Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human tumor cell lines that do not express O6-methylguanine-DNA methyltransferase (MGMT) in detectable quantities (Mer-) are hypersensitive to the effects of O6-guanine-alkylating agents. Because the Mer- phenotype enhances tumor response to such agents, we investigated possible mechanisms involved in regulation of MGMT expression in a panel of Mer+ and Mer- pediatric rhabdomyosarcoma xenograft and cell lines. All Mer- cell and xenograft lines lacked not only MGMT activity but also the protein and mRNA as well, suggesting that its expression is transcriptionally regulated. Transfection of Mer+ and Mer- rhabdomyosarcoma cell lines with MGMT gene promoter-CAT constructs yielded similar levels of CAT expression, indicating that Mer- cells possessed the necessary factors to support transcription. Methylation in the 5'-untranslated region of the MGMT gene was assayed by Southern analysis using methylation-sensitive restriction enzymes. Digestion with HpaII and its methylation-insensitive isoschizomer, MspI, revealed little overall correlation between methylation and MGMT expression. However, methylation in a single SmaI site at position-69 was observed in all MGMT deficient lines but not in any MGMT expressing lines. These results suggest that methylation of specific cytosines in the MGMT promoter may play a role in suppressing its expression, as well as being a potentially useful marker for the Mer- phenotype.
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PMID:Cytosine methylation and suppression of O6-methylguanine-DNA methyltransferase expression in human rhabdomyosarcoma cell lines and xenografts. 150 76

Thioredoxin reductase (TR) is a widely distributed flavoenzyme that provides reduced thioredoxin, a dithiol hydrogen donor for protein disulfide reduction and for the reduction of ribonucleotides to deoxyribonucleotides, the first unique step of DNA synthesis. Antitumor quinones were found to exhibit time- and concentration-dependent inhibition of purified rat liver TR that requires the presence of NADPH. Diaziquone initially shows competitive inhibition of the enzyme with 5,5'-dithiobis 2-nitrobenzoic acid as substrate with a Ki of 7.5 microM, which becomes non-competitive after 1 hour incubation with NADPH with a Ki of 0.5 microM. Doxorubicin shows non-competitive inhibition both initially and after 1 hr incubation with NADPH, with Ki values of 10 microM and 0.5 microM, respectively. Electron spin resonance spectroscopy showed the formation of semiquinone free radicals by TR incubated under anaerobic conditions with doxorubicin or diaziquone and NADPH. Redox cycling and formation of oxygen radicals does not play a major role in the inhibition of TR by antitumor quinones as shown by the minor effect on inhibition of removing O2, and the lack of effect of superoxide dismutase and catalase. Diaziquone causes time- and concentration-dependent inhibition of TR activity in intact A204 human rhabdomyosarcoma cells that is associated with growth inhibition. The results suggest that inhibition of TR by antitumor quinones could contribute to their growth inhibitory properties.
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PMID:Inhibition of thioredoxin reductase (E.C. 1.6.4.5.) by antitumor quinones. 216 13

A transforming N-ras allele was molecularly cloned from the RD human rhabdomyosarcoma cell line, and the nature of its activation studied. Construction of chimeric recombinants between the RD-transforming allele and a normal human allele enabled us to localize the alteration responsible for the activation to the second exon of the N-ras gene. The nucleotide sequence of this exon, when compared to that of the normal allele, revealed a single difference at the 61st amino acid position of the encoded protein; the CAA codon for glutamine in the normal allele was mutated to a CAT codon for histidine in the RD-transforming allele. This result is the first description of a histidine replacing glutamine in the 61st position and provides further evidence that the 61st amino acid is one of the preferential sites for N-ras activation.
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PMID:N-ras gene activation in the RD human rhabdomyosarcoma cell line. 315 13

