National Cancer Institute®
Last Modified: November 21, 2001
UI - 21288352
AU - Rubie H
TI - [New prognostic factors of neuroblastoma]
SO - Arch Pediatr 2001 May;8 Suppl 2():366s-368s
AD - Unite d'hemato-oncologie pediatrique, hopital des Enfants, 330, avenue de Grande-Bretagne, BP 3119, 31026 Toulouse, France.
UI - 21364053
AU - Hervas Benito I; Rivas Sanchez A; Bello Arques P; Canete A; Fernandez
TI - JM; Saura Quiles A; Gonzalez Cabezas P; Ruiz Rodriguez JC; Castell V; Perez Pastor JL; Monfort JA; Mateo Navarro A [Value of 123I-MIBG scanning, neuron-specific enolase and serum ferritin in the diagnosis and follow-up of patients with neuroblastoma]
SO - Rev Esp Med Nucl 2001 Aug;20(5):369-76
AD - Servicio de Medicina Nuclear del Hospital Universitario La Fe, Valencia. firstname.lastname@example.org
INTRODUCTION: The neuroblastoma (NB) is one of the most common pediatric malignant neoplasms. The most commonly used tumor markers in the diagnosis and follow-up of this tumor are the serum neuron-specific enolase (NSE), ferritin and lactic dehydrogenase and urinary vanillymandelic and homovanillic acid. The common imaging modalities are CT, MRI and 123I or 131I-meta-iodobenzylguanidine scintigraphy. AIM: The aim of this study is to assess the value of 123I-meta-iodobenzylguanidine (MIBG) scintigraphy and serum determinations of NSE and ferritin in the diagnosis and evolution of NB patients. MATERIAL AND METHODS: 20 patients (8 female, 12 male) whose ages ranged from 2 months to 9 years with a mean age of 2.64 years diagnosed of NB. 47 123I-MIBG scans, 47 NSE determinations and 47 ferritin ones were selected. RESULTS: At the time of diagnosis, 100% of the 123I-MIBG scans were positive. 65% of NSE determinations presented clearly pathological levels and 15% were very near to the cut-off point. Only 45% of the ferritin levels were increased. The differences between the lesions visible by 123I-MIBG scanning before and 3 months after treatment as well as NSE and ferritin levels were studied. When the Student's T test was applied, we found statistically significant pre and post-treatment differences in 123I-MIBG scanning and NSE. In the case of ferritin, there was no statistical significance in spite of the decrease in the values. The direct correlation and Spearman correlation between laboratory data and 123I-MIBG scanning as well as correlation between NSE and ferritin were also studied. There was a good correlation between 123I-MIBG and NSE and between NSE and ferritin. We have also studied the data in 7 relapses. CONCLUSIONS: 123I-MIBG scintigraphy and serum determination of NSE are two successful diagnostic tools for the diagnosis and evolution of NB patients.
UI - 21396154
AU - Chao KS; Kaplan C; Simpson JR; Haughey B; Spector GJ; Sessions DG;
TI - Arquette M Esthesioneuroblastoma: the impact of treatment modality.
SO - Head Neck 2001 Sep;23(9):749-57
AD - Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University Medical Center, WU Box 8224, 4939 Children's Place, Suite 5500, St. Louis, MO 63110, USA. email@example.com
BACKGROUND: We evaluated the impact of treatment modality on esthesioneuroblastoma. METHODS: Between 1976 and 1996, 25 patients with esthesioneuroblastoma were treated at Mallinckrodt Institute of Radiology. There were 11 male and 14 female patients; their ages ranged from 16 to 73 years (median, 57 years). The tumors were Kadish stage A in 3, Stage B in 13, C in 8, and modified D in 1 (cervical nodal metastasis). Seventeen patients were treated with surgery and radiation therapy, six were treated with irradiation alone, and two were treated with surgery only. Eight patients received neoadjuvant chemotherapy. Median follow-up was 8 years (range, 2-24 years). RESULTS: The 5-year actuarial overall survival, disease-free survival, and local tumor control rates were 66.3%, 56.3%, and 73.0%, respectively. Kadish stage was not a significant prognosticator for local control or disease-free survival. Five-year local control rates were 87.4% for the combination of surgery and radiation therapy and 51.2% for irradiation alone. Two patients with Kadish stage A and B disease underwent surgical resection alone; both failed locally. In contrast, 33.3% of patients (three of nine) with Kadish stage A or B disease who received adjuvant radiation therapy had a local recurrence develop. With adjuvant radiation therapy, the surgical margin status did not influence local tumor control. Among the eight patients who received neoadjuvant chemotherapy, six patients showed no response, one had partial response, and one showed a complete response. CONCLUSIONS: Surgical resection plus adjuvant radiation therapy yielded the best treatment outcome. More effective chemotherapy agents with a reproducible effectiveness are needed for patients with locally advanced esthesioneuroblastoma. Copyright 2001 John Wiley & Sons, Inc.
