large amounts of thymine and uracil in his urine. The excretion was related to progress and regress of the disease, and reached a maximum of 3.0 mol of thymine per mole of creatinine and 2.6 mol of uracil per mole of creatinine. The excretion by 20 apparently normal children was less than 0.01 mol/mol of creatinine for each of the two pyrimidines. Three children with brain tumors, two with leukemias, and one with neuroblastoma were also studied; two of them had a moderate increase in urinary pyrimidine excretion, but only up to 0.07 mol/mol of creatinine. The activity of dihydrouracil dehydrogenase (NADP+) (EC 1.3.1.2) in cultured fibroblasts from the patient was somewhat lower than in control fibroblasts. The tumor was considered to be the likely cause of the increased excretion of pyrimidines, but an impaired degradation of pyrimidines in the liver could not be ruled out.
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PMID:Urinary excretion of thymine and uracil in a two-year-old child with a malignant tumor of the brain. 28 71

1. Alterations in the levels of intracellular calcium ([Ca2+]i) and D-myo-inositol-1,4,5-trisphosphate (InsP3) were measured in the murine neuroblastoma cell line clone, N1E-115, by use of the calcium-sensitive dye, fura-2 and a radioreceptor assay, respectively. 2. Exposure of the cells to ATP (100 microM) elicited rapid and transient increases in [Ca2+]i and InsP3, with both responses reaching a maximum between 10-20 s after agonist addition. 3. Investigation of concentration-response data by use of various analogues of ATP suggests the presence of an extracellular receptor which fails to fit into the current classification of purinoceptors. 4. Cross-desensitization experiments suggest that the same receptor can also be activated by the structurally different pyrimidine base, UTP. 5. Application of the tumour-promoting agent, beta-phorbol-12,13 dibutyrate (PDBu) caused a reduction in the increases in both [Ca2+]i and InsP3, suggesting a role for protein kinase C in feedback inhibition of purinoceptor responses in this cell line. 6. In summary, we present the first evidence for the existence of an atypical purinoceptor on a cell line of CNS origin. This receptor is linked to stimulation of phosphoinositide turnover and subsequent mobilisation of intracellular calcium.
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PMID:Inositol 1,4,5-trisphosphate generation and calcium mobilisation via activation of an atypical P2 receptor in the neuronal cell line, N1E-115. 146 30

The C-1300 neuroblastoma tumor which arises spontaneously in the A/J mouse has been maintained in this mouse strain. Two different cell populations have been recognized in cultured C-1300 mouse neuroblastoma (MNB): (1) round, "neuroblast-like" cells, growing in suspension (poorly attached), that have a highly malignant behavior when injected into the A/J mouse (T1 cells); and (2) flat, "epithelioid" cells that attach well to surfaces and show low malignancy towards the inoculated animals (T2 cells). The specific activities of the pyrimidine metabolizing enzymes thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and thymidine kinase (TK) were examined in both MNB cell lines by a new radiochromatographic method. Enzymatic activities of TP and DPD in the cytosols of T2 (weakly malignant) cells were up to 15 times higher than those of T1 (strongly malignant) cells, whereas the mean TP/DPD activity ratio was 16 in either cell line. TP and DPD activity levels increased with time of growth in culture in T2 cells while no such increase was seen in the T1 cells. Maximal TK activity was similar in both cell lines but dropped more rapidly in the T2 cells as cell densities increased. The enzymatic activity levels of TP and DPD but not of TK correlated inversely with neoplastic expression of MNB cells. The observed patterns of pyrimidine metabolizing enzymes in MNB cells could result in an increased thymidine pool in T1 cells whenever TK activity is suppressed, whereas such conditions would favor the generation of thymine in the T2 cells.
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PMID:Correlations of dihydropyrimidine dehydrogenase, thymidine phosphorylase and thymidine kinase activities in strongly and weakly malignant cultured murine neuroblastoma cells. 271 95

