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)

Bovine seminal ribonuclease (BS-RNase) is a homologue of RNase A with specific antitumor activities. It is selectively toxic for neuroblastoma (NB) cells in vitro with no significant effects on the viability of normal human cells. We evaluated the antitumoral effects of BS-RNase on human NB xenografts from UKF-NB-3 cells in athymic (nude) mice. The efficacy of direct intraneoplastic, subcutaneous and systemic delivery of BS-RNase was explored. Systemic administration of BS-RNase (12.5 mg/kg/day intraperitoneally, for 20 days in the course of four weeks) suppressed tumor growth but was not able to induce any cures. Subcutaneous injections (12.5 mg/kg/day for 20 days in the course of four weeks) and intratumoral BS-RNase treatment using the same schedule resulted in complete tumor regression. During 30 days following cessation of treatment no tumor regrowth was observed and animals were free of tumors. Toxic effects of BS-RNase (e.g., on bone marrow and inner organs) were not apparent. This data indicates that BS-RNase fulfills important criteria for a candidate antitumor agent specific for NB.
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PMID:Bovine seminal ribonuclease inhibits in vivo growth of human neuroblastoma cells. 1067 87

Bovine seminal ribonuclease (BS RNase), a dimeric homolog of bovine pancreatic ribonuclease has been proven to have important biological properties as aspermatogenic, antitumor, embryotoxic and immunosuppressive activities. Recently we published preliminary results concerning the ability of bovine seminal ribonuclease (BS RNase) to induce time dependent apoptosis in Con-A stimulated human lymphocytes and in human tumor cells based on DNA content and cell cycle analysis. In this study we bring more confirmative data concerning the concentration dependent in vitro induction of apoptosis in stimulated human lymphocytes and tumor cells of three human cell lines using the most sensitive and specific cytometric method for at present apoptosis determination the indirect TUNEL. BS RNase 50 microg/ml was proven to induce 49.7, 54 and 68.1% apoptosis in the cells of the ML-2 myeloid cell line and two neuroblastoma cell lines: NB-1 and NB-2, respectively. In Con A-stimulated human lymphocytes, BS RNase also induced apoptosis, eventhough not so pronounced as in human tumor cell lines. In all cultures the induction of apoptosis was proportional to BS RNase concentration ranging from 2-50 microg/ml and correlated with proportional decrease in 3H-thymidine incorporation into the newly synthesized DNA. Side by side with the ability of BS RNase to suppress the growth of human tumors transplanted to nude mice, these biological properties determine this enzyme as a promising agent with potential clinical application.
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PMID:Bovine seminal ribonuclease induces in vitro concentration dependent apoptosis in stimulated human lymphocytes and cells from human tumor cell lines. 1113 Feb 46

RXR beta is predominantly involved in retinoid responses in neuroblastoma cells, in particular the N-type SH SY 5Y cells and the S-type SH S EP cells, both derivatives of a mixed phenotype neuroblastoma cell line. The aim of this study was to identify RXR beta isoforms expressed in neuroblastoma cells and to characterise a putative novel RXR beta transcript. RXR beta 1 and RXR beta 2 were expressed in these neuroblastoma cells. An isoform with an insertion into the ligand binding domain, RXR beta(SLSR) (referred to in previous studies as RXR beta 3), was expressed at a similar level to RXR beta. A novel RXR beta transcript was identified by RNase protection assays and was at least as abundant as the expected RXR beta transcript and expressed in other cell types. Evidence suggests that this novel transcript was transcribed from an internal promoter between exons 5 and 6, contained a retained intron (intron 6) and was alternatively spliced with and without the SLSR insertion. These data show that the pattern of RXR beta expression is complex. The relative abundance of the novel RXR beta transcript suggests that it may be an important aspect of RXR beta function or regulation in a range of cell types.
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PMID:RXR beta isoforms in neuroblastoma cells and evidence for a novel 3'-end transcript. 1159 67

