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)

A panel of monoclonal antibodies (MAbs) to P-glycoprotein was developed by immunization of mice with multidrug-resistant human neuroepithelioma and neuroblastoma cells. All the anti-P-glycoprotein MAbs reacted with the extracellular portion of P-glycoprotein. The MAbs were examined for their ability to enhance accumulation of actinomycin D, vincristine, vinblastine, and doxorubicin in the human mdr1 transfectant cell line, BRO/pFRmdr1.6. HYB-241, an IgG1 anti-P-glycoprotein MAb, was the most effective modulator, increasing actinomycin D levels in the transfectant line by 6-fold, vincristine by 2-fold, and vinblastine levels by 3-fold. None of the MAbs were capable of modifying the accumulation of doxorubicin. HYB-241 lowered the 50% inhibitory concentration values of actinomycin D by 11-fold, vincristine by 6-fold, and vinblastine by 2-fold. No effect on the 50% inhibitory concentration values of doxorubicin or gramicidin were seen. 111In-labeled HYB-241 localized in human tumor xenografts of BRO/pFRmdr1.6 in nude mice (25% injected dose/g at 120 h). Mice with established drug-resistant xenografts were treated with antibody 24 h prior to the injection of Vinca alkaloid at concentrations known to be non-growth inhibitory. The addition of HYB-241 at 25 mg/kg per injection prior to drug resulted in a significant inhibition of growth of this drug-resistant tumor.
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PMID:Reversal of Vinca alkaloid resistance by anti-P-glycoprotein monoclonal antibody HYB-241 in a human tumor xenograft. 134 13

P-glycoprotein, the product of the multidrug resistance (MDR1) gene, is an ATP-driven transmembrane pump that increases the resistance of cells by actively exporting toxic chemicals. In addition to transporting anticancer drugs, P-glycoprotein has been reported to extrude a variety of lipophilic drugs, such as calcium channel blockers, phenothiazines, cyclosporines etc. Interestingly, recent experiments suggest that steroid hormones may be physiologic substrates for P-glycoprotein. In addition, there exists a family of transporter genes with high structural homology to P-glycoprotein, the so-called ABC (ATP-binding casette) family. Although the physiological ligands for most of these transporters are unknown, there is increasing evidence that peptides may be transported by some of these proteins. Thus, the a-factor, a farnesylated pheromone with 13 amino acids, is exported from yeast cells by the product of the STE6 gene, a transporter protein with high homology to P-glycoprotein. Recently, we have cloned a novel member of the ABC-transporter gene family from neuroblastoma x glioma hybrid (NG-108-15) cells. This putative transporter gene ("NG-TRA") is expressed in the adrenal gland, kidney and in the brain. High amounts of NG-TRA mRNA are found in a variety of human brain tumors. Whether NG-TRA and/or other MDR-related transporters are involved in the transport of steroids, peptide hormones or growth factors remains to be established. If so, the cellular export of hormones by active pumps may represent a new mechanism of hormone secretion.
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PMID:New mechanisms of hormone secretion: MDR-like gene products as extrusion pumps for hormones? 135

Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro, and a similar role has been hypothesized in vivo in human malignancy. Because expression of mdr-1 is increased in neuroblastoma cell lines by differentiating agents, the authors hypothesized a similar correlation with differentiation in vivo in neuroblastomas. In 12 tumors from 11 patients, total RNA analysis demonstrated no correlation with differentiation, but a correlation could be detected in the cell-based methods of analysis. The very primitive 'stroma'-poor, poorly differentiated neuroblastomas had low levels of mdr-1/P-glycoprotein. The intermediate grades had higher levels of expression and although heterogeneity of differentiation appeared within these tumors, both primitive and more differentiated cells expressed the gene at comparable levels within the tumor. One very well-differentiated neuroblastoma, a ganglioneuroma, had no detectable expression in the neurofibrillary material, but demonstrated expression in adjacent large ganglionic cells. Thus mdr-1/P-glycoprotein expression increased with increasing differentiation among tumors, and was present in ganglionic cells in the most well-differentiated tumor. The three tumors with the highest levels of expression were obtained from patients who received preoperative chemotherapy.
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PMID:Expression of mdr-1/P-glycoprotein in human neuroblastoma. 167 52

