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

The goal of this study was to isolate and functionally characterize the human secretogranin II (SgII) gene promoter. SgII is a member of the granin family of proteins which are selectively expressed in neurosecretory cells. The human SgII promoter contains a consensus TATA box and cyclic AMP response element (CRE) 35 and 74 bp upstream of the transcription start site, respectively, elements also found in the mouse and rat SgII gene promoters. Transfection studies showed that 869 bp of the human SgII promoter were sufficient to confer cell type-specific expression of an SgII promoter-luciferase reporter gene in neurosecretory PC-12, GH and BE(2)-M17 cells. The activity of the human SgII promoter was also compared in three N-type, human neuroblastoma cell lines [BE(2)-M17, SMS-KAN and SH-SY5Y], which differ markedly in the level of SgII expression. SgII promoter activities in the neuroblastoma cell lines correlated not only with the levels of SgII but also the levels of the cyclic AMP response element-binding protein CREB which were highest in BE(2)-M17 cells and lowest in SH-SY5Y cells. To establish that the activity of the human SgII promoter in these neuroblastoma cell lines is dependent on the level of CREB, rat CREB was overexpressed in SH-SY5Y cells. SgII promoter activity was up to 8-fold higher in SH-SY5Y cells overexpressing CREB. These results suggest that SgII expression is a marker for neuronal differentiation in human neuroblastoma cell lines and is dependent on the level of CREB expression.
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PMID:Isolation and characterization of the human secretogranin II gene promoter. 1064 83

Neutrophils and mononuclear cells (MNC) can mediate antibody-dependent cellular cytotoxicity (ADCC) against cancer cells. To study cytotoxicity and growth inhibition of neuroblastoma cells by neutrophils and MNC with chimeric anti-disialoganglioside (GD2) monoclonal antibody (mAb) ch14.18, we developed digital image microscopy scanning (DIMSCAN) assays that measure fluorescence of target cells in 96-well plates after 6-18 h (cytotoxicity assay) or 7 days (growth assay). Neuroblastoma cell lines (GD2-positive: SMS-KCN, SMS-LHN, LA-N-1; GD2-negative: SK-N-SH) were preloaded with calcein acetoxymethyl ester for the cytotoxicity assay or labeled in situ after 7 days of culture with fluorescein diacetate in the growth assay. Fluorescence, as quantified by DIMSCAN, was correlated with neuroblastoma cell number in both assays (100-2000 cells/well). In the cytotoxicity test, both neutrophils and MNC effectively mediated ADCC of GD2-positive but not GD2-negative neuroblastoma cell lines. Cytotoxicity of both neutrophils and MNC increased with effector to target cell (E:T) ratio (5-50:1) and mAb ch.14.18 dose (0.1-10 microg/ml). ADCC of neutrophils, but not MNC, increased with addition of GM-CSF. Neutrophils, especially with rhGM-CSF, significantly suppressed growth of GD2-positive cell lines at a high E:T ratio (50:1) and mAb dose (10 microg/ml). Without antibody, neutrophils inhibited growth of one cell line (LA-N-1) but stimulated growth of two others (SMS-KCN, SMS-LHN). If neuroblastoma cells did not express GD2 (SK-N-SH), neutrophils stimulated growth whether or not antibody was present. Neutrophil culture supernatants increased growth of SK-N-SH, LA-N-1, and SMS-KCN cells, and MNC culture supernatants increased growth of SK-N-SH. In conclusion, neutrophils can mediate cytotoxicity and growth inhibition with a chimeric anti-GD2 antibody but also can promote tumor cell growth if antibody is not present or if GD2 is not expressed.
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PMID:Neutrophils are cytotoxic and growth-inhibiting for neuroblastoma cells with an anti-GD2 antibody but, without cytotoxicity, can be growth-stimulating. 1066 7

Histone deacetylase inhibitors (HDACIs) inhibit the growth of a variety of transformed cells in culture. We demonstrated previously that the hybrid-polar HDACI m-carboxycinnamic acid bis-hydroxamide (CBHA) induces apoptosis of human neuroblastoma in vitro and is effective in lower doses when combined with retinoids. The current study investigates the effect of CBHA on the growth of human neuroblastoma in vivo, both alone and in combination with all-trans retinoic acid (atRA), using a severe combined immunodeficiency-mouse xenograft model. CBHA (50, 100, and 200 mg/kg/day) inhibited growth of SMS-KCN-69n tumor xenografts in a dose-dependent fashion, with 200 mg/kg CBHA resulting in a complete suppression of tumor growth. The efficacy of 50 and 100 mg/kg CBHA was enhanced by the addition of 2.5 mg/kg atRA. This dose of atRA was ineffective when administered alone. Treatment was accompanied by mild weight loss in all groups except the lowest dose of CBHA. Our results suggest HDACIs alone or combined with retinoids may have therapeutic utility for neuroblastoma.
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PMID:The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid. 1132 25

