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)

Iodine-labelled metaiodobenzylguanidine (MIBG) is a radiopharmaceutical used for diagnostic imaging and targeted radiotherapy of neuroendocrine tumors. We previously reported that the ability of a neuroblastoma (NB) cell line, LAN-5, to accumulate MIBG was powerfully stimulated by interferon-gamma (IFN-gamma), a well-known NB differentiation-promoting agent. To extend the above findings, we have investigated 5 NB cell lines for their ability to accumulate 125I-MIBG in basal conditions or after various combinations of differentiative stimuli. Our results show that association of IFN-gamma and tumor necrosis factor-alpha boosts MIBG uptake in the early times of incubation in LAN-5 and GI-LI-N cells, while both SK-N-SH and SK-N-BE(2)c cells are strongly stimulated by co-treatment with IFN-gamma and all-trans retinoic acid. Moreover, although only LAN-5 and GI-LI-N cells are sensitive to IFN-gamma alone, the combination of IFN-gamma and IFN-alpha causes a synergistic increase in MIBG uptake in all the NB cell lines tested. From experiments on MIBG release we conclude that no intracellular storage within specialized structures took place during differentiation. The observed enhancement in MIBG accumulation results from an increased uptake of the drug only. This conclusion was confirmed by analyzing MIBG-transporter gene expression, which was increased in cells subjected differentiative regimens. According to these findings, inducing differentiation of NB cells in vitro appears to improve their MIBG incorporation ability powerfully.
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PMID:Increase of metaiodobenzylguanidine uptake and intracellular half-life during differentiation of human neuroblastoma cells. 869 May 31

Attenuating beta-amyloid precursor protein (beta-APP) gene expression may have relevance in diseases such as Alzheimer's disease, where beta-APP has been implicated in neuropathological processes. We report here on the transcriptional down-regulation of beta-APP by interferon-gamma (IFN-gamma) in SKNMC human neuroblastoma cells. Treatment of the cells with IFN-gamma resulted in a 85% dose-dependent inhibition of beta-APP promoter activity after 24 h of exposure, with no changes observed at 5 h. For comparison, additional cytokines and signaling agents were also investigated for effects on beta-APP promoter activity. Elevated levels of activity were observed after treatment with phorbol 12-myristate 13-acetate and basic fibroblast growth factor whereas no significant effects were seen after treatment with lipopolysaccharide or interleukin-1 beta. Thus, IFN-gamma was shown here to be a suppressor of beta-APP promoter activity and is the first cytokine reported to possess such down-regulating effects.
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PMID:Transcriptional inhibition of the beta-amyloid precursor protein by interferon-gamma. 869 21

The human neuroblastoma cell line NB-39-nu expressed mRNA coding for inducible nitric oxide synthase (iNOS) following treatment with a combination of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). The level of iNOS mRNA peaked 24 h after stimulation and had declined by about 25% after 48 h. Trace levels of iNOS mRNA were detected after treatment with IFN-gamma alone, and its mRNA level was synergistically enhanced by simultaneous treatment with TNF-alpha. Neither bacterial lipopolysaccharide nor interleukin-1 beta (IL-1 beta) showed synergistic effects as great as that of TNF-alpha on iNOS gene expression. Dexamethasone inhibited the induction of iNOS mRNA by IFN-gamma and TNF-alpha. Induction of iNOS was confirmed by NADPH-diaphorase staining and by immunostaining with human iNOS-specific antibody.
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PMID:Nitric oxide synthase expression in human neuroblastoma cell line induced by cytokines. 872 59

We have previously reported that immunization with low major histocompatibility complex (MHC) class I expressing murine neuroblastoma (neuro-2a) transduced with B7-1 fails to induce significant protection to wild-type tumor challenge. In this study we investigated whether B7-1 expressing neuro-2a cells can stimulate an effective T-cell response if they were cotransduced with the interferon-gamma (IFN-gamma) gene to upregulate MHC class I. Transfer of both the IFN-gamma and B7-1 genes into neuro-2a (N-2a/B7-1/IFN) almost completely abrogated the tumorigenic potential of this tumor and improved survival when compared with mice receiving the single transductants, N-2a/IFN and N-2a/B7-1. Rejection of N-2a/B7-1/IFN was mediated primarily by CD8+ T cells. When irradiated tumor cells were tested, IFN-gamma gene transfer into neuro-2a significantly increased immunogenicity, but transfer of the B7-1 gene did not. However, nonirradiated N-2a/B7-1, N-2a/IFN, and N-2a/B7-1/IFN cells were significantly more effective in eliciting systemic immunity against subsequent wild-type tumor challenge than their irradiated counterparts. N-2a/B7-1/IFN was more immunogenic than N-2a/B7-1 but not more than N-2a/IFN, indicating that B7-1 does not further increase immunogenicity of neuro-2a over that induced by IFN-gamma transduction. These findings should be considered when designing gene modified tumor vaccines for use in human trials.
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PMID:Irradiation of singly and doubly transduced murine neuroblastoma cells expressing B7-1 and producing interferon-gamma reduces their capacity to induce systemic immunity. 872 5