Immunohistological detection of P-glycoprotein (P-gp) with monoclonal antibody C219 was performed on serial sections of 37 neuroblastoma specimens representative of the different forms of the disease, from stage 1 ganglioneuroma to stage 4 neuroblastoma. Malignant cells, irrespective of their degree of maturation varying from neuroblasts to ganglion cells, were negative on all specimens. The expression of P-glycoprotein was detected in nine specimens, but it was restricted to normal cells within the tumour. In four specimens, C219 reacted with normal infiltrating cells in the stroma (i.e. monocytes, histiocytes or fibroblasts) representing 5 to 10% of the total population within the section; in three specimens, the residual adrenal gland was strongly positive, and in two ganglioneuromas, a weak reactivity of C219 was observed on a few satellite cells and schwann cells. Three of 15 biopsies obtained at diagnosis contained normal P-gp positive cells: two were classified as stage 1 ganglioneuromas; one was a typical stage 4 composite tumours with positive histiocytes and fibroblasts in the well-differentiated counterpart. Six of 22 biopsies obtained after patients had received our current protocol of chemotherapy contained normal P-gp positive cells: five were partially differentiated and necrotic under the effect of chemotherapy; only one positive specimen was classified as undifferentiated neuroblastoma. Among negative specimens from previously treated patients, one was obtained from a patient in relapse after high-dose chemotherapy and ABMT, two were obtained from patients who had not responded to induction therapy, and six from patients in partial remission after induction therapy. The clinical evolution was very similar in both groups of patients with P-gp negative or positive biopsies. These findings suggest that the quantitative assessment of MDR RNA by northern blotting on fresh homogenates is likely to overestimate its expression on neuroblastoma cells, and that the mechanism of chemoresistance in widespread neuroblastoma is less likely to be associated with P-gp expression.
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PMID:Expression of P-glycoprotein restricted to normal cells in neuroblastoma biopsies. 167 95

The development of resistance accounts for therapy failure in the majority of advanced cases of neuroblastoma in children. A new transplantable murine C-1300 neuroblastoma cell line was developed in vitro, by repeated exposure of a sensitive cell line to increasing, but sublethal, doses of Homoharringtonine (HHT). The ED50 of the highly resistant cells for HHT, using a standard agar colony assay, is 480 ng/ml, compared with 13 ng/ml for the sensitive parental line. The resistant cells have cross-resistance to a number of other agents, including adriamycin, vinca alkaloids, melphalan, and CCNU. Western blot analysis revealed progressive increases in P-glycoprotein, parallel to the graded development of resistance with a 29-fold elevation in the highest resistant cells. High-performance liquid chromatography (HPLC) indicated that resistant cells have a significantly lower uptake of HHT than parental sensitive cells. cyclosporine A (CsA) and dipyridamole (DPM) could modulate the acquired resistance and completely restore the cytotoxic effects of HHT and adriamycin as determined by the clonogenic assay. The reversal of resistance by CsA and DPM was dose dependent. With the relative low toxicity of dipyridamole and CsA in doses required for modulation of resistance, these agents may be candidates for clinical utilization in chemotherapy of resistant neuroblastoma.
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PMID:Modulation of drug resistance in homoharringtonine-resistant C-1300 neuroblastoma cells with cyclosporine A and dipyridamole. 168 Aug 70

