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)

We previously postulated that the single-minded 2 (SIM2) gene identified on the human chromosome 21q22.2 is a good candidate gene for the pathogenesis of mental retardation in Down syndrome because its mouse homolog exhibits preferential expression in the mouse diencephalon during early embryogenesis. We analyzed the genomic sequence of the entire SIM2 gene which consists of 11 exons and spans over 50 kb. As a step toward understanding the molecular mechanisms of SIM2 gene expression, we have analyzed the human SIM2 gene expression in nine established human cell lines. Three transcripts of 3.6, 4.4, and 6.0 kb were detected in the glioblastoma cell line, T98G, neuroblastoma cell line, TGW, and transformed embryonic kidney cell line, 293. The RACE analysis using SIM2-expressing human cell line T98G provided evidence for the transcription start site at approximately 1.2 kb upstream of the translation initiation site. The transfection assay using various deletion constructs with reporter gene suggested the presence of a presumptive promoter region. Transient transfection assay in T98G cell line revealed a significant promoter activity located in the 60 bp sequence between nt -1385 and -1325 upstream region of the translation initiation site. This 60 bp sequence contains cis-elements for c-myb, E47 and E2F transcription factors. Moreover, the gel retardation assay using oligo-DNA of various cis-element sequences indicated the presence of protein factor(s) which bind to the cis-element for c-myb. These results suggested that binding of a protein transcription factor(s) such as c-myb or that alike regulates transcription of the SIM2 gene by binding to a small upstream region.
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PMID:Molecular mechanisms of human single-minded 2 (SIM2) gene expression: identification of a promoter site in the SIM2 genomic sequence. 1140 25

Formulations of antisense oligonucleotides (asODNs) against c-myb or c-myc protooncogenes have been prepared by a new technique that sequesters cationic lipid in the interior of a lipid particle. This technique results in high loading efficiency for the asODNs, small particle size and good stability. When targeted against melanoma cells or neuroblastoma cells via anti-GD(2) coupled at the particle surface, increased cell binding to the cells could be demonstrated. Targeted formulations showed greater inhibition of cell proliferation compared to non-targeted formulations or free drug. Inhibition of cell proliferation was demonstrated to be due to down-regulation of c-myb or c-myc protein expression. The formulations have long-circulation times in vivo, and evaluation for in vivo antitumor activity is currently underway.
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PMID:Targeted delivery of antisense oligonucleotides in cancer. 1148 84

Neuroblastoma (NB) is the most common neuroectoderma derived solid tumour of paediatric age. Since conventional treatments are often inefficient, novel therapeutic interventions are required. Among these, the use of antisense oligonucleotides (asODNs) as therapeutic antineoplastic agents has been recently investigated. Oligonucleotide in vivo applicability is impaired from their high sensitivity to cellular nuclease degradation. Encapsulating them within liposomes could nevertheless increase their stability. C-myb gene expression has been reported in several solid tumours of different embryonic origin, including NB, where it is linked to cell proliferation and/or differentiation. We performed a new technique to encapsulate c-myb antisense oligonucleotides within lipid particles. Liposomes resulting from this technique were called coated cationic liposomes (CCLs), since they were made up of a central core of a cationic phospholipid bound to myb-asODNs, and an outer shell of neutral lipids. A monoclonal antibody (mAb) specific for the neuroectoderma antigen disialoganglioside GD(2), has been covalently coupled to their external surface. The resulting anti-GD(2)-targeted CCLs showed high loading efficiency for the asODNs, small particle size and good stability. In vitro, they were able to deliver myb-asODNs selectively to GD(2)-positive NB cell lines more efficiently than non-targeted liposomes or free asODNs. Consequently, targeted formulations showed greater inhibition of cell proliferation than non-targeted formulations or free asODNs. Furthermore, we demonstrated that the inhibition of cell proliferation was dependent on the down-modulation of c-myb protein expression. Pharmacokinetic studies showed that these targeted liposomal formulations were long circulating in blood. Biodistribution studies presented differences between the free and the encapsulated myb-as ODN profiles, as well. While free myb-as ODNs are widely distributed (mainly liver, kidney and spleen) even after 30 min post-injection, myb-as ODN entrapped into CCL or anti-GD(2)-CCL presents only an accumulation in the spleen after 24 h. Future studies will be performed to evaluate the antitumour efficacy of the above formulations in animal models.
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PMID:Targeted delivery system for antisense oligonucleotides: a novel experimental strategy for neuroblastoma treatment. 1288 Sep 87

