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 involvement of mitochondrial damage in the antiproliferative effects of m-iodobenzylguanidine [MIBG] and methylglyoxal bis (guanylhydrazone) [methylGAG] was studied in human neuroblastoma SK-N-SH, mouse neuroblastoma N1E115 and mouse lymphosarcoma S49 cells. Proliferation of SK-N-SH cells was insensitive to MIBG (100 microM gave 15% inhibition), but sensitive to methylGAG (IC50 = 50 microM). MIBG and methylGAG were approximately equitoxic to N1E115 cells (IC50 of 92 and 87 microM, respectively). S49 cells were most sensitive to both MIBG (IC50 = 11 microM) and methylGAG (IC50 = 5 microM). In isolated sonicated mitochondria, MIBG inhibited respiration a complex I of the respiratory chain (EC50 = 0.5 mM), whereas methylGAG was much less effective (EC50 greater than 15 mM). In intact cells, MIBG at 31 microM impaired mitochondrial respiration and stimulated the glycolytic flux. In contrast, equimolar concentrations of methylGAG had no effect on oxygen consumption, ATP content, glucose consumption and lactate production. MethylGAG significantly increased putrescine levels in N1E115 and S49 cells within 12 hr via inhibition of S-adenosylmethionine decarboxylase. No such effects were seen in SK-N-SH cells for up to 48 hr. Equimolar concentrations of MIBG had no effect on the putrescine levels in the various cell lines, suggesting that MIBG did not inhibit S-adenosylmethionine decarboxylase. It is concluded that the antiproliferative mechanisms of the guanidino compounds are essentially different. MIBG inhibited mitochondrial respiration at complex I with concomitant stimulation of the glycolytic flux but was essentially without effect on polyamine levels. On the other hand, cytotoxicity of methylGAG was not associated with mitochondrial dysfunction.
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PMID:Mitochondrial effects of the guanidino group-containing cytostatic drugs, m-iodobenzylguanidine and methylglyoxal bis (guanylhydrazone). 186 36

The cytotoxicity of dopamine (DA) and 6-hydroxydopamine (6-OHDA) on living cells, in vitro, has been previously deeply investigated in neuroblastoma cells. This study was designed to explore the possibility to use bacteria as targets for studying DA and 6-HODA cytotoxicity. Both DA and 6-HODA oxidize when added to bacteriological media. The rate of autoxidation of 6-HODA was greater than DA within the first hours. The oxidation-dependent cytotoxicity caused bacterial growth-inhibition and killing at concentration of 10(-4)M. All the bacterial strains tested were slightly more susceptible to DA than to 6-HODA. Antioxidants (sodium metabisulfite, cysteine) prevented the oxidation and abolished the growth-inhibitory activity. The addition of exogenous catalase protected the cells against the effect of the oxidation of both the catecholamines up to the concentration of 5 mM, while the addition of exogenous superoxide dismutase protected the cells only at the minimal inhibitory concentrations. Taking into account that some of the results obtained are similar to those previously reported using neuroblastoma cells as targets, the use of bacteria for studying oxygen toxicity from these catecholamines seems to be a potentially useful model system.
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PMID:An in vitro bacterial model of cytotoxicity to living cells caused by dopamine and 6-hydroxydopamine oxidation at physiological pH. 190 28