Neuroblastoma remains a significant problem in pediatric oncology. Recently a "multidrug-resistance" gene that may cause cells to become resistant to various chemotherapeutic agents has been cloned. The gene encodes the high-molecular-weight plasma membrane protein known as P-glycoprotein. To study the expression of this gene in cells exhibiting the multidrug-resistant phenotype, a panel of sublines selected with several different natural product drugs was established. The drug-sensitive parental BE(2)-C cells were clonally isolated from the human neuroblastoma SK-N-BE(2) line and exhibit a 150-fold increase in the copy number of the N-myc protooncogene. Sublines were selected by stepwise increases in the concentration of actinomycin-D, doxorubicin, vincristine, or colchicine. Gene amplification was assessed using Southern analysis, and RNA levels were determined by Northern and dot-blot analysis. Western blotting was used to determine protein levels. N-myc amplification and expression were simultaneously determined to assess possible alterations associated with development of multidrug resistance. Amplified P-glycoprotein-encoding genes were not seen in control lines but were clearly present in those that had undergone exposure to each of the chemical agents. Similarly, steady-state messenger RNA and protein levels were greatly increased in the drug-resistant sublines. We conclude that human neuroblastoma cells can acquire the multidrug-resistant phenotype after exposure to various chemotherapeutic agents.
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PMID:Multidrug resistance in human neuroblastoma cells. 171 82

Many cancers have been cured by chemotherapeutic agents. However, other cancers are intrinsically drug resistant, and some acquire resistance following chemotherapy. Cloning of the cDNA for the human MDR1 gene (also known as PGY1), which encodes the multidrug efflux protein P-glycoprotein, has made it possible to measure levels of MDR1 RNA in human cancers. We report the levels of MDR1 RNA in greater than 400 human cancers. MDR1 RNA levels were usually elevated in untreated, intrinsically drug-resistant tumors, including those derived from the colon, kidney, adrenal gland, liver, and pancreas, as well as in carcinoid tumors, chronic myelogenous leukemia in blast crisis, and cell lines of non-small cell carcinoma of the lung (NSCLC) with neuroendocrine properties. MDR1 RNA levels were occasionally elevated in other untreated cancers, including neuroblastoma, acute lymphocytic leukemia (ALL) in adults, acute nonlymphocytic leukemia (ANLL) in adults, and indolent non-Hodgkin's lymphoma. MDR1 RNA levels were also increased in some cancers at relapse after chemotherapy, including ALL, ANLL, breast cancer, neuroblastoma, pheochromocytoma, and nodular, poorly differentiated lymphoma. Many types of drug-sensitive and drug-resistant tumors, including NSCLC and melanoma, contained undetectable or low levels of MDR1 RNA. The consistent association of MDR1 expression with several intrinsically resistant cancers and the increased expression of the MDR1 gene in certain cancers with acquired drug resistance indicate that the MDR1 gene contributes to multidrug resistance in many human cancers. Thus, evaluation of MDR1 gene expression may prove to be a valuable tool in the identification of individuals whose cancers are resistant to specific agents. The information may be useful in designing or altering chemotherapeutic protocols in these patients.
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PMID:Expression of a multidrug resistance gene in human cancers. 256 56

P-glycoprotein is a plasma membrane protein believed to mediate resistance to natural product drugs such as vincristine, Adriamycin, and actinomycin D. To facilitate the study of human P-glycoprotein, monoclonal antibodies (designated HYB-612, HYB-241, and HYB-195) were raised against vincristine-resistant human neuroblastoma (SH-SY5Y/VCR) cells. The antibodies recognize a Mr 180,000 plasma membrane phosphoglycoprotein produced in increased amounts in SH-SY5Y/VCR as well as in vincristine-resistant human neuroepithelioma (MC-IXC/VCR), vinblastine-resistant human leukemia (CEM/VLB100), and actinomycin D- or vincristine-resistant Chinese hamster (DC-3F/AD X and DC-3F/VCRd-5L) cells, as compared to control cells. Radioimmunoprecipitation of proteins in cells metabolically labeled with [35S]methionine, 32Pi, or [3H]glucosamine and Western transfer procedures were used for these studies. Characterization of the HYB-612 or HYB-241 antigen by destructive degradation produced a pattern of results typical of a conformation-dependent protein epitope. HYB-612 recognizes complexes of the Mr 180,000 antigen with an iodinated photoaffinity analogue of vinblastine or with tritiated azidopine. Furthermore, pretreatment of MC-IXC and MC-IXC/VCR cells with HYB-612 or HYB-241 before measurement of tritium-labeled actinomycin D or vincristine uptake increases the amount of drug accumulation in resistant, but not in sensitive, cells. Of importance is the fact that the Mr 180,000 protein is expressed in cells which also contain a Mr 170,000 P-glycoprotein. The relative amounts of the Mr 180,000 and 170,000 species vary from one drug-resistant cell line to another. Evidence that the Mr 180,000 protein is a P-glycoprotein and that there is a conserved complex pattern of resistance-related surface proteins in multidrug-resistant cells is presented in this report.
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PMID:Characterization of monoclonal antibodies recognizing a Mr 180,000 P-glycoprotein: differential expression of the Mr 180,000 and Mr 170,000 P-glycoproteins in multidrug-resistant human tumor cells. 256 79