GTP cyclohydrolase I (GTPCH) gene expression was investigated in the human monoamine-containing neuroblastoma cell line SK-N-BE(2)M17. Northern blot analysis revealed a single GTPCH mRNA transcript that was confirmed by RNase protection assay to encode for Type 1 GTPCH; no alternatively spliced forms of GTPCH mRNA were detected with this assay. Incubation with 8Br-cAMP, but not nerve growth factor or leukemia inhibitory factor, produced a rapid increase in GTPCH mRNA and protein levels; protein levels remained elevated during the entire treatment period while mRNA content declined rapidly between 10 and 24 h. Treatment with 8Br-cAMP did not significantly modify the stability of GTPCH mRNA but did increase GTPCH transcription as determined by transient transfection assays of a luciferase reporter construct containing 1171 bp of human GTPCH 5'-flanking sequence. Cis-acting elements required for maximal basal and cAMP-dependent transcription were localized by deletion analysis to the 146 bp proximal promoter. DNase I footprint analysis of the proximal promoter using SK-N-BE(2)M17 nuclear extracts identified two protein binding domains: one an upstream Sp1-like site and the other a combined CRE-Sp1-CCAAT-box element. EMSA and supershift assays demonstrated that the combined CRE-Sp1-CCAAT-box element recruits ATF-2 and NF-Y but not Sp1-4 or Egr-1-3. NF-Y binding was confirmed using pure recombinant human NF-Y protein. Transcription of the human GTPCH gene in human SK-N-BE(2)M17 cells is thus enhanced by cAMP acting through regulatory elements located in the proximal promoter and may involve the transcription factors NF-Y and ATF-2.
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PMID:Characterization of GTP cyclohydrolase I gene expression in the human neuroblastoma SKN-BE(2)M17: enhanced transcription in response to cAMP is conferred by the proximal promoter. 1170 61

Bovine seminal ribonuclease (BS-RNase) is an antitumoral active enzyme exhibiting specific antitumoral action against a number of different cancer cell lines. However, its systemic use is limited by its pharmacokinetic properties and antigenicity. Therefore, it was conjugated to polyethylene glycol (PEG) chains to overcome these problems. Measurement of aspermatogenic effects of the preparation after s.c. injection and injection into the scrotum was chosen as a model for the distribution of the enzyme in the body mediated by the linkage to PEG chains. Additionally, the antigenicity of BS-RNase coupled to PEG chains (BS-RNase-PEG) was compared to that of free BS-RNase, as antigenicity is known to be one of the main obstacles in the use of protein-based drugs. BS-RNase-PEG caused aspermatogenic effects after systemic administration to mice in very low concentrations at which free BS-RNase is not effective. Moreover, BS-RNase possessed a very low antigenicity as long as it was coupled to the PEG chains. In order to investigate the antitumoral efficacy of BS-RNase-PEG in vivo, preliminary experiments on the effect of the conjugate on neuroblastoma growth in mice were performed in a UKF-NB-3 xeno-transplantate model, demonstrating a drastically increased anti-tumoral activity of the conjugate compared to the free enzyme.
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PMID:Coupling of the antitumoral enzyme bovine seminal ribonuclease to polyethylene glycol chains increases its systemic efficacy in mice. 1190 7

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 hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) was used for RNase A or BS-RNase modification to prevent their degradation in bloodstream or fast elimination. Two PHPMA chains (classic and star-like) were synthesized and their conjugates with both enzymes were tested on the CD-1 nude mice bearing various human tumors. These RNase conjugates injected intravenously or intraperitoneally into the mice bearing melanoma, neuroblastoma or ovarian tumor caused significant reduction of transplanted tumors following ten daily doses of 2.5 and/or 1 mg/kg, respectively, while free RNase A or BS-RNase injected in doses of 10 mg/kg exerted only negligible antitumor activity. Histological examination confirmed potent cytotoxic effect of RNase A conjugates in ovarian tumor. Despite the antitumor activity observed in vivo, the in vitro cytotoxic activity of RNase A conjugates was not pronounced and did not differ from that caused by the free RNase A. The in vitro experiments with 125I-labeled preparations demonstrated that polymer conjugates were internalized by tumor cells very poorly in contrast to the dose-dependent internalization of the wild enzyme preparation. Surprisingly, mice injected with EL-4 leukemic cells, which were preincubated for 4 h with BS-RNase conjugates, exerted significantly prolonged survival compared with the control non-treated mice. It may be supposed that both BS-RNase and RNase A conjugates with PHPMA act after administration in vivo by a mechanism different from that or those occurring under in vitro conditions because in vivo they exert an antitumor action, whereas in vitro, they are ineffective. The experiments proved that RNase A, when conjugated to PHPMA, produced identical aspermatogenic and antitumor effects as BS-RNase conjugated to this polymer and that this preparation may be regarded as a potential anticancer drug.
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PMID:Polymer-conjugated bovine pancreatic and seminal ribonucleases inhibit growth of human tumors in nude mice. 1501 35