Reducing agents such as glutathione (GSH), glutathione ester (GSE), and N-acetylcysteine (NAC) have been shown to suppress the induction of HIV expression in chronically infected cells stimulated by cytokines. We present data which show the effects of the organic thiophosphate WR-151327 on the expression of latent HIV in U1 cells. The chronically infected promonocytic cell line U1 constitutively expresses low levels of HIV that can be increased by 13-phorbol 12-myristate acetate (PMA), tumor necrosis factor alpha (TNF-alpha), and granulocyte/monocyte colony-stimulating factor (GM-CSF). WR-151327 suppressed, in dose-dependent fashion, the reverse transcriptase (RT) activity induced by TNF-alpha, GM-CSF, and PMA. The maximal decrease in RT activity was 70, 80, and 50%, respectively. Pretreatment with WR-151327 also suppressed the induction of total HIV protein synthesis, as shown by Western blot analysis. In addition, WR-151327 suppressed HIV-LTR-CAT activity in transfected human rhabdomyosarcoma cells (RD). Suppression of HIV expression by WR-151327 was observed in the absence of a cytotoxic or cytostatic effect. Incubation of WR-151327 with human recombinant TNF-alpha for 6 hr at 37 degrees C did not alter the capacity of TNF-alpha to induce the expression of HIV. Our observations further support the hypothesis that reducing agents are important in the control of HIV replication and that the clinical evaluation of WR-151327 may be indicated.
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PMID:Organic thiophosphate WR-151327 suppresses expression of HIV in chronically infected cells. 752 Nov 93

Alveolar rhabdomyosarcomas are pediatric solid tumors with a hallmark cytogenetic abnormality: translocation of chromosomes 2 and 13 [t(2;13) (q35;q14)]. The genes on each chromosome involved in this translocation have been identified as the transcription factor-encoding genes PAX3 and FKHR. The NH2-terminal paired box and homeodomain DNA-binding domains of PAX3 are fused in frame to COOH-terminal regions of the chromosome 13-derived FKHR gene, a novel member of the forkhead DNA-binding domain family. To determine the role of the fusion protein in transcriptional regulation and oncogenesis, we identified the PAX3-FKHR fusion protein and characterized its function(s) as a transcription factor relative to wild-type PAX3. Antisera specific to PAX3 and FKHR were developed and used to examine PAX3 and PAX3-FKHR expression in tumor cell lines. Sequential immunoprecipitations with anti-PAX3 and anti-FKHR sera demonstrated expression of a 97-kDa PAX3-FKHR fusion protein in the t(2;13)-positive rhabdomyosarcoma Rh30 cell line and verified that a single polypeptide contains epitopes derived from each protein. The PAX3-FKHR protein was localized to the nucleus in Rh30 cells, as was wild-type PAX3, in t(2;13)-negative A673 cells. In gel shift assays using a canonical PAX binding site (e5 sequence), we found that DNA binding of PAX3-FKHR was significantly impaired relative to that of PAX3 despite the two proteins having identical PAX DNA-binding domains. However, the PAX3-FKHR fusion protein was a much more potent transcriptional activator than PAX3 as determined by transient cotransfection assays using e5-CAT reporter plasmids. The PAX3-FKHR protein may function as an oncogenic transcription factor by enhanced activation of normal PAX3 target genes.
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PMID:The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. 786 45

Earlier studies have revealed a distinct class of regulatory proteins known as trans-activator proteins in diverse biological systems. These proteins have been shown to act on both homologous and heterologous promoter targets. Activation of heterologous targets is speculated to be an integral part of virus-induced pathogenesis. To verify this hypothesis, stable Tat-producing human rhabdomyosarcoma (RD) cell lines were generated. These cell lines produced significant levels of functional Tat, as measured by transfection with the reporter plasmid pLTR-CAT. Tat-producing cells, although morphologically similar to the control, exhibited a slower growth rate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of the cellular proteins from control (tat-) and tat+ cells revealed increased quantities of 34- and 40-kD proteins along with the appearance of a new 74-kD protein in tat+ cells. Subsequent two-dimensional gel analysis revealed several additional differences. Tat+ cell lines produced two proteins of M(r) 19.5 and 44 kD anew, while proteins with M(r) 14.5, 42, and 52.5 kD were in greater abundance. Interestingly, a 26-kD protein that was originally present in the G418+/tat- (control) sample disappeared in the presence of Tat. These data support a possible modulator role for Tat in cellular gene expression.
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PMID:Changes in cellular proteins associated with the expression of human immunodeficiency virus type 1 trans-activator protein Tat. 821 53

