Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

During the last two decades new diagnostic and therapeutic tools have been utilized to improve the poor survival chances of children with stage 4 neuroblastoma. This study reviews the risk profiles and the long-term outcome of patients from five consecutive German neuroblastoma trials. A total of 96% of all German patients registered at the German childhood cancer registry with neuroblastoma stage 4 over 1 year of age at diagnosis entered one of the trials during 1979-2001. Eight hundred and twenty-eight consecutive children were analyzed retrospectively. In spite of having significantly improved diagnostic tools like bone marrow superstaging and mIBG scintigraphy the stage 4 incidence did not increase after reaching completeness of the registry (5.4 cases/100,000 children at 1-14 years of age; P=0.52). The distribution of the primary tumors and of metastases was constant over the periods. The amount of bone marrow infiltration did not change with time. The risk factors lactate dehydrogenase, ferritin and MYCN, and the clinical risk groups 4A, 4B, 4C also remained constant over the trials with a few exceptions for NB97. The 5-year event free survival increased from 0.01+/-0.01 (NB79) to 0.14+/-0.03 (NB85), 0.16+/-0.04 (NB82), 0.27+/-0.02 (NB90), and 0.33+/-0.04 (NB97). The overall survival rates improved similarly from 0.04 (NB79) to 0.44 (NB97). In conclusion, the improved survival was associated with better treatment and not caused by lower risk profiles in stage 4 neuroblastoma patients.
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PMID:Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. 1288 Sep 54

Neuroblastoma (NBL) is a common pediatric cancer originated from the neuronal precursor cells of sympathoadrenal lineage. NBLs show a variety of clinical phenotypes from spontaneous regression to malignant progression with acquirement of resistance to therapy. To understand the molecular mechanism of the genesis, progression, and regression of NBL, we need to identify key molecules determining the neuronal development of sympathoadrenal lineage. To this end, we have performed the NBL cDNA project. It includes (1) mass-cloning of the expressed genes from oligo-capping cDNA libraries derived from primary NBLs with different clinical and biological features; (2) mass-identification of differentially expressed genes between favorable and unfavorable subsets; and (3) molecular and functional analyses of the novel genes, which could be useful prognostic indicators. To date, 10,000 cDNA clones in total, approximately 40% of which contained novel sequences, were randomly picked up and DNA sequenced. We have identified approximately 500 differentially expressed genes between favorable and unfavorable subsets of NBL, among which more than 250 were the genes with unknown function.
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PMID:Neuroblastoma oligo-capping cDNA project: toward the understanding of the genesis and biology of neuroblastoma. 1288 Sep 61

Vascular endothelial growth factor A (VEGF-A) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis. SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase. We have developed a reproducible murine model for neuroblastoma, a childhood cancer, based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells. We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels, that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume > 1.4 ml, and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals. Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity. SU5416 treatment also suppressed tumor angiogenesis, despite an increase in plasma VEGF-A levels per ml tumor volume during therapy. Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma.
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PMID:Importance of vascular endothelial growth factor A in the progression of experimental neuroblastoma. 1290 18

Our understanding of the clinical and cellular pharmacology of drugs commonly used in the treatment of childhood cancer have increased greatly over the past two decades. However, with the exception of childhood acute lymphoblastic leukaemia (ALL), our current knowledge of factors such as inter-patient pharmacokinetic variability and cellular determinants of chemosensitivity has not been utilized in the design of integrated clinical studies. Recent pre-clinical and clinical evaluation of the topoisomerase I inhibitors topotecan and irinotecan has highlighted the potential importance of pharmacological factors in their effectiveness as cytotoxics. In this review, the clinical and cellular pharmacology of vincristine, actinomycin D, doxorubicin, cyclophosphamide, ifosfamide, cisplatin, carboplatin and etoposide will be discussed in relation to the major paediatric solid tumours. For each disease type, knowledge of the clinical and cellular pharmacology of a candidate drug will be related to pharmacodynamic responses such as response, toxicity and prognosis. For diseases such as Wilms' tumour, osteogenic sarcoma and Ewing's tumour, histological response to initial induction chemotherapy is of prognostic significance, and the depth of response is increasingly recognised as an important determinant of prognosis for high-risk neuroblastoma. For several of these tumour types, the dose-intensity of chemotherapy may be an important variable in determining prognosis. However the relationship between pharmacokinetic variability, cellular pharmacology and the major determinants of chemosensitivity to those drugs employed in first line therapy is unknown. The study of these relationships, by means of up front window studies in children who present with high-risk disease, may be as important as the introduction of new agents. Indeed, the optimisation of current therapies may be required to allow a fully informed selection of those children for whom novel therapies are truly needed. Funding and international collaboration at the clinical and scientific level would be required to achieve these aims.
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PMID:Clinical and cellular pharmacology in relation to solid tumours of childhood. 1292 66

