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)

Neuroblastoma-inoculated A/J mice were treated with various anticancer chemotherapeutic agents, including cyclophosphamide, daunorubicin, vincristine, alpha-bungarotoxin, dihydroxytryptamine, and diaminopropane. Cyclophosphamide and diaminopropane inhibited neuroblastoma as effectively as bromoacetylcholine and bromacetate. The effectiveness of these drugs could be related to the inhibition of ornithine decarboxylase, a rate-limiting enzyme for the synthesis of polyamines.
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PMID:Chemotherapy of neuroblastoma in mice with anticancer agents. 738 52

Six loci, apoliproprotein B (including Ag(x) antigen), immunoglobulin kappa constant region (IGKC), luteinizing hormone/choriogonadotrophin receptor, avian myelocytomatosis viral related oncogene, neuroblastoma derived, ornithine decarboxylase, and proopiomelanocortin (adrenocorticotropin/beta-lipotropin) (POMC), were newly assigned to sheep chromosome 3p using a chromosomally characterized minipanel of sheep-hamster cell hybrids. Isotopic in situ hybridization of IGKC to sheep chromosome 3p22-p17 is reported, confirming the cell hybrid assignment. As these loci are all known to map to human chromosome 2p, this study demonstrates that this chromosomal segment is extensively conserved in sheep. Only POMC has been previously assigned to cattle chromosome 11, which is the equivalent of sheep chromosome 3p. Therefore, we predict that the other loci assigned in this study to sheep 3p are likely to be located on cattle 11. The provisional assignment of an additional locus, annexin-like to sheep chromosome 3p is also reported.
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PMID:Six loci mapped on to human chromosome 2p are assigned to sheep chromosome 3p. 773 12

Little is known regarding early biochemical events in organophosphate-induced delayed neurotoxicity (OPIDN) except for the essential inhibition of neurotoxic esterase (NTE). We hypothesized that a trophic factor may be produced in situ shortly after exposure to the OP which participates in the progression of OPIDN. To bioassay for such a growth-modulating factor(s), we treated chickens with the neuropathic agents diisopropylfluorophosphate (DFP) or cyclic phenyl saligenin phosphate (PSP), with or without phenylmethylsulfonyl fluoride (PMSF, a chemical which markedly modifies OPIDN). Soluble extracts of cervical spinal cord (a region of the nervous system which degenerates with OPIDN) were collected 24 h later and these were incubated with human neuroblastoma SY5Y cells in culture. The cells were allowed to grow for another 6 days and observed for changes in morphology and growth. After 3 days in culture, tissue extracts from OP-treated chickens caused SY5Y cells to begin to elongate and extend processes (neurites), similar to cells treated with nerve growth factor (1 microgram/ml). Extracts from chickens not receiving OP had no or minimal effects on cell morphology. In addition, extracts from chickens in which OPIDN was prevented by pretreatment with PMSF did not cause the marked extension of cell processes exhibited after exposure of SY5Y cells to extracts from chickens given regimens known to cause OPIDN. In parallel-treated animals. DFP and PSP caused clinical dysfunction characteristic of OPIDN, PMSF posttreatment markedly amplified the clinical deficits and PMSF pretreatment prevented OPIDN. In vivo DFP treatment also caused a marked reduction in the activity of the growth-related enzyme ornithine decarboxylase (ODC) in spinal cord but DFP was without effect on ODC activity in vitro (up to 1 mM final concentration). Characterization of this growth-modulating factor(s) may aid in the elucidation of pathological mechanisms of OPIDN.
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PMID:Possible involvement of a neurotrophic factor during the early stages of organophosphate-induced delayed neurotoxicity. 786 17

We have previously shown that asparagine alone induces a 10-15-fold increase in ornithine decarboxylase (ODC) mRNA level in DF-40 mouse neuroblastoma cells. The induction is due to an accumulation of ODC mRNA through a post-transcriptional stabilization mechanism (Chen, Z.P. and Chen, K.Y. (1992) J. Biol. Chem., 267, 6946-6951). In the present study we showed that asparagine induced ODC gene expression in v-Ha-ras-transformed 3T3 (ras-3T3) cells but not in 3T3 cells. Other growth related genes including c-src, c-ras, and c-fos were not affected by asparagine in ras-3T3 cells. Southern blot analysis indicated that the pronounced asparagine effect was not due to ODC gene amplification in ras-3T3 cells. The effect of asparagine on the induction of ODC mRNA could account for the significant increases in the ODC activity in ras-3T3 cells. We also examined the effect of asparagine on ODC gene expression in human KD cells and their transformed counterparts. Our findings strongly suggest that the induction of ODC mRNA by asparagine may represent a component of an altered growth regulatory program associated most prominently with cell transformation.
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PMID:Asparagine markedly induces the expression of ornithine decarboxylase gene in transformed mammalian cells but not in their untransformed counterparts. 795 61