Natural antisense transcripts, because of their potential to form double-stranded RNA (dsRNA) molecules, recently emerged as a mechanism acting on eukaryotic gene regulation at multiple levels. CHRNA3 and CHRNA5, coding for alpha3 and alpha5 subunits of the neuronal nicotinic acetylcholine receptor, have been reported to overlap at their 3'ends in human and bovine genomes. In the present paper, four CHRNA3 and three CHRNA5 human transcripts were characterised, leading to the identification of different antisense complementary regions. Since the two genes are coexpressed in some neuronal and non-neuronal tissues, we ventured on the in vivo identification of RNA-RNA duplexes in both humans and cattle. Using an RNase protection-based approach, CHRNA3/CHRNA5 duplexes were detected in human neuroblastoma SY5Y cells, but not in bovine cerebellum. A semi-quantitative analysis of overlapping transcript levels was performed by real-time RT-PCR. Possible consequences of sense-antisense interaction are discussed.
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PMID:In vivo RNA-RNA duplexes from human alpha3 and alpha5 nicotinic receptor subunit mRNAs. 1571

DEAD box proteins are a family of putative RNA helicases associated with all aspects of cellular metabolism involving the modification of RNA secondary structure. DDX1 is a member of the DEAD box protein family that is overexpressed in a subset of retinoblastoma and neuroblastoma cell lines and tumors. DDX1 is found primarily in the nucleus, where it forms two to four large aggregates called DDX1 bodies. Here, we report a rapid redistribution of DDX1 in cells exposed to ionizing radiation, resulting in the formation of numerous foci that colocalize with gamma-H2AX and phosphorylated ATM foci at sites of DNA double-strand breaks (DSBs). The formation of DDX1 ionizing-radiation-induced foci (IRIF) is dependent on ATM, which was shown to phosphorylate DDX1 both in vitro and in vivo. The treatment of cells with RNase H prevented the formation of DDX1 IRIF, suggesting that DDX1 is recruited to sites of DNA damage containing RNA-DNA structures. We have shown that DDX1 has RNase activity toward single-stranded RNA, as well as ADP-dependent RNA-DNA- and RNA-RNA-unwinding activities. We propose that DDX1 plays an RNA clearance role at DSB sites, thereby facilitating the template-guided repair of transcriptionally active regions of the genome.
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PMID:A role for DEAD box 1 at DNA double-strand breaks. 1871 Sep 41

Phorbol ester treatment of human SH-SY5Y neuroblastoma cells, which leads to mature neuron-like cells with a sympathetic phenotype, induces outgrowth of neurites which are terminated by growth cones. The neurite extension is parallelled by an increased expression of the growth-associated protein, GAP-43. At the mRNA level, two GAP-43 mRNA species of 1.4 and 1.6 kb, respectively, were detected in SH-SY5Y cells. Both the low- and high-molecular-weight GAP-43 transcripts cosedimented with a polysomal fraction, indicating translation of both types of transcripts. To structurally characterize these GAP-43 mRNAs, several cDNA clones were isolated. The only difference identified corresponded to various size extensions in the 5'-untranslated region. A human genomic DNA fragment extending 1145 bp 5' of the GAP-43 translation start site, including a putative promoter region of the GAP-43 gene, was also characterized. Comparison of human and rat GAP-43 genomic sequences revealed an 85% identity between the first 900 bp 5' of translation start site. By RNase protection analysis, two clusters of putative transcription start sites, located approximately 200 bp apart, were identified. DNaseI footprinting analyses, using nuclear extracts prepared from untreated and TPA-treated SH-SY5Y cells, revealed specific footprints primarily detected in extracts prepared from differentiating cells. These clustered at positions immediately 5' of the two putative transcription start site regions. GAP-43 mRNA expression was finally studied using a probe which specifically recognizes the high-molecular-weight GAP-43 transcripts. Five tested human neuroblastoma cell lines and human fetal brain tissue expressed these transcripts. Furthermore, during differentiation of SH-SY5Y and LA-N-5 cells, both sizes of GAP-43 transcripts were transiently induced with the larger slightly preceeding the smaller mRNA species.
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PMID:Human GAP-43 Gene Expression: Multiple Start Sites for Initiation of Transcription in Differentiating Human Neuroblastoma Cells. 1991 63


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