Therapeutic advances in the treatment of pediatric neoplasms have improved the prognosis but have also increased the risk of developing rare second malignant neoplasms (SMNs). Primary neoplasms that are often associated with SMNs include lymphoma, retinoblastoma, medulloblastoma, neuroblastoma, and leukemia. The most common SMNs are central nervous system (CNS) tumors, sarcomas, thyroid and parotid gland carcinomas, and leukemia, particularly acute myeloblastic leukemia. Genetic predisposition, chemotherapy, and especially radiation therapy are implicated as pathogenic factors in SMN. All survivors of childhood cancer should have lifelong follow-up, preferably with magnetic resonance imaging, which does not require ionizing radiation and provides greater anatomic detail and resolution in the head and neck region and the CNS. A new or progressive lesion may represent recurrence of the primitive neoplastic process, late radiation injury, or, more infrequently, an SMN. Differential diagnosis can be very difficult, and outcome is often fatal. Treatment protocols should be modified to reduce the risk for SMN without compromising the effectiveness of initial therapy. Clinicians should individualize treatment for patients who are genetically predisposed to SMN. In addition, radiologists should be familiar with the long-term consequences of antineoplastic therapy to facilitate diagnosis and anticipate adverse outcomes.
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PMID:Second malignancies in pediatric patients: imaging findings and differential diagnosis. 1297 7

In the last few years molecular genetic studies of childhood cancer have acquired great importance. Advances in these techniques have increased knowledge of the various genes involved in tumoral development. Genetic alterations can occur in three large groups of genes: oncogenes, tumor suppressor genes, and DNA repair genes. Cytogenetic analyses (karyotyping) are complemented by various molecular techniques, such as fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR) and spectral karyotyping (SKY). These are the most reliable techniques and improve the sensitivity of karyotyping. The present article reviews the most representative and best characterized genes involved in the molecular etiology of childhood cancer, both hematologic malignancies (leukemia and lymphoma) and solid tumors (brain tumors, neuroblastoma, Wilms' tumor, hepatoblastoma, rhabdomyosarcoma, Ewing's sarcoma and retinoblastoma). Molecular techniques have enabled more precise diagnosis as well as identification of new prognostic factors and the development of more effective treatments. These techniques can also be useful in identifying minimal residual disease during and after treatment for leukemias, neuroblastomas and sarcomas, with the aim of predicting recurrence.
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PMID:[The role of molecular genetics in childhood cancer]. 1451 4

Tumor angiogenesis, a major requirement for tumor outgrowth and metastasis, is regulated by pro- and antiangiogenic factors. Methylation-associated inactivation of the angiogenesis inhibitor thrombospondin-1 (TSP-1) has been observed recently in some adult tumors. To investigate the role of TSP-1 in pediatric cancer, we examined its pattern of expression and mechanisms of regulation in neuroblastoma (NB). TSP-1 was silenced in a subset of undifferentiated, advanced-stage tumors and NB cell lines. In contrast, most localized tumors expressed this angiogenesis inhibitor, and a significant correlation between morphological evidence of neuroblast differentiation and TSP-1 expression was observed. Luciferase assays demonstrated the presence of nuclear factors required for TSP-1 transcription in both TSP-1-positive and -negative cell lines, but no correlation between TSP-1 promoter activity and the level of TSP-1 mRNA expression was seen. Our studies indicate that the transcriptional silencing of TSP-1 was caused by methylation. TSP-1 promoter methylation was detected in all of the NB cell lines lacking TSP-1 mRNA and in 37% of the NB clinical tumors analyzed. Furthermore, treatment with the demethylating agent, 5-Aza-2'-deoxycytidine (5-Aza-dC), restored TSP-1 expression in NB cell lines. Disrupting methylation with 5-Aza-dC also led to significant inhibition of NB in vivo and re-expression of TSP-1 in a subset of NB xenografts. These results suggest that 5-Aza-dC inhibits NB growth by augmenting the expression of TSP-1 along with other genes that suppress tumor growth. Demethylating agents may prove to be effective candidates for the treatment of children with NB.
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PMID:Methylation-associated silencing of the thrombospondin-1 gene in human neuroblastoma. 1455 17