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

Cells from two human cell lines were irradiated both as multicellular tumor spheroids (MTS) and in monolayer culture. Radiation response of MTS was quantified in terms of specific growth delay and proportion cured, and as clonogenic cell survival for monolayer cells. Radiation was applied either as a single or as a split dose with time intervals of 1, 2, and 4 h to determine the rate of sublethal damage repair. Using as endpoint the fraction of MTS cured at an iso-effect level, in MTS of NB-100 neuroblastoma cells repair of sublethal damage was complete within 1 h, whereas in MTS of HN-1 squamous cell carcinoma cells there was still some unrepaired damage left. At a larger dose for NB-100 MTS the repair curve showed a similar shape as for HN-1 spheroids. Using as endpoint specific growth delay, no difference in repair between the various time intervals was observed. In monolayer cells from both cell lines sublethal damage was not fully repaired in the time intervals used. Polarographic microelectrode measurements of oxygen tension inside MTS showed a marked difference in steepness of oxygen tension profiles between MTS from both cell lines. In HN-1 squamous cell carcinoma MTS with diameters up to 500 microns the central pO2 amounted to about 100 Torr, whereas in NB-100 neuroblastoma MTS with the same diameters central pO2-values lower than 30 Torr were observed. NB-100 MTS were irradiated with doses of 5 and 10 Gy gamma rays and subsequently the oxygen tension was measured 1 and 5 h after irradiation. A reoxygenation effect could not be observed, either after single dose or after split dose irradiation. If spheroids may be regarded as a suitable model for tumor responses in vivo, the results from these experiments indicate that reoxygenation is a process eluding polarographic measurements, or that no dramatic changes in oxygen tension are to be expected shortly after high single doses or early in a fractionation scheme.
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PMID:Oxygen tensions in two human tumor cell lines grown and irradiated as multicellular spheroids. 201 61

The effects of hyperbaric oxygen on uracil nucleotide metabolism in B104 rat neuroblastoma cells were investigated. Cells exposed to 10 atm O2 for 4 h incorporated markedly less [3H]uridine into the acid-soluble fraction and RNA compared to cells kept in ambient air. The acid-soluble fraction of the oxygen-treated cells contained less total [3H]uridine phosphates ([3H]UMP + [3H]UDP + [3H]UTP) than air-treated cells. Uridine kinase activity, assayed in cytosolic extracts from cells exposed to 10 atm O2 for 4 h, was decreased by 46% compared to the air controls. The reduced enzyme activity which appears to account for the depressed [3H]uridine incorporation, may contribute to the lethal effects of oxygen in these cells.
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PMID:Adverse effects of hyperbaric oxygen on [3H]uridine incorporation and uridine kinase activity in B104 rat neuroblastoma cells. 216 39

Four established cell lines (mouse neuroblastoma, N2A; Chinese hamster lung, V79; Chinese hamster ovary, CHO; and rabbit kidney, RK13) were made O2-tolerant by repetitive exposure to hyperbaric oxygen (HBO). The cultures were exposed to 100% O2 at pressures ranging from 6 to 10 ATA for time periods up to 3 h, and the surviving cells were regrown to monolayer confluency and reexposed; by the end of three cycles of treatment these cells were tolerant to exposures of 10 ATA O2 for greater than 5 h. The development of O2 tolerance was measured by enzyme and morphologic indices. Results showed that all of the cell lines tested could be made O2 resistant. However, qualitative differences were found. RK13 cells were more resistant to HBO than the other cell types tested. The technique provides a powerful adjunct to current methods that study the effects of oxidative stress in mammalian cells. The ability to generate O2-resistant cells in only 3-4 wk provides a considerable time savings over published efforts (12-20 mo.). In addition, rapid screening of various cell lines may lead to discovery of O2-resistant cell types which will provide insight into the factors inherent in the development of oxygen tolerance.
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PMID:Sensitivity of cultured mammalian cells to oxidative stress: adaptation to repeated exposures of hyperbaric oxygen. 216 98

Macrophages and cultured human monocytes can mediate efficient antibody-dependent cytotoxicity (ADCC) against human tumor cells using monoclonal antibodies (mAbs). The mechanism of this killing is usually assumed to involve secreted factors (reactive oxygen intermediates, tumor necrosis factor, or other cytotoxic factors) leading to target cell lysis. In this study, we present evidence that phagocytosis of intact target cells is the principal mechanism of antitumor cytotoxicity in our in vitro model of ADCC by cultured monocytes. Human monocytes cultured in recombinant human macrophage colony-stimulating factor ingested up to 100% of fluorochrome-labeled melanoma and neuroblastoma target cells, in the presence of an appropriate antitumor mAb. Electron microscopy demonstrated phagocytosis of intact tumor cells by cultured monocytes during ADCC. All of the radionuclide in radiolabeled target cells was taken up by monocytes during phagocytosis. By preventing the release of radioisotope tracers, phagocytosis thus prevents the detection of this very efficient form of cytotoxicity by most conventional assays.
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PMID:Phagocytosis of tumor cells by human monocytes cultured in recombinant macrophage colony-stimulating factor. 219 96