Neuroblastomas are heterogeneous tumors arising from sympathetic precursors in the neural crest. Growth factor stimulation of neuroblastomas promote diverse biological responses (mitogenesis, differentiation, cell death) depending on the particular tumor studied. Here we show that brief treatment with retinoic acid (RA) rendered the human neuroblastoma lines SY5Y, NGP, SMS-KCNR, and SK-N-SH dependent on brain-derived neurotrophic factor (BDNF) for survival. The BDNF- and trkB-expressing line SMS-KCN was dependent on an autocrine BDNF/trkB survival without exposure to RA. We conclude that the BDNF/trkB pathway plays an important role in neuroblastoma survival and speculate on a possible role in tumor pathogenesis.
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PMID:BDNF dependence in neuroblastoma. 1134 Jun 42

We have studied cytogenetic rearrangements in karyotypes of five neuroblastoma cell lines [SK-N-AS, SK-N-SH, SH-SY5Y, SK-N-MC, SMS-KCNR] by G-banding, cross species color banding (RxFISH), and fluorescence in situ hybridization (FISH) with chromosome painting probes. Each neuroblastoma cell line had unique modal karyotypic characteristics and showed a variable number of numerical and structural clonal cytogenetic aberrations. The number of rearranged chromosomes in SK-N-AS, SK-N-SH, SH-SY5Y, SK-N-MC, and SMS-KCNR was 11, 3, 7, 14 (tetraploid, 20-21), and 6, respectively. The origins of abnormal chromosomes were effectively analyzed by RxFISH and FISH with multiple chromosome painting probes. The chromosomal origin of the homogeneously staining region in SH-SY5Y was identified as coamplification of chromosome bands 2p13 and 2p24 by chromosome microdissection and FISH. The non-random rearrangements of chromosomes were determined on 1p34 approximately p36, 6q16 approximately q21, 8q24, 9q34, 11q13 approximately q23, 16q23 approximately q24, 17q21, and 22q31. These results may provide useful information for further molecular characterization of neuroblastoma.
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PMID:Chromosomal aberrations in neuroblastoma cell lines identified by cross species color banding and chromosome painting. 1250 68

To provide investigative tools for the study of neuroblastoma (NB) biology and therapy, we have characterized five orthotopic (adrenal) human xenograft models of NB. Initial experiments compared subcutaneous (heterotopic) with adrenal (orthotopic) injections of two NB cell lines (SK-N-AS and SMS-KCNR) in Beige-SCID mice. These studies demonstrated more relevant tumor biology, including angiogenic phenotype, and enhanced spontaneous distant metastasis for orthotopic versus heterotopic tumors. RNase protection assay demonstrated differences in the expression of angiogenesis-associated genes (flt1, TIE1, angiopoietin, and endoglin) between adrenal and subcutaneous xenografts. Orthotopic models were used to define and characterize the three remaining NB cell lines (SH-SY5Y, LA-1-15N, and IMR32). The pattern of angiogenesis was distinctive for each xenograft model and included a variety of vascular structures. The sites for metastases were distinct for each cell line and included lymph nodes, liver, ovaries, lungs, bone marrow and local bone extension. These well characterized, relevant, highly angiogenic, and metastatic orthotopic models of NB will be a valuable resource to improve our understanding of the biology and treatment of NB.
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PMID:Biologically relevant orthotopic neuroblastoma xenograft models: primary adrenal tumor growth and spontaneous distant metastasis. 1207 75

The promyelocytic leukemia (PML) protein, whose fusion with retinoic acid receptor alpha is responsible for the tumorigenesis of acute promyelocytic leukemia, acts as a tumor suppressor in various types of human cancers. We analyzed the expression patterns of PML, in both primary neuroblastic tumors ( n=20) and two human neuroblastoma (NB) cell lines, SMS-KCNR (KCNR) and SH-SY5Y (SY5Y). The expression of PML, revealed as speckled or microgranular staining in the nuclei, was positively correlated with the differentiation status of NB cells in vivo, and was upregulated during the differentiation of KCNR and SY5Y cells following retinoic acid treatment. Screening of PML expression in human brain and sympathetic ganglia showed restricted expression of PML in mature neurons and glial cells, a result that was consistent with that in differentiated NB tumors. All these findings strongly suggest that increased PML expression is associated with growth inhibition and differentiation of human NB cells, and that it is of critical significance in the biology of NBs and in human nervous system development.
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PMID:Expression of promyelocytic leukemia protein increases during the differentiation of human neuroblastoma cells. 1264 19