Human neuroblastoma (NB) is a highly heterogeneous childhood cancer secreting a high level of vascular endothelial growth factor (VEGF). Its vascularization has been clearly correlated with metastatic progression and poor outcome. Thus, molecules that target the vascular endothelium are regarded as new therapeutics of clinical interest. Angiostatin, an internal fragment of plasminogen containing the first four kringle structures, has been described as a powerful angiogenic inhibitor. We used a recombinant adenovirus encoding the human angiostatin kringle 1-3 directly fused to human serum albumin HSA (AdK3-HSA). Coupling to HSA has been previously shown to increase the in vivo half-life of this angiostatic factor, and to lead to tumor growth inhibition in the MDA-MB-231 carcinoma model. For the assessment of antiangiogenic gene therapy in the human NB IGR-N835 tumor model, 5 x 10(9) PFU of AdK3-HSA were intravenously injected in tumor-bearing athymic mice presenting either of the following experimental settings: early stage, established, and minimal residual tumors. No delay in tumor growth was observed in animals treated with AdK3-HSA as compared to those treated with the empty virus AdCO1. In early-stage tumors, kinetics of tumor occurrence and tumor growth were similar in AdK3-HSA- and AdCO1-treated animals. K3-HSA was found to be expressed at high levels (the mean value for the three experiments being 19.4+/-15.9 microg/ml) in the circulation of all animals up to 21-35 days after virus injection. In addition, IGR-N835 tumors were found to be highly vascularized and to release high amounts of angiogenic factors, in particular VEGF (665+/-370 pg/mg total protein). Thus, in spite of high circulating levels, K3-HSA may be unable to displace the NB proangiogenic switch. In this regard, a more promising target to inhibit NB angiogenesis seems to be the VEGF/VEGFR system.
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PMID:High level of stabilized angiostatin mediated by adenovirus delivery does not impair the growth of human neuroblastoma xenografts. 1460 72

Neuroblastomas are the most frequently occurring solid tumors in children under 5 years. Spontaneous regression is more common in neuroblastomas than in any other tumor type, especially in young patients under 12 months. Unfortunately, the full clinical spectrum of neuroblastomas also includes very aggressive tumors, unresponsive to multi-modality treatment and accounting for most of the pediatric cancer mortalities under 5 years of age. It is generally emphasized that more than one biological entity of neuroblastoma exists. Structural genetic defects such as amplification of MYCN, gain of chromosome 17q and LOH of 1p and several other chromosomal regions have proven to be valuable as prognostic factors and will be discussed in relation to their clinical relevance. Recent research is starting to uncover important molecular pathways involved in the pathogenesis of neuroblastomas. The aim of this review is to discuss several important aspects of the biology of the neuroblast, such as the role of overexpressed oncogenes like MYCN and cyclin D1, the mechanisms leading to decreased apoptosis, like overexpression of BCL-2, survivin, NM23, epigenetic silencing of caspase 8 and the role of tumor suppressor genes, like p53, p73 and RASSF1A. In addition, the role of specific proteins overexpressed in neuroblastomas, such as the neurotrophin receptors TrkA, B and C in relation to spontaneous regression and anti-angiogenesis will be discussed. Finally, we will try to relate these pathways to the embryonal origin of neuroblastomas and discuss possible new avenues in the therapeutic approach of future neuroblastoma patients.
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PMID:Pediatric neuroblastomas: genetic and epigenetic 'danse macabre'. 1469 5

Neuroblastoma (NB) is a childhood cancer that arises in the adrenal gland and often shows differentiated neuronal and glial elements. The RET receptor signal pathway is functional in most NB, while loss of nerve growth factor (NGF) receptor (trkA) gene expression correlates with an aggressive phenotype. Thus, we hypothesized that the RET and TRKA signal pathways collaborate to instruct NB differentiation, reminiscent of normal neuronal maturation. Here, we demonstrate that activation of the RET receptor by glial cell line-derived neurotrophic factor (GDNF) increases expression of the RET receptor complex in a panel of malignant human NB cell lines, indicative of a positive feedback mechanism. GDNF also induces growth cessation concomitant with an arrest of cells in the G(0)/G(1) phase of the cell cycle. Furthermore, GDNF synergizes with ciliary neurotrophic factor (CNTF) to enhance TRKA receptor expression, thereby strengthening the NGF-mediated differentiation signal. Differentiated NB cells downregulate expression of the amplified N-myc gene, concurrent with the arrest of cell proliferation, while expressing neuron-specific markers (i.e., SCG10). Interestingly, maintenance of differentiated NB cells in culture is independent of the trophic activity of GDNF, but depends on TRKA signaling, thereby re-enacting the differentiation of normal sympathoadrenal (SA) progenitor cells.
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PMID:The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. 1471 26


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