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)

In this study, we show that an inhibitor of glycosphin-golipid biosynthesis, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), increases the chemosensitivity of neuroblastoma tumor cells for Taxol and vincristine. At noneffective low doses of Taxol or vincristine, the addition of a noneffective dose of PDMP resulted in 70% cytotoxicity, indicating synergy. Such an effect was not observed for etoposide (VP16). PDMP caused an early (6 h) increase in ceramide (Cer) levels, but the excess Cer was metabolically removed in the long-term (96 h). However, upon incubation with PDMP in combination with Taxol, but not with etoposide, Cer levels remained elevated at 96 h. These results suggest that neuroblastoma cells are normally able to metabolically remove excess Cer, but lose this capacity upon exposure to microtubule modulating anticancer agents (Taxol or vincristine). In addition, PDMP treatment resulted in a decreased efflux of [14C]Taxol and [3H]vincristine from neuroblastoma cells, similar to treatment with PSC833 or MK571, suggesting an effect of PDMP on the transporter proteins P-glycoprotein and/or multidrug resistance protein. PDMP did not further reduce [14C]Taxol or [3H]vincristine efflux in PSC833-treated cells, although it did further diminish cell survival under these conditions. We conclude that a combined administration of nontoxic concentrations of PDMP and either Taxol or vincristine results in highly sensitized neuroblastoma cells. This appears to involve a sustained elevation of Cer levels, possibly in concert with increased drug accumulation.
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PMID:1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine. 1074 19

We have previously reported that C-1300 murine neuroblastoma (rMNB) cells made resistant to the nucleoside analogue, (Z)-5'-fluoro-4', 5'-didehydro-5'deoxyadenosine (MDL), an irreversible inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase have an increased expression of the S-adenosylmethionine (AdoMet) synthetase gene. Results of the immunoblot analysis of DNA (cytosine) methyltransferase with anti-human DNA (cytosine) methyltransferase specific polyclonal antibody demonstrated a significant increase ( approximately 2-fold, p<0.01) in expression of DNA (cytosine) methyltransferase protein in rMNB/MDL cells compared to wild-type C1300 MNB (wMNB) cells. To rule out the possibility that multidrug resistance (MDR) genes are involved in development of acquired drug resistance in murine neuroblastoma (rMNB/MDL) cells made resistant to MDL, the expression of Mdr1a, Mdr1b, Mdr2 (multidrug resistance/P-glycoprotein), and Mrp-1 (multidrug resistance associated protein) was examined in rMNB-MDL cells. The analysis of Mdr and Mrp-1 expression was performed by RT-PCR using PCR specific primers to respective genes. No significant difference was observed in the expression of MDR1a, Mdr1b and Mrp-1 genes between wMNB and rMNB-MDL cells, however, a slight decrease was noticed in Mdr1 expression in some samples. Expression of the Mdr2 (human MDR3) gene, which is not associated with the acquired drug resistance phenotype, was significantly decreased in rMNB-MDL cells. These findings were also confirmed by the immunoblot analyses using specific monoclonal antibodies to Mdr1/3 proteins. Expression of N-Myc gene--a prognostic factor in neuroblastoma tumors was also not altered in rMNB-MDL cells. Results of the present study suggest that acquired drug resistance in rMNB-MDL cells to MDL is associated to the overexpression of DNA (cytosine) methyltransferase, and could be due to genetic or epigenetic changes in particular to DNA hypermethylation in response to an increased AdoMet synthetase gene expression.
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PMID:DNA (cytosine) methyltransferase overexpression is associated with acquired drug resistance of murine neuroblastoma cells. 1117 99

This study was planned to evaluate the prognostic role of glutathione S-transferase pi (GST-pi) and P-glycoprotein (P-gp) expressions in children with neuroblastoma. Sections from formalin-fixed paraffin-embedded tumor blocks from 52 neuroblastoma cases (17 with localized, 35 with advanced disease) were subjected to immunohistochemistry for P-gp and GST-pi expressions. The overall number of tumors positive for P-gp and GST-pi were 19 (36.5%) and 21 (40.4%), respectively. Twenty-two tumors were negative for both GST-pi and P-gp expressions, whereas 10 expressed both proteins. The distribution of staining status of samples in the groups of both proteins showed no significant difference. No relation between the expressions of both proteins and the clinical characteristics of the patients was demonstrable. The differenes between the survival rates of patients with positive and negative staining for P-gp expression were not statistically significant. Although 2 common mechanisms of multiple drug resistance, P-gp and GST-pi, might be responsible for drug resistance in neuroblastoma, this complex mechanism has no direct significant impact on prognosis. Multiple mechanisms at cellular levels are responsible for the resistance against antineoplastic therapies in neuroblastoma.
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PMID:Glutathione S-transferase and P-glycoprotein expressions in neuroblastoma. 1207 65