Severe and often therapy-limiting side effects are a major obstacle in cancer chemotherapy. New delivery concepts reducing systemic side effects are needed in order to optimize anticancer therapies. Several approaches have been followed, most of them concentrating on macromolecular carriers like liposomes, monoclonal antibodies, serum proteins or polyethylene glycol. We present here a novel type of anthracycline conjugate, using a small carrier peptide derived from the peptide hormone human calcitonin (hCT). The carrier peptide hCT(9-32) has so far been shown to be capable of transporting fluorophores or proteins across cellular membranes. Two different carrier peptide-daunorubicin conjugates were prepared, one with an acid-stable amide bond, the second with an acid-labile hydrazone bond. In vitro studies with daunorubicin linked to the carrier peptide via an acid-labile hydrazone bond demonstrated comparable cytotoxicity to daunorubicin in various daunorubicin sensitive cell lines (neuroblastoma cell lines SK-N-MC and SMS-KAN; HEK 293 T cells). In addition, fluorescence microscopy provided further insight into the mechanism of uptake of the carrier peptide hCT(9-32), indicating that endosomal compartments with reduced pH are involved in the intracellular release of daunorubicin.
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PMID:Novel daunorubicin-carrier peptide conjugates derived from human calcitonin segments. 1452 41

Recent findings link increased expression of the structurally complex 'b' pathway gangliosides GD1b, GT1b, GQ1b (CbG) to a favourable clinical and biological behaviour in human neuroblastoma (NB). Seeking a model to probe these observations, we evaluated four human NB cell lines. Very low CbG content (4-10%) in three of the four cell lines (LAN-5, LAN-1, SMS-KCNR) reflected the ganglioside pattern observed in the most aggressive NB tumours. Pharmacological alterations of complex ganglioside synthesis in vitro by a 5-7 day exposure to 5-10 microM retinoic acid, which is employed in maintenance therapy of disseminated NB, included markedly increased (i) relative expression of CbG (6.6+/-2.0-fold increase, P=0.037), (ii) relative expression of the analogous 'a' pathway gangliosides, termed CaG (6.4+/-1.4-fold increase in GM1a and GD1a; P=0.010), and (iii) total cellular ganglioside content (2.0-6.3-fold), which in turn amplified the accumulation of structurally complex gangliosides. Substantial increases (2.7-2.9-fold) in the activity of GD1b/GM1a synthase (beta-1,3-galactosyltransferase), which initiates the synthesis of CbG and CaG, accompanied the all-trans retinoic acid (ATRA)-induced ganglioside changes. Thus, increased CbG synthesis in NB cell lines is attributable to a specific effect of ATRA, namely induction of GD1b/GM1a synthase activity. Since the shift towards higher expression of CbG and CaG during retinoic acid-induced cellular differentiation reflects a ganglioside pattern found in clinically less-aggressive tumours, our studies suggest that complex gangliosides may play a role in the biological and clinical behaviour of NB.
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PMID:Alterations in neuroblastoma ganglioside synthesis by induction of GD1b synthase by retinoic acid. 1518 99

A simple and accurate high-performance liquid chromatography (HPLC) method was developed to measure levels of N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) and its main metabolite N-(4-methoxyphenyl)retinamide (4-MPR) in tissue. Following ultrasonic extraction of fresh tissue in acetonitrile (ACN), 4-HPR and 4-MPR were measured by HPLC with UV absorbance detection at 340 nm, using isocratic elution with ACN, H(2)O, and acetic acid. N-(4-ethoxyphenyl)retinamide (4-EPR) was employed as an internal standard. The 4-HPR and 4-MPR recovery in bovine liver or bovine brain tissue samples spiked with known amounts of 4-HPR and 4-MPR ranged from 93 to 110%. The detection limit of the method was 50 ng/ml. The method was tested on actual samples from an athymic (nu/nu) mouse carrying a subcutaneous tumor xenograft originating from SMS-KCNR neuroblastoma cells. The tissues were harvested and analyzed following a 3 day long treatment with intraperitoneal injections of 4-HPR/Diluent-12. 4-HPR and the metabolite 4-MPR were detected and quantitated in the tested tissues including tumor, liver, and brain. This method can be used to quantify 4-HPR and 4-MPR in different tissues to determine the bioavailability of 4-HPR.
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PMID:Liquid chromatography method for quantifying N-(4-hydroxyphenyl)retinamide and N-(4-methoxyphenyl)retinamide in tissues. 1526 5


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