UI - 21468608
AU - Jones TA; Flomen RH; Senger G; Nizetic D; Sheer D
TI - The homeobox gene MEIS1 is amplified in IMR-32 and highly expressed in other neuroblastoma cell lines.
SO - Eur J Cancer 2000 Dec;36(18):2368-74
AD - Human Cytogenetics Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, UK.
Neuroblastoma is a childhood tumour of the sympathetic nervous system that demonstrates striking clinical heterogeneity. In order to determine which genes are abnormally expressed in neuroblastoma, we screened regions of amplification from the short arm of chromosome 2 in the neuroblastoma cell line IMR-32 and found that the homeobox gene, myeloid ecotropic integration site 1 (MEIS1), is highly amplified. MEIS1 normally maps to chromosome band 2p14. High expression of MEIS1 without amplification was also found in other neuroblastoma cell lines, with and without MYCN amplification, and in medulloblastoma and crythroleukaemia cell lines. MEIS1 is highly expressed in cerebellum and ubiquitously expressed in normal immunohaematopoietic tissues and is thought to be important in cell proliferation and differentiation. While several lines of evidence point towards a role for homeobox genes in the development of other malignancies, this is the first report showing the amplification of a homeobox gene in neuroblastoma.
UI - 21160442
AU - Corrias MV; Occhino M; Croce M; De Ambrosis A; Pistillo MP; Bocca P;
TI - Pistoia V; Ferrini S Lack of HLA-class I antigens in human neuroblastoma cells: analysis of its relationship to TAP and tapasin expression.
SO - Tissue Antigens 2001 Feb;57(2):110-7
AD - Laboratorio di Oncologia, Istituto Scientifico G. Gaslini, Genoa, Italy.
We studied the constitutive and the interferon (IFN)-gamma-induced expression of HLA class I antigen heavy chain, beta2-microglobulin (beta2m), TAP-1, TAP-2 and tapasin in a panel of eleven neuroblastoma cell lines. Surface expression of HLA class I antigens was low in eight out of eight neuroblastoma cell lines bearing MYC-N amplification and/or 1p deletion, while two out of three neuroblastoma cell lines lacking these genetic alterations showed normal expression. IFN-gamma treatment restored HLA class I antigen surface expression in all neuroblastoma cell lines. Eight out of 11 neuroblastoma cell lines did not express TAP-1 mRNA and three of them also lacked TAP-2 mRNA. beta2 m mRNA was barely detectable or absent in five neuroblastoma cell lines, while tapasin mRNA was always expressed. IFN-gamma upregulated the expression of HLA class I heavy chain, beta2 m, TAP-1, TAP-2 and tapasin, as detected at mRNA or protein level. Post-transcriptional events were involved in altered TAP-1 and beta2 m expression in one peculiar neuroblastoma cell line. These data indicate that multiple mechanisms play a role in the HLA class I antigen-deficient phenotype of human neuroblastoma.
UI - 21219828
AU - Jang IS; Juhnn YS
TI - Adaptation of cAMP signaling system in SH-SY5Y neuroblastoma cells following expression of a constitutively active stimulatory G protein alpha, Q227L Gsalpha.
SO - Exp Mol Med 2001 Mar 31;33(1):37-45
AD - Department of Biochemistry and Cancer Research Institute, Seoul National University College of Medicine, Korea.