The poor prognosis of glioma patients is partly based on the minor success obtained from chemotherapeutic treatments. Resistance mechanisms at the tumor cell level may be, in addition to the blood-brain barrier, involved in the intrinsic chemo-insensitivity of brain tumors. We investigated the expression of the drug-transporter proteins P-glycoprotein (P-gp) and multidrug-resistance protein 1 (MRP1) in cell lines (N = 24) and primary cell cultures (N = 36) from neuroectodermal tumors, as well as in brain tumor extracts (N = 18) and normal human astrocytes (N = 1). We found that a considerable expression of P-gp was relatively rare in glioma cells, in contrast to MRP1, which was constitutively overexpressed in cells derived from astrocytomas as well as glioblastomas. Also, normal astrocytes cultured in vitro expressed high amounts of MRPI but no detectable P-gp. Meningioma cells frequently co-expressed P-gp and MRP1, while, most of the neuroblastoma cell lines express higher P-gp but lower MRP1 levels as compared to the other tumor types. Both, a drug-exporting and a chemoprotective function of P-gp as well as MRP1 could be demonstrated in selected tumor cells by a significant upregulation of cellular 3H-daunomycin accumulation and daunomycin cytotoxicity via administration of transporter antagonists. Summing up, our data suggest that P-gp contributes to cellular resistance merely in a small subgroup of gliomas, but frequently in neuroblastomas and meningiomas. In contrast, MRP1 is demonstrated to play a constitutive role in the intrinsic chemoresistance of gliomas and their normal cell counterpart.
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PMID:Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrug-resistance protein 1 in human brain tumor cells and astrocytes. 1212 64

Disseminated neuroblastoma usually calls for chemotherapy as the primary approach for treatment. Treatment failure is often attributable to drug resistance. This involves a variety of cellular mechanisms, including increased drug efflux through expression of ATP-binding cassette transporters (e.g., P-glycoprotein) and the inability of tumor cells to activate or propagate the apoptotic response. In recent years it has become apparent that sphingolipid metabolism and the generation of sphingolipid species, such as ceramide, also play a role in drug resistance. This may involve an autonomous mechanism, related to direct effects of sphingolipids on the apoptotic response, but also a subtle interplay between sphingolipids and ATP-binding cassette transporters. Here, we present an overview of the current understanding of the multiple levels at which sphingolipids function in drug resistance, with an emphasis on sphingolipid function in neuroblastoma and how modulation of sphingolipid metabolism may be used as a novel treatment paradigm.
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PMID:Sphingolipids in neuroblastoma: their role in drug resistance mechanisms. 1237 1

Sixteen children and young adults were treated with high-dose cyclosporin combined with a combination of cytotoxics (epirubicin, vincristine and etoposide) (EVE) known to be influenced by P-glycoprotein-mediated multidrug resistance (MDR). Tumour types were neuroblastoma 3, Ewing's sarcoma 2, rhabdomyosarcoma 5, osteosarcoma 3, desmoplastic small round cell tumour 1, nephroblastoma 1, T-acute lymphoblastic leukaemia (ALL) 1. All had progressed or relapsed following at least two of the drug types included in EVE. Acute reactions to cyclosporin and myelosuppression were the major toxicities documented. Renal and hepatic toxicity was rarely severe and always transient. Partial responses (PR) were observed in 2 patients (1 rhabdomyosarcoma, 1 Ewing's sarcoma). We conclude that this combination is tolerable in heavily pretreated patients and may be suitable for further evaluation in untreated poor risk tumours.
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PMID:EVE/cyclosporin (etoposide, vincristine, epirubicin with high-dose cyclosporin)-chemotherapy selected for multidrug resistance modulation. 1246 Jul 76

