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)

N-bromosuccinimide-cytochromes c (Myer, Y. P. (1972), Biochemistry 11, 4195) and formyl-cytochrome c (Aviram, I and Schejter, A. (1971), Biochim. Biophys. Acta 229, 113) have been chromatographically purified, and the resulting components have been characterized in terms of their structure, conformation, and function. The activity measurements are considered in terms of the oxidizability, as the transference of an electron to solubilized cytochrome c oxidase, and reducibility, as the tendency to accept an electron from NADH-cytochrome c reductase. Conformational characterization has been carried out by absorption measurements, pH-spectroscopic behavior, circular dichroism, thermal denaturation, ionization of phenolic hydroxyls, the tendency to form the CO complex, and autoxidation with molecular oxygen. NBS-cytochrome c yields two major components, the relative proportions of which, with increasing modification of the protein, exhibit a pattern typical of the formation of the two in a consecutive manner. The first product contains the modification of the Trp-59 and Met-65 side chains, and the second contains the added modification of Met-80. The former in both valence states of iron is more or less like the native protein, except for an apparently slightly loosened heme crevice; the latter, as in other modifications involving modification of centrally coordinated Met-80, was found to be in a conformational state characteristic of the native protein with a disrupted central coordination complex, a loosened heme crevice, and small, but finite derangement of the polypeptide conformation. Functionally, the first component reflected 55% of the reducibility property and an unimpaired oxidizability property, while the latter exhibited derangement of both aspects of cytochrome c activity. Formyl-cytochrome c yielded a single component with modification of Trp-59. Conformationally, in both valence states, it is a molecular form with a disrupted central coordination complex, a loosened heme crevice, and gross derangement of the overall protein conformation. It exhibits a minimal reducibility property, 12%, whereas it retains a native-like tendency to transfer an electron to cytochrome c oxidase. The data from the NBS-cytochrome c components are analyzed with reference to the two forms in the earlier studies of the unpurified preparations. The results are found to be in agreement with one another. The selectivity between the reducibility and the oxidizability exhibited by the first NBS component and formyl-cytochrome c, irrespective of significant differences in the conformational and coordinational configurations of the two, has been viewed in light of a two-path, two-function model for oxidoreduction, as well as with reference to conformational and structural requirements for the oxidizability and reducibility properties of the molecule.
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PMID:Conformational and functional studies of chemically modified cytochromes: N-bromosuccinimide- and formyl-cytochromes c. 16 5

The specific, precise detection of volatile metal chelates has been obtained by coupling the effluent from a gas chromatograph directly to the burner head of a commerical atomic absorption spectrometer (AAS). Quantitation of chromium in the nanogram range has been accomplished with a detection limit of 1.0 ng. The chelation-extraction-gas chromatographic separation procedure coupled with the selective detection by AAS gives a relatively interference-free system that has been used to quantitatively analyse for chromium in standard biological materials NBS SRM 1571 Orchard Leaves and SRM 1569 Brewers Yeast. Metal chelates of iron, copper and cobalt have also been detected by this system.
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PMID:Coupled gas chromatography-atomic absorption spectrometry. 32 71

A commercially available enzyme immunoassay was used to determine ferritin content and subsequently the loading and release of iron from ferritin in neuroblastoma cells. LS cells were incubated with 59Fe for 24 h, lysed, and the cytoplasmic ferritin was bound to monoclonal antibodies coupled to globules. After determination of the ferritin content the same globules with bound radioactive ferritin were measured in a gamma-counter. To illustrate the applicability of this test system, increased iron loading of cellular ferritin could be demonstrated in cycloheximide-treated cells; furthermore, release of iron was documented after incubation of LS cells with a combination of 6-hydroxydopamine and ascorbate. The assay turned out to be a simple method for determination of changes in 59Fe content of ferritin in neuroblastoma cells.
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PMID:A simple assay for determination of iron release from ferritin in neuroblastoma cells. 143 Jul 87