m-Iodobenzylguanidine (MIBG) is a functional analogue of the neurotransmitter norepinephrine. Radio-iodinated 131I-MIBG is used clinically as a tumor-targeted radiopharmaceutical agent in the diagnosis and treatment of adrenergic tumors. Native MIBG has previously been demonstrated to be cytotoxic in cultured cells and to produce anti-tumor responses in animals when non-toxic schedules are used. In this study the effect of MIBG was investigated on isolated rat liver mitochondria and on various tumor cell lines (human neuroblastoma SK-N-SH, mouse neuroblastoma N1E115 and mouse lymphosarcoma S49). Results revealed that MIBG inhibits respiration of isolated liver mitochondria at complex I of the respiratory chain, without affecting F1 ATP-ase. In cell lines, impairment of the mitochondrial respiration was evident from reduced oxygen consumption and decreased intracellular ATP levels. In response to this effect, the glycolytic flux was stimulated as shown by increased glucose consumption and lactic acid production. Cytotoxicity of MIBG was proportional to drug-induced alterations in glucose metabolism.
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PMID:Impaired mitochondrial respiration and stimulated glycolysis by m-iodobenzylguanidine (MIBG). 238 75

Granulocytes from healthy donors lyse human neuroblastoma cells in the ADCC-reaction using antibody MAb 14.18 directed to ganglioside GD2 present on the surface of most neuroblastoma cells. Addition of catalase, superoxide dismutase and azide do not impair this process. Granulocytes from patients with chronic granulomatous disease (CGD) kill neuroblastoma cells even better than those collected from healthy donors. These results indicate that reactive oxygen intermediates (ROI) are not involved in killing of neuroblastoma cells using MAb 14.18, and that granulocytes from patients with CGD may compensate for defects in generation of reactive oxygen intermediates by more effective oxygen-independent killing mechanisms. One patient with CGD was treated with interferon-gamma. During and after treatment, generation of ROI could not be detected and neuroblastoma cell killing was not significantly altered.
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PMID:Lysis of neuroblastoma cells by the ADCC-reaction: granulocytes of patients with chronic granulomatous disease are more effective than those of healthy donors. 250 32

6-Hydroxydopamine(6-OHDA) and Merocyanine-540(MC-540) have been used clinically for purging of neuroblastoma cells prior to autologous bone marrow transplantation. Both substances were found to be more toxic against neuroblastoma cells than against hematopoietic stem cells. The more pronounced cytotoxic effects of 6-OHDA against neuroblastoma cells were not caused by its selective uptake; the rapid autooxidation at physiological pH leads to the formation of H2O2 already in the incubation medium. Cytotoxic effects were not detected in short-time test systems (4 hour chromium-51 release assay) but only after longer incubation periods. In contrast, MC-540 proved to be toxic almost equally in short- and long-time test systems. 4-Hydroxynonenal(4-HNE) that may be formed in the plasma membrane subsequently to photoactivation of MC-540 was only slightly more toxic to neuroblastoma cells than to hematopoietic cells. Although the use of 6-OHDA and MC-540 in bone marrow purging has some limitations, the sensitivity of neuroblastoma cells against reactive oxygen compounds may be exploited more generally for therapy of this tumor.
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PMID:Cytotoxic effects of 6-hydroxydopamine, merocyanine-540 and related compounds on human neuroblastoma and hematopoietic stem cells. 251 Oct 86


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