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

Dihydropyrimidine dehydrogenase (DPD), the initial, rate-limiting step in pyrimidine degradation, was studied in two cell lines of murine neuroblastoma (MNB-T1 and MNB-T2) that were derived from C-1300 MNB tumor carried in A/J mice. The MNB-T2 (low malignancy) cell line was originally derived from the in situ tumor and carried in tissue culture for more than 100 passages; the MNB-T1 (high malignancy) line consisted of a new sub-culture that was also established from the in situ MNB tumor. DPD activity was determined in cytosolic preparations of MNB utilizing high performance liquid chromatography to separate the radiolabeled substrate ([2-14C]thymine) from [2-14C]dihydrothymine. The apparent affinity of DPD for NADPH in MNB cells (Km approximately 0.08 mM) was identical to that of A/J mouse brain and liver. The DPD activity of the high malignancy (MNB-T1) cell line was 14.3% of that observed in the low malignancy (MNB-T2) line. In situ tumors formed after implantation of high malignancy (MNB-T1) cells into A/J mice had only 25.2% of the DPD activity observed in tumors derived from low malignancy (MNB-T2) cells. When MNB-T2 cells were injected into naive A/J mice, tumors developed in only 68% of animals, the tumor growth rate was slow and a mortality of 20% was observed. In contrast, tumors derived from injected MNB-T1 cells showed a faster growth rate and 100% mortality. Most MNB-T2 derived tumors were not lethal and ultimately resolved while the MNB-T1 derived tumors were invariably lethal. These studies support the concept that the levels of DPD activity in neoplastic cells are inversely related to their malignant expression and also provide a model to study differences between neuroblastoma cell lines derived from the same in situ tumor but which manifest different neoplastic behavior.
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PMID:Pyrimidine base degradation in cultured murine C-1300 neuroblastoma cells and in situ tumors. 333 27

5-Bromodeoxyuridine induces the differentiation of mouse neuroblastoma C1300 to cells that morphologically resemble mature neurons. The induced differentiation can take place in the absence of DNA synthesis. This suggests that the halogenated pyrimidine need not be incorporated into DNA to alter the phenotype of the cell.
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PMID:5-bromodeoxyuridine-induced differentiation of a neuroblastoma. 527 16

Our clinical study to prevent relapse and metastases in several sarcomas and malignant lymphomas of the head and neck region with a long-term treatment with mopidamole was initiated in 1972 because the pyrimido-pyrimidine derivative was shown to inhibit platelet aggregation in vivo and to increase significantly the circulation time of intravenously injected, 32P-labelled Ehrlich ascites tumour cells in mouse blood. The aggregation of platelets to circulating tumour cells and their subsequent adhesion to vascular endothelium in turn appeared to be part of the early stages of the metastatic process. It seems, however, that other related mechanisms are also involved in the clinical results obtained. Mopidamole, as other related derivatives, probably inhibits platelet aggregation by inhibition of PDE-induced decomposition of cAMP and may stimulate the synthesis and/or release of prostacyclin from the vessel wall which in turn activates adenylate cyclase involved in cAMP synthesis. The latter mechanism was definitely shown only for the related pyrimido-pyrimidine derivative dipyridamole, the methyl-xanthine derivative pentoxifylline and the methyl-pyrazoline derivative nafazatrom. The increase of cAMP levels by mopidamole results in an inhibition of 3H-thymidine incorporation into human neoplastic cells and a direct inhibition of its mitotic rate. The adding of mopidamole to a culture of a human promyelocytic leukemic cell line promotes a reverse transformation of the malignant cells to normal which appears to be a permanent phenotypic change. Furthermore, mopidamole was shown to diminish significantly spontaneous lung metastases in syngenic Wilms' tumor (nephroblastoma) of the rat, the C1300-neuroblastoma of the mouse and the HM-Kim mammary carcinoma of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Modification of metastasis formation by inhibition of platelet aggregation. Experimental and clinical results]. 636 51