Thirteen patients with Stage III (3 patients) or Stage IV (10 patients) neuroblastoma were treated with a new iron chelation-cytotoxic therapy regimen. Deferoxamine given for five consecutive days followed by 3 days of cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT) caused moderate to severe myelotoxicity. In 39 courses there were four episodes of sepsis; platelet and packed red blood cell transfusions were required in 72% and 82% of courses, respectively. Mild nausea and vomiting occurred in 52% of courses. Objective responses after two courses were observed in 12 of 13 patients. Three of four partial responses were achieved in previously treated relapsed patients, and seven of eight complete responses (four of which were surgically documented) were achieved in previously untreated patients. This cytoreduction regimen appears to be an improvement over other initial induction regimens and may be worth testing in larger populations.
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PMID:Deferoxamine, cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT): a new cytoreductive chelation-chemotherapy regimen in patients with advanced neuroblastoma. 151 28

Deferoxamine at concentrations of 3.28 microM to 32.8 microM for five days causes in vitro growth inhibitory and cytolytic activities in human neuroblastoma and neuroectodermal cell lines. These effects are most likely due to intracellular iron depletion and vary with each cell line tested. A 3.28 microM threshold for cytolytic effects was observed in the most sensitive cell lines SK-N-DZ and SK-PN-LI, while proportionate responses ranging from lysis to relative growth inhibition was observed in the more refractory VA-N-BR, SK-N-LO and SK-N-AS cell lines. Cytolytic effects may represent an artifact of the in vitro setting where maximum exposure of cells to the drug can be achieved. Different sensitivities to deferoxamine in controlled in vitro conditions suggest variable anti-tumor effects can be expected in the clinical setting. Deferoxamine in patients may require a maximum tolerated dosage as a constant infusion for greater than 72 hours.
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PMID:Deferoxamine and human neuroblastoma and primitive neuroectodermal tumor cell lines. 158 May 65

Among children with advanced neuroblastoma, serum concentrations of the iron storage protein ferritin correlate inversely with prognosis. To determine whether ferritin stimulates tumor cell growth, the effects of graded concentrations on cell number were studied for each of three neuroblastoma cell lines (CHP-126, CHP-100, IMR-32) plated in serum-free tissue culture medium. Ferritin extracted from human liver, spleen, or CHP-126 cells (150 ng/ml, final concentration) but not from human heart (150-300 ng/ml) resulted in 1.4-fold +/- 0.2-fold increases in cell numbers over 72 hours as measured spectrophotometrically after reduction of a tetrazolium dye. Higher concentrations of isoferritins (up to 1000 ng/ml) did not further increase cell number, but stimulation was abrogated by rabbit immunoglobulin G antiferritin. Although specific receptors for iodine 125-labeled ferritin could not be demonstrated on the two cell lines tested, deoxyribonucleic acid (DNA) synthesis, measured by incorporation of 3H-thymidine, also increased after addition of ferritin, by approximately 25%. We conclude that ferritin has mitogenic activity for human neuroblastoma cells in vitro which may explain the clinical correlation between levels of that protein and prognosis. Possible implications for therapy are discussed.
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PMID:Stimulation of growth of neuroblastoma cells by ferritin in vitro. 174 Jun 26

