Expression of the Gene for Multidrug-Resistance–Associated Protein and Outcome in Patients with Neuroblastoma

Norris, Murray D.; Bordow, Sharon B.; Marshall, Glenn M.; Haber, Paul S.; Cohn, Susan L.; Haber, Michelle

doi:10.1056/nejm199601253340405

Cited by 281 publications

(159 citation statements)

References 36 publications

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“…Although neither the sizes of the 1p deletions nor the extent of N-MYC ampli®cations in these patients was described, it is tempting to speculate that these patients either had the larger 1p deletion at the time of diagnosis or developed it in association with progression and concurrent N-MYC amplification. Norris et al (1996) have observed that overexpression of the gene encoding the multidrugresistance-associated protein (MRP) in untreated, advanced stage NBL with N-MYC ampli®cation correlated with reduced event-free and overall survival. Although this may potentially explain the inherent drug-resistance of NBL, it is noteworthy that the di erence in MRP expression between favorable and unfavorable NBLs, although significant, were 5twofold.…”

Section: Neuroblastoma (Nbl)mentioning

confidence: 99%

MYC oncogenes and human neoplastic disease

1999

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c-myc, N-myc and L-myc are the three members of the myc oncoprotein family whose role in the pathogenesis of many human neoplastic diseases has received wide empirical support. In this review, we ®rst summarize data, derived mainly from non-clinical studies, indicating that these oncoproteins actually serve quite di erent roles in vivo. This concept necessarily lies at the heart of the basis for the observation that the deregulated expression of each MYC gene is reproducibly associated with only certain naturally occurring malignancies in humans and that these genes are not interchangeable with respect to their aberrant functional consequences. We also review evidence implicating each of the above MYC genes in speci®c neoplastic diseases and have attempted to identify unresolved questions which deserve further basic or clinical investigation. We have made every attempt to review those diseases for which signi®cant and con®rmatory evidence, based on studies with primary tumor material, exists to implicate MYC members in their causation and/or progression.

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Section: Neuroblastoma (Nbl)mentioning

confidence: 99%

MYC oncogenes and human neoplastic disease

1999

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“…15 The mouse ACTB (beta-actin) gene was used as an internal control for all reverse transcription PCRs. Human MYCN, murine odc and murine mrp1 gene expression was determined by real-time PCR analysis using the ΔΔC t method as previously described.…”

Section: Rna Isolation and Gene Expression Analysismentioning

confidence: 99%

“…11,12 MRP1 is a membrane-bound glycoprotein that confers resistance to many of the cytotoxic drugs used in the treatment of neuroblastoma. 13 We have previously shown a strong correlation between both MYCN and MRP1 expression, 10,[14][15][16] as well as MYCN and ODC gene expression. 17 Human neuroblastoma cell lines have been shown to consist of a mix of different cell types including neuroblastic (N-type) cells, substrate-adherent (S-type) cells and morphologically intermediate (I-type) stem cells that display a capacity for phenotypic interconversion between both N-type and S-type lineages.…”

Section: Introductionmentioning

confidence: 99%

Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma

Cheng

Ford

et al. 2007

European Journal of Cancer

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Overexpression of the human MYCN oncogene driven by a tyrosine hydroxylase promoter causes tumours in transgenic mice that recapitulate the childhood cancer neuroblastoma. To establish an in vitro model to study this process, a series of isogenic cell lines were developed from these MYCN-driven murine tumours. Lines were established from tumours arising in homozygous and hemizygous MYCN transgenic mice. Hemizygous tumours gave rise to cell lines growing only in suspension. Homozygous tumours gave rise to similar suspension lines as well as morphologically distinct substrate-adherent lines characteristic of human S-type neuroblastoma cells. FISH analysis demonstrated selective MYCN transgene amplification in cell lines derived from hemizygous mice. Comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH) analysis confirmed a range of neuroblastoma-associated genetic changes in the various lines, in particular, gain of regions syntenic with human 17q. These isogenic lines together with the transgenic mice thus represent valuable models for investigating the biological characteristics of aggressive neuroblastoma.

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“…Also, possibly as a consequence of the PI3K/Akt pathway inhibition, N-myc protein levels were also reduced in response to ARC treatment. This is especially significant given the fact that one-third of neuroblastoma tumors shows amplification of N-myc, which has a strong correlation with chemotherapy resistance (Norris et al, 1996;DuBois et al, 1999). Though it is still possible that in addition to antagonizing the prosurvival pathways indicated above, ARC-induced apoptosis may also involve as yet unrecognized events, our data provide at least a partial picture of the mechanism of action of ARC and suggest that it could be an attractive candidate for drug development against neuroblastoma tumors.…”

Section: Targeting Akt In Neuroblastoma Cells Sk Radhakrishnan Et Almentioning

confidence: 99%

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

et al. 2007

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We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7-b-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1-b-Dribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARCinduced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.

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Expression of the Gene for Multidrug-Resistance–Associated Protein and Outcome in Patients with Neuroblastoma

Abstract: High levels of MRP gene expression in patients with neuroblastoma correlate strongly with poor outcome. The findings suggest that expression of this multidrug-resistance gene accounts for the association between N-myc amplification and reduced survival.

Cited by 281 publications

References 36 publications

MYC oncogenes and human neoplastic disease

MYC oncogenes and human neoplastic disease

Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

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