dTMP kinase (E.C.2.7.4.9.) catalyzes the phosphorylation of dTMP to the corresponding diphosphate. This enzyme is essential for DNA synthesis in vivo and is an important intermediate enzyme in the pathway of many pyrimidine analog drugs. In this report, we describe the isolation of the human dTMP kinase gene by functional complementation of a Saccharomyces cerevisiae cell cycle mutant, cdc8. The cDNA sequence revealed an open reading frame that encodes a protein with the molecular weight of 23,806. The deduced protein sequence was compared to known dTMP kinase sequences from different organisms. Although functionally complementary and structurally conserved, expressed human dTMP kinase in yeast shows little enzymatic activity. In contrast, active human dTMP kinase can be expressed from the gene cloned into the baculovirus expression system, as evidenced by increased enzymatic activity by four- to five-fold. Unlike yeast dTMP kinase, human dTMP kinase does not contain a cysteine residue after the conserved glycine-rich loop, but its enzymatic activity is still affected by the sulfhydryl inhibitor, 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB). The levels of dTMP kinase mRNA and its enzymatic activity fluctuate during the cell cycle, peaking at the S phase. Thus, like Saccharomyces cerevisiae CDC8 (encoding dTMP kinase), the human homolog mRNA and enzymatic activity are also cell cycle regulated. We have also examined four neuroblastoma cell lines for dTMP kinase mRNA levels and its kinase activities, which appear to vary according to cell growth rate. Our results suggest that the expression of the dTMP kinase gene and its activity coincide with various stages of cell growth. The identification of the human dTMP kinase gene and expression of its product in the baculovirus expression system should facilitate study of the mechanism of gene regulation and its role in pyrimidine metabolism.
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PMID:Human dTMP kinase: gene expression and enzymatic activity coinciding with cell cycle progression and cell growth. 802 90

A cDNA corresponding to human ribosomal protein L37a (hL37a) was obtained by screening a SHSY5Y neuroblastoma library. The full-length cDNA contained 366 nucleotides (nt) in addition to a poly(A) tail. The pyrimidine-rich sequence, CTTTCT, that is common to many ribosomal protein-encoding cDNAs was present at the 5' terminus. The nt sequence displayed 85% identity with rat L37a (rL37a) cDNA. The predicted protein contains 92 amino acids with a M(r) of 10,277, is highly basic, and has 100% sequence identity with rL37a. A putative zinc-finger domain is present in the central region of the protein. Human lymphocytes and several human cell lines express hL37a mRNA at significantly higher levels than the rat cell lines and rat tissues tested. The hL37a gene does not contain introns.
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PMID:Human ribosomal protein L37a: cloning of the cDNA and analysis of differential gene expression in tissues and cell lines. 822 75

From the study using cultured human and mouse neuroblastoma cells, we found that a new type of synthetic bicyclic pyrimidine compounds possessing piperazine moiety strongly promoted neurite outgrowth in neuroblastoma cell lines human GOTO and mouse neuro 2a. The most effective compounds of these 2-piperazinopyrimidine derivatives possessing nerve growth factor (NGF)-like activity were 2-piperazino-6-oxo-5,6-dihydro(7H)pyrrolo[2,3-d]pyrimidine and 2-piperadino-6-methyl-5-oxo-5,6-dihydro(7H)pyrrolo[3,4-d]pyrimidin e. The piperazinopyrimidine compounds were also shown to potentiate NGF-induced neurite sprouting of rat pheochromocytoma PC12 cells. The compounds were more effective in cell cultures than isopropylaminopyrimidine (isaxonine) which had been previously developed and then withdrawn. We discussed the merit of the method of the screening of neurotropic compounds by neurite sprouting activity in cultured neuroblastoma cells.
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PMID:Neurotropic pyrimidine heterocyclic compounds. I. The newly synthesized pyrimidine compounds promote neurite outgrowth of GOTO and neuro 2a neuroblastoma cell lines, and potentiate nerve growth factor (NGF)-induced neurite sprouting of PC 12 cells. 836 68


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