Heterotrimeric GTP-binding proteins (G protein) are known to participate in the transduction of signals from ligand activated receptors to effector molecules to elicit cellular responses. Sustained activation of cAMP-G protein signaling system by agonist results in desensitization of the pathway at receptor levels, however it is not clear whether such receptor responses induce other changes in post-receptor signaling path that are associated with maintenance of AMP levels, i.e. cAMP-forming adenylate cyclase (AC), cAMP-degrading cyclic nucleotide phosphodiesterase (PDE) and cAMP-dependent protein kinase (PKA). Experiments were performed to determine the expression of AC, PDE, and PKA isoforms in SH-SY5Y neuroblastoma cells, in which cAMP system was activated by expressing a constitutively activated mutant of stimulatory G protein (Q227L Gsalpha). Expression of ACI mRNA was increased, but levels of ACVIII and ACIX mRNA were decreased. All of the 4 expressed isoforms of PDE (PDE1C, PDE2, PDE 4A, and PDE4B) were increased in mRNA expression; the levels of PKA RIalpha, RIbeta, and RIIbeta were increased moderately, however, those of RIIalpha and Calpha were increased remarkably. The activities of AC, PDE and PKA were also increased in the SH-SY5Y cells expressing Q227L Gsalpha. The similar changes in expression and activity of AC, PDE and PKA were observed in the SH-SY5Y cells treated with dbcAMP for 6 days. Consequently, it is concluded that the cAMP system adapts at the post-receptor level to a sustained activation of the system by differential expression of the isoforms of AC, PDE, and PKA in SH-SY5Y neuroblastoma. We also showed that an increase in cellular cAMP concentration might mediate the observed changes in the cAMP system.
UI - 21256790
AU - Antony P; Freysz L; Horrocks LA; Farooqui AA
TI - Effect of retinoic acid on the Ca2+-independent phospholipase A2 in nuclei of LA-N-1 neuroblastoma cells.
SO - Neurochem Res 2001 Jan;26(1):83-8
AD - Laboratoire de Neurobiologie Moleculaire des Interactions Cellulaires, Institut de Chimie Biologique, Faculte de Medecine, Strasbourg, France.
LA-N-1 neuroblastoma cell cultures contain Ca2+-independent phospholipases A2 hydrolyzing phosphatidylethanolamine and ethanolamine plasmalogens. These enzymes differ from each other in their molecular mass, substrate specificity, and kinetic properties. Subcellular distribution studies have indicated that the activity of these phospholipases is not only localized in the cytosol but also in non-nuclear membranes and in nuclei. The treatment of LA-N-1 neuroblastoma cell cultures with retinoic acid results in a marked stimulation of Ca2+-independent phospholipases A2 hydrolyzing phosphatidylethanolamine and plasmenylethanolamine. The increase of the activities of both enzymes was first observed in nuclei followed by those present in the cytosol. No effect of retinoic acid on either phospholipase activity could be observed in non-nuclear membranes. The stimulation of these enzymes may be involved in the generation and regulation of arachidonic acid and its metabolites during differentiation.
UI - 21409967
AU - Moukheiber AK; Nicollas R; Roman S; Coze C; Triglia JM
TI - Primary pediatric neuroblastic tumors of the neck.
SO - Int J Pediatr Otorhinolaryngol 2001 Aug 20;60(2):155-61
AD - Department of Pediatric Otorhinolaryngology, Head and Neck Surgery, La Timone Children's Hospital, Marseille Medical School, Boulevard Jean Moulin, 13385 Marseille cedex 5, France.
Neuroblastic tumors are the third most common cause of solid tumors in early childhood. Cervical tumors account for only 5% of cases. In this report, we describe a series of four pediatric neuroblastic tumors of the neck. The histological diagnosis was ganglioneuroblastoma in three cases and neuroblastoma in one case. Presenting signs were solitary cervical mass in two cases and respiratory distress in association with Claude-Bernard Horner's syndrome in two cases. Mean age at presentation was 15 months. Cervical computed tomography scan and/or magnetic resonance imaging depicted calcifications within the tumor in 50% of cases and allowed accurate assessment of extension. Increased urine catecholamine levels were observed only in the patient with neuroblastoma. Scintigraphy with iodine-methyliodobenzylguanidine demonstrated selective uptake by the tumor in two cases. Amplification of N-myc oncogene, a documented unfavorable prognostic sign, was not found in any case. Surgical treatment was performed in all patients. Neoadjuvant chemotherapy was performed in one case. All patients underwent regular surveillance. No evidence of recurrence has been observed with a mean follow-up period of 7 years.