In cultured human neuroblastoma cells (SK-N-MC), a plasma membrane-bound besides a lysosomal ganglioside GM3 sialidase was detected. Both activities can be distinguished by the specific activation with detergents, as well as differential inhibition by Cu++. Plasma membrane and lysosomal sialidase specific activities showed strikingly different behaviour during the growth phase of neuroblastoma cells. Thus, the plasma membrane sialidase increased about 15-fold and mirrored cell growth, it differed from the kinetics of ornithine decarboxylase, an early marker of cell proliferation. The lysosomal sialidase, on the other hand, exhibited constant specific activities during growth of the cells, as did lysosomal and plasma membrane marker enzymes. When the sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid was included in the culture medium, a profound change in proliferation kinetics was observed, indicating a release from density-dependent control of cell division. Additionally, the inhibitor abolished the increase of the biochemical differentiation marker acetylcholinesterase. The results suggest an important role of the ganglioside sialidase of the plasma membrane in the processes of proliferation control and differentiation in this neuronal cell system.
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PMID:Role of plasma membrane ganglioside sialidase of human neuroblastoma cells in growth control and differentiation. 814 59

To elucidate the contribution of the N-Myc protein to neuroblastomas we have used a synthetic inducible expression system on the basis of the tetracycline repressor of E coli to reversibly express N-myc in a human neuroblastoma cell line in which expression of endogenous N-myc is barely detectable. Like the c-Myc protein, N-Myc up-regulates the expression of both alpha-prothymosin and ornithine decarboxylase. Induction of N-myc increases both the rate of DNA-synthesis and the proliferation rate, and shortens the G1 phase of the cell cycle. A comparison of cell populations in which the presence of N-Myc protein was restricted to different parts of G(zero)/G1 revealed that N-Myc is rate-limiting for cell cycle progression during the first 5 h after serum stimulation of quiescent cells providing direct evidence that Myc-proteins act early after mitogenic stimulation of quiescent cells.
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PMID:Conditional expression of N-myc in human neuroblastoma cells increases expression of alpha-prothymosin and ornithine decarboxylase and accelerates progression into S-phase early after mitogenic stimulation of quiescent cells. 876 2

Previous studies have revealed that the MYCN gene spans approximately 7kb, while the amplicon has been estimated to be 100 kb to 1 Mb long [1-3]. This implies that several other genes may be present on the MYCN amplicon. Such co-amplified genes could contribute to the malignant phenotype and might provide an explanation for why not all patients with MYCN amplification have a poor outcome. We investigated 7 neuroblastoma cell lines and 167 primary tumours for the co-amplification of candidate genes known to be present near the MYCN locus: ornithine decarboxylase, ribonucleotide reductase, syndecan-1 and a DEAD box protein gene, DDX1. We also investigated further the pG21 expressed sequence previously reported to be co-amplified with MYCN. No co-amplification with the first 3 genes was found in any of the cell lines or tumour samples. DDX1 was found to be amplified along with MYCN in 4/6 (67%) cell lines and 18/38 (47%) of the MYCN amplified tumours. No amplification of DDX1, ODC1, RRM2 or syndecan-1 was found in the absence of MYCN amplification. DDX1 co-amplification was observed to occur mainly in stage 4 or 4S patients. With the exclusion of those with 4S disease, patients with DDX1 co-amplification had a significantly shorter mean (+/- SE) disease-free interval (4.1 +/- 1.4, n = 8 months) compared with patients with MYCN amplification alone (19.6 +/- 4.5, n = 17) (P = 0.04, Welch's unpaired t-test). The pG21 sequence was identical to part of the DDX1 gene. These observations indicate that there is at least 1 other gene co-amplified with MYCN in a proportion of cases and that those patients with DDX1 co-amplification tend to relapse more quickly. It also implies that the MYCN amplicon is of varied size and/or position relative to the MYCN gene.
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PMID:Analysis of candidate gene co-amplification with MYCN in neuroblastoma. 951 49

