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 fundamental event in prion diseases involves a conformational change in one or more of the alpha-helices of the cellular prion protein (PrP(C)) as they are converted into beta-sheets during the formation of the pathogenic isoform (PrP(Sc)). Here, we show that exposure of scrapie-infected mouse neuroblastoma (ScN2a) cells to reagents known to stabilize proteins in their native conformation reduced the rate and extent of PrP(Sc) formation. Such reagents include the cellular osmolytes glycerol and trimethylamine N-oxide (TMAO) and the organic solvent dimethylsulfoxide (DMSO), which we refer to as 'chemical chaperones' because of their influence on protein folding. Although the chemical chaperones did not appear to affect the existing population of PrP(Sc) molecules in ScN2a cells, they did interfere with the formation of PrP(Sc) from newly synthesized PrP(C). We suggest that the chemical chaperones act to stabilize the alpha-helical conformation of PrP(C) and thereby prevent the protein from undergoing a conformational change to produce PrP(Sc). These observations provide further support for the idea that prions arise due to a change in protein conformation and reveal potential strategies for preventing PrP(Sc) formation.
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PMID:Chemical chaperones interfere with the formation of scrapie prion protein. 897 63

High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg(-1)), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 microg h ml(-1)) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 microg h ml(-1)). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens.
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PMID:Busulphan is active against neuroblastoma and medulloblastoma xenografts in athymic mice at clinically achievable plasma drug concentrations. 1007 Aug 70

The retinoblastoma family of nuclear factors is composed of RB, the prototype of the tumour suppressor genes and of the strictly related genes p107 and Rb2/p130. The three genes code for proteins, namely pRb, p107 and pRb2/p130, that share similar structures and functions. These proteins are expressed, often simultaneously, in many cell types and are involved in the regulation of proliferation and differentiation. We determined the expression and the phosphorylation of the RB family gene products during the DMSO-induced differentiation of the N1E-115 murine neuroblastoma cells. In this system, pRb2/p130 was strongly up-regulated during mid-late differentiation stages, while, on the contrary, pRb and p107 resulted markedly decreased at late stages. Differentiating N1E-115 cells also showed a progressive decrease in B-myb levels, a proliferation-related protein whose constitutive expression inhibits neuronal differentiation. Transfection of each of the RB family genes in these cells was able, at different degrees, to induce neuronal differentiation, to inhibit [3H]thymidine incorporation and to down-regulate the activity of the B-myb promoter.
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PMID:The RB-related gene Rb2/p130 in neuroblastoma differentiation and in B-myb promoter down-regulation. 1020 Apr 89

Symmetrically hindered methylphenols 1 react smoothly with NBS to form transient intermediates, p-benzoquinone methides (BM), which can be further processed to give hydroxybenzaldehydes in the presence of DMSO. This reaction is initiated by the formation of the phenoxy radical, followed by disproportionation to afford BM. None of the side-chain-brominated product is observed. The existence of BM is supported by the following observations: the formation of BM in solution can be monitored by GC and GC-MS; the electrophilic methine part participates in electrophilic aromatic substitution with anisoles to give hydroxybenzylated products 15; and the double bond character of the exocyclic methine plays a role in [4 + 2] cycloaddition with diene to afford Diels-Alder adducts. In contrast, unsymmetrically hindered or simple methylphenol (p-cresol) with NBS gives the nuclear brominated products, as usual. The energies of symmetrically hindered BMs, unsymmetrically hindered BM, and simple BM were calculated using density functional theories. Relative stabilization energies calculated at the B3LYP/6-31G//B3LYP/6-31G level by an isodesmic equation are enhanced 3-6 kcal/mol for symmetrically hindered BMs.
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PMID:NBS-Promoted reactions of symmetrically hindered methylphenols via p-benzoquinone methide 1081 3