UI - 21449311
AU - Neitzschman H; Ram SK; Beiderman B; Ram PB
TI - Radiology case of the month. Posterior mediastinal mass.
SO - J La State Med Soc 2001 Aug;153(8):399-400
AD - Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
An 11-year-old white boy presented with gradual onset of persistent shortness of breath for the previous few weeks. X-ray, CT, and MRI of the chest were performed.
UI - 21443306
AU - Mora J; Cheung NK; Juan G; Illei P; Cheung I; Akram M; Chi S; Ladanyi M;
TI - Cordon-Cardo C; Gerald WL Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell.
SO - Cancer Res 2001 Sep 15;61(18):6892-8
AD - Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
The coexistence of neuroblastic and Schwannian stromal (SS) cells in differentiating neuroblastoma (NB), and derivation of Schwannian-like cells from neuroblastic clones in vitro, were accepted previously as evidence of a common pluripotent tumor stem line. This paradigm was challenged when SS cells were suggested to be reactive in nature. The advent of microdissection techniques, PCR-based allelic analysis, and in situ fluorescent cytometry made possible the analysis of pure cell populations in fresh surgical specimens, allowing unequivocal determination of clonal origins of various cell subtypes. To overcome the complexity and heterogeneity of three-dimensional tissue structure, we used: (a) Laser-Capture Microdissection to obtain histologically homogeneous cell subtype populations for allelotype analysis at chromosomes 1p36, 11q23, 14q32, and 17q and study of MYCN copy number; (b) multiparametric analysis by Laser-Scanning Cytometry of morphology, DNA content, and immunophenotype of intact cells from touch imprints; and (c) bicolor fluorescence in situ hybridization on touch imprints from manually microdissected neuroblast and stroma-rich areas. Histologically distinct SS and neuroblastic cells isolated by Laser-Capture Microdissection had the same genetic composition in 27 of 28 NB analyzed by allelic imbalance and gene copy number. In all 20 cases studied by Laser-Scanning Cytometry, SS cells identified by morphology and S-100 immunostaining had identical DNA content and GD2-staining pattern as their neuroblastic counterparts. In 7 cases, fluorescence in situ hybridization demonstrated the same chromosomal makeup for SS and neuroblastic cells. These results provide unequivocal evidence that neuroblastic and SS cells in NB are derived from genetically identical neoplastic cells and support the classical paradigm that NB arises from tumoral cells capable of development along multiple lineages.
UI - 21450511
AU - Kawakami M; Koda M; Matsunaga N; Kishimoto Y; Shabana M; Kato H;
TI - Nishimuki E; Kojo H; Miura K; Kawasaki H Adult-type neuroblastoma originated in retroperitoneum beginning with obstructive jaundice.
SO - Clin Imaging 2001 Jul-Aug;25(4):284-7
AD - Second Department of Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-machi, Yonago, Tottori 683-0802, Japan.
Abdominal neuroblastoma in adults is a rare neoplasm and only 30 patients have been described in Japan since 1985. The patient was a 43-year-old woman with jaundice. The tumor originated from retroperitoneum. The enlarged gall bladder and dilatation of intrahepatic bile ducts were noted by ultrasonography and computed tomography. We report the first adult-type neuroblastoma with obstructive jaundice.
UI - 20370603
AU - Hornick CA; Anthony CT; Hughey S; Gebhardt BM; Espenan GD; Woltering EA
TI - Progressive nuclear translocation of somatostatin analogs.
SO - J Nucl Med 2000 Jul;41(7):1256-63
AD - Department of Physiology, The Stanley S. Scott Cancer Center, New Orleans, Louisiana, USA.