Expression of a multidrug resistance gene (mdr1) and its protein product, P-glycoprotein (Pgp), has been correlated with the onset of multidrug resistance in vitro in human cell lines selected for resistance to chemotherapeutic agents derived from natural products. Expression of this gene has also been observed in normal tissues and human tumors, including neuroblastoma. We therefore examined total RNA prepared from human neuroblastoma cell lines before and after differentiation with retinoic acid or sodium butyrate. An increase in the level of mdr1 mRNA was observed after retinoic acid treatment of four neuroblastoma cell lines, including the SK-N-SH cell line. Western blot (immunoblot) analysis demonstrated concomitant increases in Pgp. However, studies of 3H-vinblastine uptake failed to show a concomitant Pgp-mediated decrease in cytotoxic drug accumulation. To provide evidence that Pgp was localized on the cell surface, an immunotoxin conjugate directed against Pgp was added to cells before and after treatment with retinoic acid. Incorporation of [3H]leucine was decreased by the immunotoxin in the retinoic acid-treated cells compared with the undifferentiated cells. These results demonstrate that whereas expression of the mdr1 gene can be modulated by differentiating agents, increased levels of expression are not necessarily associated with increased cytotoxic drug accumulation.
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PMID:Expression of a drug resistance gene in human neuroblastoma cell lines: modulation by retinoic acid-induced differentiation. 257 30

Multidrug resistance (MDR) in tumors is associated with P-glycoprotein (Pgp) expression. In vivo quantitation of Pgp may allow MDR to be evaluated noninvasively prior to treatment planning. The purpose of this study was to radiolabel MRK-16, a monoclonal antibody that targets an external epitope of P-glycoprotein, and perform in vivo quantitation of P-glycoprotein in a MDR xenograft nude mouse model. MRK-16 was labeled with 125I by the iodogen method, with subsequent purification by size exclusion chromatography. Groups of 10 Balb c mice were each xenografted with colchicine-resistant or sensitive neuroblastoma cell lines, respectively. Whole body clearance and tumor uptake over time was quantitated by gamma camera imaging, and biodistribution studies were performed with [125I]MRK-16 and an isotype matched control antibody, A33. Quantitative autoradiography and immunohistochemistry analysis of tumors was also evaluated to confirm specific targetting of [125I]MRK-16. Peak tumor uptake was at 2-3 days post-injection, and was significantly greater in resistance compared to sensitive tumors (mean % injected dose/g +/- SD) (18.76 +/- 2.94 vs 10.93 +/- 0.96; p < 0.05). Quantitative autoradiography verified these findings (19.13 +/- 0.622 vs 12.08 +/- 0.38, p < 0.05). Specific binding of [125I]MRK-16 was confirmed by comparison to [131I]A33 in biodistribution studies, and localized to cellular components of tissue stroma by comparison of histologic and autoradiographic sections of sensitive and resistant tumors. Immunoblot analysis demonstrated a 4.5-fold difference in P-glycoprotein expression between sensitive and resistant cell lines without colchicine selective pressure. We conclude that in vivo quantitation of P-glycoprotein in MDR tumors can be performed with [125I]MRK-16.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo imaging and specific targeting of P-glycoprotein expression in multidrug resistant nude mice xenografts with [125I]MRK-16 monoclonal antibody. 755 27


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