Terminal differentiation of myocytes involves withdrawal from the cell cycle, induction of myogenin expression, and finally formation of myotubes. To study the factors that regulate the initial phase of muscle differentiation, we analyzed the binding activities of transcription factors AP-1, Sp-1, and NF-kappa B in L6, C2C12, and rhabdomyosarcoma BA-Han-1C cells. Temporal changes in transcription factor binding activities were compared to the activation of myogenin promoter-driven CAT reporter gene and the expression level of myogenin, a master gene of myogenic differentiation. We observed a prominent decrease in the nuclear binding activities of AP-1, Sp-1, and NF-kappa B already 12 to 24 h after the transfer of cells to differentiation medium. The response was very similar in L6 and C2C12 myocytes and in BA-Han-1C rhabdomyosarcoma cells. The down-regulation clearly preceded the activation of myogenin promoter and the induction of myogenin and retinoblastoma expression, as well as the initiation of myocyte fusion. Cholera toxin and okadaic acid, established inhibitors of myogenin expression and muscle differentiation, strongly up-regulated the binding activities of AP-1, Sp-1, and NF-kappa B in differentiation medium. Myogenin expression and myocyte fusion were also inhibited. Levels of nuclear c-Fos and c-Jun proteins, components of the AP-1 complex, showed a prominent decrease already after 12 h in differentiation medium. These results show that the down-regulation of the proliferation-promoting transcription factors is a prerequisite to the initiation of myocyte differentiation.
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PMID:Down-regulation of transcription factors AP-1, Sp-1, and NF-kappa B precedes myocyte differentiation. 895 80

The objective of the present study was to investigate the efficacy of (111)In-DTPA-octreotide (OC) for in vivo scintigraphic imaging of these relatively uncommon tumors. Thirteen patients (9 males, 4 females, mean age 59 years) with known sarcomatous lesions were studied. All patients had known lesions as demonstrated by previous investigation with other modalities, e.g. CAT, MRI. Following intravenous injection of 10 microg of OC labeled with 2.8-4.2 mCi (111)In, planar imaging was done at 6 +/- 1 and 22 +/- 2 h, respectively. Histologic verification was obtained in all cases, either from fine needle aspiration or from surgically removed tissue. Positive imaging was observed in 12/13 cases (92.3%). One scan was false-negative (7.7%). Occult lesions were demonstrated in two patients. The histologic typing and the scintigraphy results were: fibrosarcoma (1+/1), embryonic rhabdomyosarcoma (1+/1), leiomyosarcomas (3+/3), liposarcomas (2+/2), uterine sarcomas (2+/2), HIV (-) Kaposi sarcoma (1+/1), osteosarcoma (1+/1), chondrosarcoma (1-/1) and neurogenous sarcoma (1+/1). OC appears to have properties that lead to a new indication for its use. Other possible applications relate to the therapeutic use of octreotide either unlabeled or labeled with a beta-emitting radionuclide, as well as its use in radioimmunoguided surgery. Regarding the latter, our preliminary results are encouraging.
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PMID:Scintigraphic imaging of sarcomatous tumors with [(111)In-DTPA-phe-1]-octreotide. 1064 36

A child with an unusual association of cancers is described. The patient first presented with a rhabdomyosarcoma of the right scapular muscle, and was successfully treated with chemotherapy. Six years after diagnosis of the first malignancy, the child presented with two synchronous malignancies: osteosarcoma of the jaw and adrenocortical carcinoma. Genetic mutation analysis was performed and revealed a germline p53 mutation of CGT > CAT at codon 273. The family history was negative for any other cancer consistent with the Li-Fraumeni syndrome. This case highlights the need for close surveillance of patients with p53 mutation for malignancy and describes the occurrence of two malignancies synchronously.
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PMID:Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. 1539 Feb 94

The aim of the study was to determinate mitochondrial oxidative phosphorylation (OXPHOS) functions in rat rhabdomyosarcoma R1H (R1H) and rat skeletal muscles. For that purpose skinned fiber technique and multiple substrate inhibitor titration were adapted to tumor samples. In our animal tumor model (R1H) functional abnormalities of OXPHOS were found compared to skeletal muscles. In R1H the state 3 respiration of pyruvate + malate was decreased: 0.56 +/- 0.28 nmol O(2)/mg/min versus 2.32 +/- 1.19 nmol O(2)/mg/min, P < 0.001, whereas the state 3 respiration of succinate + rotenone was increased: 36 +/- 14% versus 19 +/- 11%, P < 0.001. In R1H the rotenone-insensitive respiration reached higher levels than the antimycin A-insensitive respiration, whereas in normal muscles the converse was observed. Additionally, the obvious difference between the CAT- and the antimycin A-independent respiration indicates an increased part of leak respiration in R1H. By now, the high feasibility of these techniques is appreciated for the investigation of muscles and prospectively for tumors, too.
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PMID:Mitochondrial OXPHOS functions in R1H rhabdomyosarcoma and skeletal muscles of the rat. 1727 27


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