Optimal cancer radiotherapy using Auger electron emitters requires selective localization of radionuclides in close proximity to tumor DNA. METHODS: Intracellular trafficking of (125)I-Tyr1-somatostatin-14 somatotropin-release inhibiting factor (SRIF) and 2 of its analogs, (125)I-WOC 4a and (111)In-pentetreotide, was studied in human neuroblastoma cells. RESULTS: After 24-h incubation, SRIF was degraded or recycled, whereas its protease-resistant analogs progressively accumulated in nuclear fractions. (111)In-pentetreotide binding to DNA increased over time in somatostatin receptor-positive cells but not in somatostatin receptor-negative cells. CONCLUSION: These in vitro studies show that prolonged exposure to radiolabeled SRIF analogs significantly increases their cellular internalization, nuclear translocation, and DNA binding. Clinically, infusion of radiolabeled somatostatin analogs may enhance tumor uptake and retention and provide more effective in situ radiotherapy.
UI - 21282068
AU - Campus R; Conte M; Rizzo A; Granata C; Gambini C; Carlini C; De Bernardi
TI - B; Di Battista C; Jasonni V [Intractable diarrhea and neuroblastoma: report of a clinical case]
SO - Pediatr Med Chir 2000;22(1):47-8
AD - Divisione e Cattedra di Chirurgia Pediatrica, Istituto Giannina Gaslini, Genova, Italia.
One of the typical presentations of neuroblastoma is intractable diarrhea or wdha (watery diarrhea, hypokalemia, achloridria). The case admitted to our Pediatric Surgery Department presented watery diarrhea due to VIP hyperincretion caused by a stage 1 neuroblastoma, whose ablation allowed a complete resolution of the clinical conditions. This case report can be useful in the discussion of the differential diagnosis of the most common clinical pictures.
UI - 21341704
AU - Mehes G; Luegmayr A; Ambros IM; Ladenstein R; Ambros PF
TI - Combined automatic immunological and molecular cytogenetic analysis allows exact identification and quantification of tumor cells in the bone marrow.
SO - Clin Cancer Res 2001 Jul;7(7):1969-75
AD - Children's Cancer Research Institute, St. Anna Kinderspital, A-1090 Vienna, Austria.
PURPOSE: To improve the detection of disseminated tumor cells in bone marrow (BM) and peripheral blood samples of solid tumor patients, a novel computer-assisted scanning system for automatic search, image analysis, and repositioning of these cells was developed. This system allows precise identification and quantification of tumor cells by sequential immunological and molecular cytogenetic analysis. In this study, we attempt to demonstrate the practical use of this approach by analyzing BM samples from neuroblastoma patients. EXPERIMENTAL DESIGN: The disialo-ganglioside (GD2) molecule was used as the immunological target. The GD2 molecule was described as being specific for neuroblastoma cells, although false positive reactions had been suspected. To verify or disprove the neoplastic nature of the immunologically positive cells, sequential fluorescence in situ hybridization was performed on these cells to search for those genetic aberrations found in the corresponding primary tumors. A total of 115 samples from 40 newly diagnosed patients were evaluated for the presence of GD2(+) cells in the BM. RESULTS: GD2 positivity was detected in 95.2% of stage 4 patients, in 100% of stage 4s patients, and in 38.5% of patients with localized/regional disease. In stage 4 and 4s BM samples, the GD2(+) cells were unequivocally identified as tumor cells based on the molecular cytogenetic aberrations found by fluorescence in situ hybridization. However, in BM samples from patients with localized/regional disease, all GD2(+) cells were concluded to represent false positivity due to the absence of genetic aberrations. CONCLUSIONS: Automatic search and sequential molecular cytogenetic analysis of the immunologically positive cells provide precise information on both the number and cytogenetic profile of disseminated tumor cells.
UI - 21403127
AU - Teitz T; Lahti JM; Kidd VJ
TI - Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death.