Cytotoxic drug treatment of neuroblastoma often leads to the development of drug resistance and may be associated with increased malignancy. To study the effects of long-term cytotoxic treatment on malignant properties of tumor cells, we established 2 neuroblastoma cell sublines resistant to vincristine (VCR) and doxorubicin (DOX). Both established cell lines (UKF-NB-2(r)VCR(20) and UKF-NB-2(r)DOX(100)) were highly resistant to VCR, DOX and vice-versa but retained their sensitivity to cisplatin. UKF-NB-2(r)VCR(20) and UKF-NB-2(r)DOX(100) expressed significant amounts of P-glycoprotein, while parental cells were P-glycoprotein negative. GD2 expression was upregulated, whereas NCAM expression was decreased in both resistant cells. Spectral karyotype (SKY) analysis revealed complex aberrant karyotypes in all cell lines and additional acquired karyotype changes in both resistant cells. All cell lines harbored high levels of N-myc amplification. Compared to parental cells, UKF-NB-2(r)VCR(20) and UKF-NB-2(r)DOX(100) exhibited more than 2-fold increase in clonal growth in vitro, accelerated adhesion and transendothelial penetration and higher tumorigenicity in vivo. We conclude that development of drug resistance and acquisition of certain karyotypic alterations is associated with an increase of additional malignant properties that may contribute to the poor prognosis in advanced forms of NB. The 2 novel neuroblastoma cell sublines also provide useful models for the study of drug resistance in aggressive forms of neuroblastoma.
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PMID:Development of resistance to vincristine and doxorubicin in neuroblastoma alters malignant properties and induces additional karyotype changes: a preclinical model. 1253 17

The sphingolipid composition and multidrug resistance status of three human neuroblastoma cell lines were established. SK-N-FI cells displayed high expression and functional (efflux) activity of P-glycoprotein, while multidrug resistance-related protein 1 was relatively abundant and most active in SK-N-AS cells. These two cell lines exhibited higher sphingolipid levels, compared to SK-N-DZ, which had the lowest activity of either ATP-binding cassette transporter protein. SK-N-DZ cells also differed in ganglioside composition with predominant expression of b-series gangliosides. In conclusion, these three neuroblastoma cell lines offer a good model system to study sphingolipid metabolism in relation to ATP-binding cassette transporter protein function.
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PMID:Differential expression of sphingolipids in P-glycoprotein or multidrug resistance-related protein 1 expressing human neuroblastoma cell lines. 1288 2

P-glycoprotein (P-gp), a pump located in the cell membrane, extrudes several clinically important drugs from the cell, and hence causes multidrug resistance (MDR). Reversing MDR is possible by using agents that inhibit the activity of P-gp. In this study, we tried to elucidate the prognostic relevance of P-gp in childhood acute lymphoblastic leukemia (ALL) and neuroblastoma. In a first prospective study in childhood ALL, an immunocytochemical APAAP assay was applied. Children scoring positive had a significantly worse outcome than those with a negative test result. In a second prospective study, the prognostic relevance of P-gp was confirmed, using the combination of immunocytochemistry and a functional flow cytometric assay. The combination of immunocytochemistry with the flow cytometric functional assay is being promoted as the most sensitive and clinically relevant amongst the different techniques. In neuroblastoma, ganglioneuroblastoma and ganglioneuroma, P-gp is detected by different assays: immunocytochemistry, flow cytometric immunological and functional tests and an in vivo imaging technique using 99mTc sestamibi. Immunocytochemistry alone did not provide a prognostic role for P-gp in neuroblastoma. On the contrary, using flow cytometric tests, many neuroblastomas scored positive and a discordance was found between the expression and activity of P-gp. P-gp was found more frequently in low-stage neuroblastoma, differentiated tumours and tumours after chemotherapy. A good correlation between flow cytometric results and imaging results was seen. Consequently, 99mTc sestamibi scintigraphy is not useful as an in vivo predictor of MDR in neuroblastoma. Unlike the findings in childhood ALL, P-gp does not contribute to MDR in neuroblastoma but seems to be a marker of differentiation.
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PMID:[The prognostic significance of P-glycoprotein in children with acute lymphoblastic leukemia and neuroblastoma]. 1582 6

The proteasome inhibitor bortezomib (Velcade) was recently approved for the treatment of therapy-refractive multiple myeloma and is under investigation for numerous other types of cancer. A phase I clinical trial in paediatric patients resulted in tolerable toxicity. Since the emergence of chemoresistance represents one of the major drawbacks in cancer therapy, we investigated the influence of bortezomib on multi-drug resistant human neuroblastoma cell lines characterised by P-glycoprotein expression and p53 mutation. Nanomolar concentrations of bortezomib inhibited the cell cycle and induced apoptosis in chemosensitive as well as in chemoresistant cell lines. In vivo growth of chemosensitive and chemoresistant neuroblastoma cell lines was inhibited to a similar extent. In addition, bortezomib inhibited vessel formation in neuroblastoma xenografts. These findings and the favourable toxicity profile of bortezomib in children make it reasonable to further pursue additional development of the drug for the treatment of neuroblastoma and other paediatric solid tumours.
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PMID:Anti-cancer effects of bortezomib against chemoresistant neuroblastoma cell lines in vitro and in vivo. 1639 99


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