Neuroblastoma cells accumulate ascorbic acid and iron. It was hypothesized that these features could be exploited for sensitizing neuroblastoma cells for therapy in combination with reactive oxygen intermediates. In the present study the effects of 6-hydroxydopamine (6-OHDA) and H2O2 on metabolic parameters critical for cell survival were investigated in cells with low and high ferritin content in the presence and absence of ascorbate. Human neuroblastoma SK-N-SH cells were pretreated with 100 microM FeSO4 and 10 microM desferrioxamine, respectively, for 24 h yielding cells with different ferritin contents. The effects of 6-OHDA and H2O2 (25 microM-250 microM) in the absence and presence of 1 mM ascorbic acid on DNA strand break formation, activation of poly(ADP-ribose) polymerase, and finally decrease in NAD+ and ATP concentration were investigated. All these parameters were influenced by 6-OHDA and H2O2 in a concentration-dependent manner in a similar way. The effects were most pronounced in ferritin-rich cells and in the presence of ascorbic acid. Using isolated CCC PM2 DNA, 6-OHDA and ascorbic acid caused strand breaks that were prevented in the presence of mannitol or desferrithiocine. H2O2-mediated strand breaks were observed only in the presence of ascorbic acid. Based on these data and data published by others a model explaining the deleterious effects of ascorbic acid on neuroblastoma cells is presented. It is suggested that continuous application of a high dosage of ascorbic acid might be a useful approach in neuroblastoma therapy.
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PMID:Ascorbic acid enhances the effects of 6-hydroxydopamine and H2O2 on iron-dependent DNA strand breaks and related processes in the neuroblastoma cell line SK-N-SH. 193 70

The presence of the trivalent metallic cations, aluminum and boron, in the culture medium of differentiated human LAN-5 neuroblastoma cells results in increased amounts of specific isomers of microtubule-associated tau proteins. The cells were differentiated to a neuronal phenotype by the addition of retinoic acid. Six-day exposures of the differentiated cells to a 1-mM dose of aluminum or boron yielded increases in tau protein immunoreactivity to the monoclonal antibodies Tau-1 and Alz-50. Significant increases in immunoreactivity were seen at treatment levels of aluminum down to 100 microM. The increases in tau proteins were independent from increases in levels of total cell protein. Control cultures treated with the divalent cations zinc and iron showed no increases in levels of tau proteins.
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PMID:Effects of aluminum on tau proteins in human neuroblastoma cells. 195 63

Ferritin is an iron-containing protein which is a normal component of serum. The levels of ferritin are increased in the sera of some children with neuroblastoma, and this increase appears to be a potent indicator of prognosis. To determine whether synthesis of ferritin by the tumor cells contributes to these increased serum levels, we examined incorporation of radiolabeled leucine by CHP 126, a neuroblastoma derived cell line, into ferritin. Using sequential immunoprecipitation and gel electrophoresis of sonicates from cells maintained in medium containing iron in amounts standard for tissue culture, incorporation of label into ferritin was 0.04% of that into total protein synthesized over the same time period. Addition of up to 40 micrograms of iron as ferric ammonium citrate increased ferritin synthesis to a maximum of 0.16% without altering synthesis of total protein. The pattern of iron-induced enhancement in the neuroblastoma cells was similar to that which was seen using Chang liver cells, a cell line well known to be capable of ferritin synthesis. These results confirm that neuroblastoma cells can synthesize ferritin and that synthesis is regulated by exogenous iron.
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PMID:Synthesis of ferritin by neuroblastoma. 238 59

Deferoxamine previously has been shown to have potent activity in vitro against human neuroblastoma cells, activity that results from its ability to chelate iron. To further understand the mechanism of deferoxamine-induced cytotoxicity, we looked at its effects on cell cycling and on DNA, RNA, and protein synthesis by CHP 126, a cell line that is derived from tumor tissue of a patient with a neuroblastoma and that is known to be drug sensitive. After 24 hours of exposure to 60 mumol/L deferoxamine, there was a 35% increase in the percent of cells in the nonproliferating and prereplicative phases of the cell cycle and a corresponding decrease in the percent of cells in the DNA synthesis, postreplicative, and mitotic phases of the cell cycle, results that are consistent with a block of cell cycle progression at the early DNA synthesis phase. The inhibitory effects of deferoxamine on DNA synthesis were confirmed by demonstration of a 60% decrease in thymidine incorporation into DNA in short-term cultures of CHP 126. Effects on RNA and protein synthesis were minimal. Equivalent effects on growth were seen by using several chelators that interact with different iron pools, suggesting that both intracellular and extracellular iron are required for growth of neuroblastoma cells.
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PMID:Mechanism of antineuroblastoma activity of deferoxamine in vitro. 245 79


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