SO - J Mol Med 2001 Aug;79(8):428-36
AD - Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA. firstname.lastname@example.org
Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation. to identify tumor suppressor genes in this group of neuroblastomas we analyzed the expression and function of both apoptosis-related cell cycle regulatory genes in cell lines and patient tumor samples. We found that in a high percentage of neuroblastoma cell lines and patient samples with amplified MYCN, caspase-8 mRNA is not expressed. The caspase-8 gene, CASP8, was deleted or silenced by methylation in the neuroblastoma cell lines while methylation of its promoter region was the predominant mechanism for its inactivation in the patient tumor samples. Reintroduction of caspase-8 into the neuroblastoma cell lines resensitized these cells to drug-induced and survival factor dependent apoptosis. Subsequently others have also shown that caspase-8 is silenced by methylation in neuroblastoma and peripheral neural ectodermal tumors, and that the caspase-9 regulator Apaf-1 is silenced by methylation in melanoma cell lines and patient samples. We conclude that caspase-8 acts as a tumor suppressor gene in neuroblastomas, that its silencing provides a permissive environment for MYCN gene amplification once the tumors are treated with chemotherapeutic drugs/irradiation, and that expression of this gene in these tumor cells may be of clinical benefit. We also discuss the possible significance of the neural crest cell progenitor cell origin and the silencing of important apoptotic regulators via methylation in both neuroblastoma and melanoma tumors.
UI - 21443723
AU - Kopitz J; von Reitzenstein C; Andre S; Kaltner H; Uhl J; Ehemann V;
TI - Cantz M; Gabius HJ Negative regulation of neuroblastoma cell growth by carbohydrate-dependent surface binding of galectin-1 and functional divergence from galectin-3.
SO - J Biol Chem 2001 Sep 21;276(38):35917-23
AD - Institut fur Pathochemie und Neurochemie and the Pathologisches Institut, Klinikum der Ruprecht-Karls-Universitat, Im Neuenheimer Feld 220, D-69120 Heidelberg, Germany.
The cell density-dependent growth inhibition of human SK-N-MC neuroblastoma cells is initiated by increased ganglioside sialidase activity leading to elevated cell surface presentation of ganglioside GM1, a ligand of galectin-1. We herein show that the extent of the cell surface expression of the galectin coincides with marked increases of the sialidase activity. Reverse transcriptase-polymerase chain reaction analysis excludes a regulation at the transcriptional level. Exposure of cells to purified galectin-1 reveals its carbohydrate-dependent activity to reduce cell proliferation. Assays to detect DNA fragmentation biochemically and cytometrically and to block caspases render it unlikely that galectin-1 acts as a classical proapoptotic factor on these cells. Because the chimeric galectin-3 shares binding sites and binding parameters with galectin-1 for these cells, we tested whether this galectin will elicit the same response as the homodimeric cross-linking galectin-1. Evidently, galectin-3 fails to affect cell growth by itself but interferes with galectin-1 upon coincubation. Its proteolytically truncated variant, the C-terminal lectin domain with impaired capacity to form aggregates when surface bound, has only weak binding properties. Thus, the way in which the galectin-1 interacts topologically with an apparently common set of ligands relative to galectin-3 is crucial for eliciting post-binding events. We conclude that galectin-1 is a probable effector in the sialidase-dependent growth control in this system. Moreover, the experiments with galectin-3 reveal functional divergence, most probably based on different topologies of presentation of homologous carbohydrate-binding sites.
UI - 21372266
AU - Gohil A; Croffie JM; Fitzgerald JF; Gupta SK; Del Rosario MA
TI - Reversible intestinal pseudoobstruction associated with neural crest tumors.
SO - J Pediatr Gastroenterol Nutr 2001 Jul;33(1):86-8
AD - James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, IN 46202, U.S.A.
UI - 21523829
AU - Guzhova I; Hultquist A; Cetinkaya C; Nilsson K; Pahlman S; Larsson LG
TI - Interferon-gamma cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells.
SO - Int J Cancer 2001 Oct 1;94(1):97-108
AD - Department of Genetics and Pathology, University of Uppsala, University Hospital, Uppsala, Sweden.