The development of monoclonal antibodies against differentiation antigens on human haematopoietic cells has led to a new concept in stem cell purification: the positive selection. In terms of autologous PBSC transplantation, the immature stem cells are identified by their expression of a specific antigen, the CD34. The CD34 antigen is expressed on early lymphohaematopoietic stem cells and progenitor cells, but not on mature blood cells or on tumour cells of several diseases. CD34+ cells are found in low numbers in bone marrow (<2%) and in even lower numbers in steady state blood (<0.01%) but may increase from 1 to 5% after mobilization using chemotherapy and/or growth factors. Several techniques have been set up to enrich PBSC grafts in CD34+ stem cells. The quality of each system is here analysed in terms of CD34 purity of the selected cell fraction, the CD34 cell recovery, the tumour cell depletion efficiency and the functional capacity ex vivo and in vivo of the selected cells. The final CD34+ cell purity of the selected fractions is correlated to the concentration of CD34+ cells before selection. The optimal recoveries and the highest purities were generally obtained when the initial CD34 content was roughly over 1%. Below this figure, the final purity seems to be less predictable. Besides the better tolerance resulting from the reduction in the number of autologous cells, and consequently the total volume of DMSO reinfused to the patient, the selective enrichment of the CD34 cell population offers a new approach to tumour purging. The procedure by itself results in elimination of about 99% in the total number of initial cells, thus allowing reduction of the overall tumour cell number in the final autograft. However, its major interest is that, in diseases where tumour cells do not express the CD34 antigen, it is theoretically able to completely eliminate the tumour contamination of the graft. Based on previous data showing that lymphoma, myeloma, neuroblastoma and breast cancer cells are not CD34+, pilot clinical trials for the separation and transplantation of CD34+ cells selected from PBSC of patients with these diseases have recently been conducted. The efficacy of CD34 selection in reducing the tumour load of the PBSC of patients with these diseases has been reported. However, the efficacy of purging may greatly differ between individual patients, and complete eradication of contaminating cells from PBSC grafts was not always reached. There is now evidence that purified CD34+ cells are capable of supporting haematopoietic reconstitution in autologous transplantation. However, until now no study has demonstrated clear evidence that the reduction of tumour cells from PBSC of patients by CD34+ cell selection resulted in a lower relapse rate post-transplant, as compared to unselected PBSC infusion.
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PMID:Positive selection of autologous peripheral blood stem cells. 1100 Sep 84

Methyl- and phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6 were reacted with NBS in wet DMSO to afford bromohydrins. Mixtures of unrearranged 6-exo-bromo-5-endo-hydroxy-2-azabicyclo[2.2.0]hexanes 7a,b and rearranged 5-anti-bromo-6-anti-hydroxy-2-azabicyclo[2.1.1]hexanes 8a,b were formed stereoselectively from the parent alkene 6a and 4-methyl alkene 6b. The 5-methyl alkene 6c affords only unrearranged bromohydrin 7c and dibromohydrin 9. By contrast, solely rearranged 3-endo-substituted-2-azabicyclo[2.1.1]hexane bromohydrins 8d-f result from additions to 3-endo-methyl alkene 6d, 3-endo-4-dimethyl alkene 6e, and 3-endo-phenyl alkene 6f. As an alternative route to bromohydrins, the parent 5,6-exo-epoxide 10a and 5-endo-methyl-5,6-exo-epoxide 10b were ring opened with bromine/triphenylphosphine to afford unrearranged 5-endo-bromo-6-exo-hydroxy-2-azabicyclo[2.2.0]hexanes 11a,b, while the 3-endo-methyl epoxide 10c afforded solely the rearranged 5-anti-bromo-6-anti-hydroxy-3-exo-methyl-2-azabicyclo[2.1.1]hexane isomer 8g. Tributyltin hydride reduction of bromohydrins 7a,b and 11a afforded novel 2-azabicyclo[2.2.0]hexan-5-ols 13a,b and -6-ol 14, and bromohydrins 8a,b, 8d-g afforded new 2-azabicyclo[2.1.1]-hexan-5-ols 15a,b and 15d-g.
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PMID:Synthesis of novel 2-azabicyclo[2.2.0]- and [2.1.1]hexanols. 1126 32