The human neuroblastoma cell line NB-39-nu expressed inducible nitric oxide synthase (iNOS) mRNA following treatment with a combination of interferon-gamma (IFN-gamma) and cis-diamminedichloroplatinum(II) (cisplatin). The level of iNOS mRNA peaked at 48 hr after treatment, and dexamethasone inhibited the induction of iNOS mRNA expression. Cisplatin induced tumor necrosis factor-alpha (TNF-alpha) mRNA expression, and an anti-TNF-alpha neutralizing antibody inhibited the induction of iNOS expression by a combination of cisplatin and IFN-gamma in NB-39-nu cells. Thus, iNOS expression in NB-39-nu cells by a combination of cisplatin and IFN-gamma involves in the TNF-alpha-mediated signal transduction mechanism.
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PMID:TNF-alpha mediates inducible nitric oxide synthase expression in human neuroblastoma cell line by cisplatin. 916 34

Human T-lymphotropic virus-I (HTLV-I) has been etiologically linked with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurologic disease. The characteristic pathological finding in HAM/TSP is marked mononuclear infiltration of the CNS with destruction of the long tracts of the spinal cord. An increased expression of HLA surface antigens and cytokines in the CNS is associated with this inflammatory response. Furthermore, there is evidence for the presence of HTLV-I in HAM/TSP CNS specimens using in situ hybridization and polymerase chain reaction techniques. The relationship between HTLV-I infection of CNS cells and the observed upregulation of surface antigens in the CNS is not well understood. It has been previously demonstrated that HTLV-I infection of neuroblastoma cells leads to induction of HLA surface antigens. As an extension of these studies, HFGC and HCN-1a, neuronal cell lines of nontumorigenic origin, were infected with HTLV-I and the effect on HLA upregulation was studied. Infection of the neuronal cells was demonstrated by the presence of HTLV-I gp46 surface antigen on CD4 negative cells and by the in situ presence of HTLV-I RNA in neurofilament positive cells. Concurrent to HTLV-I infection, HLA class II surface antigen was observed on neurofilament positive cells. Upregulation of HLA class II was not observed in neuronal cells grown in the presence of interferon-gamma or tissue necrosis factor-alpha.
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PMID:Induction of HLA class II in HTLV-I infected neuronal cell lines. 922 53

Interleukin-15 (IL-15) is an important lymphokine regulating natural killer (NK) activity, T-cell proliferation, and T-cell cytotoxic activities. We hypothesized that the reduced expression and production of IL-15 from cord blood (CB) may contribute to the immaturity of CB immunity and potentially delay immune reconstitution after CB transplantation. We compared the expression and production of IL-15 from activated cord versus adult mononuclear cells (MNCs) and the regulatory mechanisms associated with IL-15 expression in CB MNCs. We have also studied the effect of exogenous IL-15 stimulation on CB and adult peripheral blood (APB) MNCs in terms of NK and lymphokine-activated killer (LAK) activities and cytokine induction. Lipopolysaccharide (LPS)-stimulated CB and APB MNCs were used to determine IL-15 expression and protein production by Northern analysis and Western immunoblot analysis. IL-15 mRNA expression and protein accumulation in CB MNC were 25% +/- 2.0% (12 hours, n = 4, P < .05) and 30% +/- 2.5% (12 hours, n = 3, P < .05), respectively, when compared with APB MNCs. Nuclear run-on assays showed no differences between CB and APB MNCs during basal levels of transcription and after transcriptional activation. However, the half-life of IL-15 mRNA was approximately twofold lower in activated CB MNCs than in activated APB MNCs (CB: 101 +/- 5.8 minutes v APB: 210 +/- 8.2 minutes, n = 3, P < .05). Exogenous IL-15 significantly enhanced CB NK and LAK activities up to comparable levels of APB (P < .05). IL-15 also significantly induced interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) protein production (days 1, 3, and 6, P < .05, n = 3) in CB MNCs. IL-15-stimulated LAK cells induced a significant lytic response against two acute lymphoblastic cell lines and two pediatric neuroblastoma cell lines. Both NK and LAK activities were augmented by the combination of IL-12 and IL-15, and the low-dose combination of IL-12 and IL-15 achieved similar levels of in vitro NK and LAK cytotoxicity compared with higher doses of either lymphokine. The present study suggests that IL-15 mRNA and protein expression is decreased in activated CB, secondary, in part, to altered posttranscriptional regulation. The reduced production of IL-15 from CB MNCs in response to stimulation may contribute to the decrease in IFN-gamma and TNF-alpha production and CB cellular immunity. However, exogenous IL-15 enhanced IFN-gamma and TNF-alpha production and NK and LAK cytotoxicities in CB MNCs. The reduced production of IL-15 from activated CB may contribute to the immaturity of CB cellular immunity and delayed immune reconstitution after unrelated CB transplantation. Exogenous IL-15 administration may compensate for the immaturity of CB immunity. The synergistic in vitro effects of low-dose IL-12 and IL-15 also implies the possible use of low doses each of IL-12 and IL-15 for enhancing immune reconstitution and/or possibly as a form of antitumor immunotherapy after CB transplantation.
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PMID:Decreased interleukin-15 from activated cord versus adult peripheral blood mononuclear cells and the effect of interleukin-15 in upregulating antitumor immune activity and cytokine production in cord blood. 937 92

Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody-IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell-dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell-deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell-stimulating agents, such as poly I:C or recombinant mouse interferon-gamma. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.
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PMID:Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy. 947 37

The N-myc oncogene plays a key role in the biology of neuroblastoma and the differentiation process. N-myc expression is associated with metastatic disease, as well as the undifferentiated state of normal neuroblasts migrating from the neural crest during embryogenesis. Its down-regulation is a pivotal event in the differentiation of neuroblastoma cells by retinoic acid (RA). Our previous work has shown that RA works synergistically with other agents, such as interferon-gamma (IFN-gamma), to down-regulate N-myc expression and induce differentiation. The present study demonstrates that IFN-gamma, like RA, decreases N-myc transcription. However, functional analysis of N-myc upstream regulatory sequences using 5' deletion mutants of a promoter-CAT construct containing germ line sequences from nucleotide position -887 to +151 showed that IFN-gamma and RA act through different sites on the N-myc promoter. In addition to its transcriptional effect, IFN-gamma was also found to shorten the half-life of N-myc mRNA. Taken together, these findings provide a mechanistic basis for the synergistic action of IFN-gamma and RA in inducing neuroblastoma differentiation and a rationale for the possible development of combination differentiation therapy for clinical use.
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PMID:Interferon-gamma and retinoic acid down-regulate N-myc in neuroblastoma through complementary mechanisms of action. 957 Mar 57

In situ and in vitro studies suggest that activation of locally produced complement factors may act as a mediator between amyloid deposits and neurodegenerative changes seen in Alzheimer's disease (AD). C1-esterase inhibitor (C1-Inh), which regulates activation of C1 of the complement classical pathway, can be detected immunohistochemically in its inactivated form in activated astrocytes and dystrophic neurites in AD plaque areas. In this study, designed to investigate the cellular source of C1-Inh, C1-Inh was found to be secreted in a functionally active form by astrocytes cultured from postmortem human brain specimens as well as by neuroblastoma cell lines. Recombinant human interferon-gamma (IFN-gamma), which stimulates C1-Inh synthesis in various cell types, several-fold stimulated C1-Inh protein secretion by cultured human astrocytes derived from different regions of the central nervous system and by one (SK-N-SH) of two neuroblastoma cell lines (SK-N-SH and IMR-32) included in this study. In contrast to IFN-gamma, other cytokines [interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha] that can be found in brain areas affected by AD, did not stimulate C1-Inh secretion by astrocytes or neuroblastomas in vitro. This inability to secrete C1-Inh is probably due to unresponsiveness at the transcriptional level, since C1-Inh secretion paralleled the expression of the 2.1-kb C1-Inh mRNA. In situ hybridization with a C1-Inh RNA antisense probe labeled neurons rather than astrocytes, suggesting a role for neurons as producers of complement regulatory proteins in vivo. Since IFN-gamma is apparently lacking in the brain parenchyma, and amyloid plaque-associated cytokines (IL-1beta, IL-6, TNF-alpha) do not stimulate C1-Inh expression in vitro, the nature of the stimulus responsible for neuronal C1-Inh expression in AD brains remains to be investigated.
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PMID:Complement C1-inhibitor expression in Alzheimer's disease. 975 62


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