Overexpression of specific transcription factors by tumor cells can be exploited to regulate expression of proteins that induce apoptosis or activate prodrugs, thereby producing tumor-selective toxicity. A majority of advanced-stage neuroblastomas overexpress the transcription factor N-MYC, and this overexpression is associated with poor prognosis. This study describes regulation of expression by N-MYC, via the ornithine decarboxylase (ODC) promoter, of a rabbit liver carboxylesterase (CE) that activates the prodrug CPT-11. Chloramphenicol acetyltransferase reporter assays and CE activity assays in transiently transfected neuroblastoma cell lines (SJNB-1, SJNB-4, NB-1691) and rhabdomyosarcoma cell lines (JR1neo20, JR1Nmyc6, JR1Nmyc9) support this approach as a potential method for sensitizing tumor cells to CPT-11. Clonogenic assays with IMR32 human neuroblastoma cells which express N-MYC and that had been stably transfected with a plasmid containing an ODC promoter/CE cassette corroborated results of enzyme activity assays. Specifically, IMR32.ODC.CE cells expressed approximately eightfold more CE activity than IMR32.CMV.neo cells; and 5 microM CPT-11 reduced the clonogenic potential of IMR32.ODC.CE cells to zero, while 50 microM CPT-11 was required to produce the same effect with IMR32.CMV.neo cells. Current experiments focus on adenoviral delivery of an ODC promoter/CE cDNA cassette for potential virus-directed enzyme prodrug therapy applications.
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PMID:Use of the ornithine decarboxylase promoter to achieve N-MYC-mediated overexpression of a rabbit carboxylesterase to sensitize neuroblastoma cells to CPT-11. 1093 67

One of the advantages of viral-directed enzyme prodrug therapy (VDEPT) is its potential for tumor-specific cytotoxicity. However, the viruses used to deliver cDNAs encoding prodrug-activating enzymes transduce normal cells as well as tumor cells, and several approaches to achieve tumor-specific expression of the delivered cDNAs are being investigated. One such approach is to regulate transcription of the prodrug-activating enzyme with a promoter that is preferentially activated by tumor cells. Published data suggest that the most promising transcription factor/promoter/enhancer combinations are those activated by a tumor-specific transcription factor to retain tumor cell specificity but that are equal in strength to nonspecific viral promoters in their ability to up-regulate target cDNAs. This report identifies MYC-responsive, modified ornithine decarboxylase (ODC) promoter/enhancer sequences that up-regulate target protein expression in tumor cells overexpressing either N-MYC or c-MYC protein. The most efficient of the four constructs assessed contained six additional CACGTG MYC binding sites 5' to the endogenous ODC promoter (R6ODC). Reporter assays with this chimeric promoter/enhancer regulating expression of chloramphenicol acetyltransferase demonstrated 50-250-fold more activity in MYC-expressing cells compared with similar assays with promoterless plasmids. The R6ODC regulatory sequence was approximately equivalent to the CMV promoter in inducing expression of the neomycin resistance gene in c-MYC-expressing SW480 and HT-29 colon carcinoma cells and in N-MYC-expressing NB-1691 neuroblastoma cells. The modified ODC promoter may, therefore, be useful in achieving tissue-specific expression of target proteins in tumor cells that overexpress c- or N-MYC.
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PMID:Use of a modified ornithine decarboxylase promoter to achieve efficient c-MYC- or N-MYC-regulated protein expression. 1130 86

The transcription factor and proto-oncogene MYCN is reviewed as a potential specific target for cancer therapy. Amplification of MYCN is frequently found in a number of advanced-stage tumours, including neuroblastoma (25%), small cell lung cancers (7%), alveolar rhabdomyosarcoma and retinoblastoma. It is associated with rapid tumour progression and poor outcome in human neuroblastoma. MYCN is a member of the myc family of proto-oncogenes which encode nuclear proteins that form heterodimers with MAX protein through their conserved HLHZip domains. The MYC/MAX complexes transactivate a number of MYC-target genes in a sequence-specific manner. MYC-MAX interaction is essential for MYC-induced cell cycle progression, cellular transformation, and transcriptional activation. A causal link between the transformed phenotype and MYCN has been established by a range of in vitro and in vivo studies, including a transgenic model of neuroblastoma in which MYCN overexpression is targeted to neuronal tissue by the use of a tyrosine hydroxylase promoter. Downregulation of MYCN expression either by antisense treatment targeted against MYCN mRNA or by retinoids has been shown to decrease proliferation and/or induce neuronal differentiation of neuroblastoma cells. Inhibition of MYC-MAX dimerisation by small-molecule antagonists has recently been shown to interfere with MYC-induced transformation of chick embryo fibroblasts, indicating that functional inhibitors of the MYC family of oncoproteins have potential as therapeutic agents. Finally, we describe the development and validation of a functional MYCN reporter gene assay using neuroblastoma cells (NGP) which have been stably transfected with a luciferase gene construct under control of the ornithine decarboxylase gene promoter. This assay has been used for a pilot screen of 2800 compounds from the Cancer Research-UK collection, identifying five compounds showing a consistent significant reduction of MYCN-dependent luciferase activity (>50%) in repeated screens. This cell-based, MYCN reporter gene assay will be scaled up for high throughput screens of compound libraries and will aid in the future development of specific therapeutic strategies in neuroblastoma and other tumours in which MYCN amplification has been implicated.
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PMID:The MYCN oncoprotein as a drug development target. 1288 Sep 71


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