Neuroectodermal tumors are highly malignant and increasingly common tumors. Because the cure rate of these neoplasias by conventional treatment is very low, new therapeutic approaches are needed. Entrapping high concentrations of cytotoxic drugs and/or oligonucleotides within stabilized liposomal formulations represents an emerging modality of antitumor treatment. Here, we tested the in vitro and in vivo antitumor effects of a novel antisense oligodeoxynucleotide (asODN) liposomal formulation, the coated cationic liposomes (CCL), by targeting the c-myc and the c-myb oncogenes on melanoma and neuroblastoma, respectively, through the use of a monoclonal antibody against the disialoganglioside GD2, selectively expressed by neuroectoderma-derived tumors. Our methods produced GD2-targeted liposomes that stably entrapped 90 percent of added asODNs. These liposomes showed selective binding for GD2-positive tumor cells in vitro. Neuroblastoma cells treated with free myb-as or nontargeted CCL-myb-as showed the same level of c-myb protein expression as control cells. In contrast, c-myb protein expression of cells treated with aGD2-CCL-myb-as was inhibited by approximately 70 percent. Melanoma and neuroblastoma cell proliferation was inhibited to a greater extent by GD2-targeted liposomes containing c-myc or c-myb asODNs than by nontargeted liposomes or free asODNs. Mice bearing established subcutaneous human melanoma xenografts treated with aGD2-CCL-myc-as exhibited significantly reduced tumor growth and increased survival. The mechanism for the antitumor effects appears to be downregulation of the expression of the c-myc protein, induction of p53, and inhibition of Bcl-2 proteins, leading to extensive tumor cell apoptosis. In contrast, the increased life span obtained in a neuroblastoma pseudometastatic mouse model with the liposomal c-myb asODNs seems to be due to a synergistic mechanism: specific targeting to neuroblastoma cancer cells, downmodulation of c-myb protein expression, and stimulation of the innate immune system. These results suggest that inhibition of c-myc or c-myb proto-oncogenes by GD2-targeted antisense therapy could provide an effective approach for the treatment of neuroectodermal tumors in an adjuvant setting.
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PMID:Targeted delivery of oncogene-selective antisense oligonucleotides in neuroectodermal tumors: therapeutic implications. 1565 Feb 35

Liposome encapsulation of anticancer agents results in reduced side effects of the entrapped drug and improved therapeutic efficacy. The external surface of the lipidic envelope can be coupled with antibodies directed against tumor-associated antigens. The resulting immunoliposomes allow to increase the therapeutic index of cytotoxic drugs while minimizing their systemic toxicity. In this regard, the disialoganglioside GD2 is a very promising tumor-associated antigen since it is expressed at high intensity on human neuroblastoma cells, but is detected only in normal cerebellum and peripheral nerves. Immunoliposomes can be used as vectors to deliver antisense oligonucleotides to cancer cells with the aim to modulate oncogene expression. Furthermore, antisense oligonucleotides have attracted much interest because of their ability to stimulate immune responses. Here, we will describe a novel experimental therapeutic approach for neuroblastoma based on anti-GD2 liposomal c-myb-selective antisense oligonucleotides.
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PMID:Neuroblastoma targeting by c-myb-selective antisense oligonucleotides entrapped in anti-GD2 immunoliposome: immune cell-mediated anti-tumor activities. 1593 40

The c-myb transcriptional regulator plays a crucial role in the control of several proliferative/differentiative processes in haematopoietic cells. Its expression and function is not lineage-restricted, since c-myb is also expressed in solid tumours such as neuroblastomas, where its transcription is decreased by retinoic acid. In response to retinoic acid, neuroblastomas differentiate either towards a neuronal phenotype or undergo apoptosis. The temporal relationship between reduction in c-myb mRNA levels and the differentiative/proliferative/apoptotic processes suggests that c-myb may play a key role in the control of growth of these neuroectodermal tumours. Transfection of neuroblastoma cells with expression vectors containing segments of human c-myb cDNA in antisense orientation yielded fewer transfectant clones, with a far slower proliferation rate, than transfection with the corresponding sense construct. The dramatic growth arrest and reduction in cell number in the antisense transfectants is due to the induction of apoptosis. Apoptosis in the c-myb antisense-transfected cells is further increased in reduced serum conditions.
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PMID:c-myb down regulation is associated with apoptosis in human neuroblastoma cells. 1718 21


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