Treatment of 5,10,15,20-tetraarylporphyrins (1) with perfluoroalkyl iodides (2) in the presence of Na(2)S(2)O(4)/NaHCO(3) in DMSO-CH(2)Cl(2) at 30-40 degrees C for several hours gives the corresponding 2-perfluoroalkylporphyrins (3). Nucleophilic attack on 3 with dimethyl malonate, diethyl malonate, malonitrile, or cyano acetate (Nu) anion results in the formation of (E)-3-Nu-2-perfuoroalkyl(methylenyl)chlorins. Electrophilic substitution on 3 with NBS or NO(2) affords regioselectively the corresponding 12(or 13)-bromo- and 12,13-dibromo- or nitroporphyrins.
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PMID:Fluoroalkylation of porphyrins: synthesis and reactions of beta-fluoroalkyltetraarylporphyrins. 1273 71

A new method for the oxidation of nucleoside phosphite triester into phosphate triester under nonbasic and nonaqueous conditions using NBS-DMSO in CH(3)CN has been developed. The utility of this method for solution- and solid-phase synthesis of oligonucleotide is demonstrated.
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PMID:NBS-DMSO as a nonaqueous nonbasic oxidation reagent for the synthesis of oligonucleotides. 1450 65

Familial Creutzfeldt-Jakob disease (CJD) comprises a group of neurodegenerative disorders for which currently there is no treatment. In this study, we evaluated the efficacy of drugs approved for human use, and protein folding agents in reversing the mutant phenotype of familial CJD H187R in a cell model. For an efficient experimental readout, green fluorescent protein (GFP)-tagged mutant prion protein (PrP(187R-GFP)) and wild-type PrP (PrP(C-GFP)) were expressed in human neuroblastoma cells. We report that unlike PrP(C-GFP) that is expressed on the cell surface, PrP(187R-GFP) accumulates in the lysosomes of transfected cells. Treatment of PrP(187R-GFP) cells with quinacrine or doxycycline, agents known to inhibit the replication of PrP-scrapie (PrP(Sc)) in experimental models, gave conflicting results; doxycycline reverted the mutant phenotype of PrP(187R-GFP) cells, whereas quinacrine had no effect. The concentration of doxycycline used in these studies is well within the plasma concentration of patients receiving a 250-600 mg dose two to three times daily. Interestingly, exposure of PrP(187R-GFP) cells to low temperature (28 degrees C) or to the chemical chaperones dimethyl sulphoxide (DMSO) and glycerol also reversed the mutant phenotype. These data suggest that doxycycline and protein folding agents may hold promise as therapeutic agents for familial CJD H187R and other familial disorders that share similar pathogenic mechanisms.
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PMID:Doxycycline and protein folding agents rescue the abnormal phenotype of familial CJD H187R in a cell model. 1504 64

Neuroblastomas constitute about 10% of childhood cancers and are responsible for 15% of pediatric cancer mortality. We evaluated the efficacy and the mechanism of cell death induced by CAY10404, a selective cyclooxygenase-2 (Cox-2) inhibitor in four human neuroblastoma cell lines (SH-EP, SH-SY5Y, SK-N-MC and MSN). Treatment with CAY10404 in the range of 15-115 microM revealed a dose-dependent decrease in cell number and an average IC50 (inhibitory concentration 50%) of 60 microM. About 20-30% of the cells were terminal deoxynucleotidyltransferase-mediated UTP nick-end-labeling (TUNEL) positive 48 h after treatment. Western blot analysis of CAY10404-treated cells showed poly(ADP-ribose) polymerase (PARP) cleavage and cleaved caspase-3 signifying caspase activity and apoptotic cell death. Inhibitor-of-apoptosis proteins including X-linked inhibitor-of-apoptosis protein (XIAP) and survivin did not change significantly after CAY10404 treatment. Fluorescence activated cell sorter (FACS) analysis performed in two different cell lines 48 h following CAY10404 treatment showed a reduction in the number of cells in the G1 phase of the cell cycle and an increase in the number of cells in the G2 phase. When radioresistant SH-EP cells were treated with CAY10404, a 49% decrease in cell viability was observed relative to DMSO-treated cells; pretreatment with CAY10404 followed by ortho-voltage irradiation further enhanced cell death (58%) suggesting radiosensitization by CAY10404.
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PMID:Inhibition of human neuroblastoma cell growth by CAY10404, a highly selective Cox-2 inhibitor. 1569 Jan 29


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