The prognosis of patients with advanced stages of neuroblastoma with N-myc amplification remains poor despite escalated therapy, a situation that has called for alternative therapeutic approaches. Neuroblastoma cells, which represent immature peripheral neuronal cells, treated with certain physiologic and nonphysiologic agents such as retinoic acid (RA), phorbol esters and interferons (IFN) in vitro undergo cellular differentiation and stop to divide, a process that mimics normal neuronal development. Such "differentiation therapy" using RA after autologous bone marrow transplantation has recently given encouraging results in neuroblastoma patients with advanced disease. Considering approaches for improved differentiation therapy, we investigated possible synergistic effects of combining agents known to influence neuroblastoma growth and differentiation in vitro. Our results show that combined treatment with IFN-gamma and RA or the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA) had synergistic or enhancing effects on morphologic differentiation and neurite outgrowth in 5 of 5 neuroblastoma cell lines, 3 of which expressed very high levels of N-myc mRNA due to N-myc amplification. The combinations RA+IFN-gamma or TPA+IFN-gamma also enhanced induced growth inhibition in all 5 cell lines, in several cases resulting in complete growth arrest under conditions where cells stimulated with either agent alone continued to grow. The phenotypic effects of the combined RA+IFN-gamma or TPA+IFN-gamma treatments were in most, but not all, investigated cases accompanied by moderate reductions in N-myc expression, suggesting that the cooperative signals may counteract N-Myc activity at several levels. The cooperativity between IFN-gamma and other differentiation signals may be relevant for approaches to improve the therapy for high-risk neuroblastoma with N-myc-amplification. Copyright 2001 Wiley-Liss, Inc.
UI - 21523848
AU - Rossig C; Bollard CM; Nuchtern JG; Merchant DA; Brenner MK
TI - Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes.
SO - Int J Cancer 2001 Oct 15;94(2):228-36
AD - Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Genetic engineering of human T lymphocytes to express tumor antigen-specific chimeric immune receptors is an attractive means for providing large numbers of effector cells for adoptive immunotherapy while bypassing major mechanisms of tumor escape from immune recognition. We have applied this strategy to the targeting of a G(D2)-positive tumor, neuroblastoma, which is the commonest extracranial solid tumor of childhood. Chimeric immune receptors were generated by joining an extracellular antigen-binding domain derived from either of the 2 ganglioside G(D2)-specific antibodies sc7A4 and sc14.G2a to a cytoplasmic signaling domain. The variable domains of hybridoma antibody 14.G2a were cloned and selected using a phage display approach. Upon coincubation with G(D2)-expressing tumor cell targets, human T lymphocytes transduced with recombinant retroviruses encoding chimeric receptors based on sc14.G2a, but not sc7A4, secreted significant levels of cytokines in a pattern comparable to the cytokine response obtained by engagement of the CD3 receptor. T cells transduced with the sc14.G2a-based chimeric T-cell receptors also displayed specific lysis of G(D2)-positive neuroblastoma cells, which was blocked in the presence of monoclonal antibody 14.G2a. In the absence of nonspecific stimulation of transduced cells, their functionality declined over time and antigenic stimulation of the chimeric receptor alone did not induce commitment to proliferation. These results support the feasibility of redirecting human T lymphocytes to a tumor-associated ganglioside epitope but emphasize that successful chimeric receptor-mediated adoptive immunotherapy will require additional strategies that overcome functional inactivation of gene-modified primary T lymphocytes. Copyright 2001 Wiley-Liss, Inc.
UI - 21475583
AU - Rana B; Pearson AD; Redfern CP
TI - RXR beta isoforms in neuroblastoma cells and evidence for a novel 3'-end transcript.
SO - FEBS Lett 2001 Sep 28;506(1):39-44
AD - Department of Endocrinology, Medical Molecualr Biology Group, Medical School, University of Newcastle upon Tyne, UK.
RXR beta is predominantly involved in retinoid responses in neuroblastoma cells, in particular the N-type SH SY 5Y cells and the S-type SH S EP cells, both derivatives of a mixed phenotype neuroblastoma cell line. The aim of this study was to identify RXR beta isoforms expressed in neuroblastoma cells and to characterise a putative novel RXR beta transcript. RXR beta 1 and RXR beta 2 were expressed in these neuroblastoma cells. An isoform with an insertion into the ligand binding domain, RXR beta(SLSR) (referred to in previous studies as RXR beta 3), was expressed at a similar level to RXR beta. A novel RXR beta transcript was identified by RNase protection assays and was at least as abundant as the expected RXR beta transcript and expressed in other cell types. Evidence suggests that this novel transcript was transcribed from an internal promoter between exons 5 and 6, contained a retained intron (intron 6) and was alternatively spliced with and without the SLSR insertion. These data show that the pattern of RXR beta expression is complex. The relative abundance of the novel RXR beta transcript suggests that it may be an important aspect of RXR beta function or regulation in a range of cell types.
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