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: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Western blotting, indirect immunolocalization, flow cytometry, and a functional assay for drug-induced strand breakage were utilized to examine topoisomerase (topo) II levels during granulocytic maturation in HL-60 human progranulocytic leukemia cells and in samples of normal human marrow. Indirect immunofluorescence revealed that the intensity of the signal for topo II in unsynchronized log phase HL-60 cells varied widely. Indirect immunolabeling combined with propidium iodide staining and two-parameter flow cytometry revealed that topo II levels increased an average of 2-fold as cells progressed from G1 to G2/M. When HL-60 cells were induced to mature toward granulocytes, topo II levels progressively decreased and became undetectable by functional assays, by indirect immunoperoxidase staining, and by Western blotting with an antibody which identified Mr 170,000 and Mr 180,000 forms of topo II. Similar changes were detected during normal granulocytic maturation in human marrow in vivo. Western blotting revealed that levels of the Mr 170,000 (proliferation-associated) isoform of topo II were highest in marrow fractions enriched in progranulocytes and myelocytes, intermediate in unfractionated marrow from normal volunteers, and undetectable in mature granulocytes. The Mr 180,000 topo II polypeptide was also diminished or absent from mature granulocytes. In further experiments, marrow samples from normal volunteers were subjected to flow cytometry after labeling of topo II and various cell surface markers. Levels of the Mr 170,000 topo II polypeptide in CD34-positive cells (multipotent and committed progenitors from several hematopoietic lineages) were indistinguishable from levels observed in the HL-60 leukemia cell line. These results suggest that topo II levels in highly proliferative normal human myeloid cells in vivo approach levels found in corresponding neoplastic cell lines in vitro. Conversely, as the same cells mature into granulocytes in vivo or in vitro, levels of both molecular weight forms of topo II diminish. These results provide a framework for the further investigation of topo II levels and drug sensitivity in human leukemia.
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PMID:Topoisomerase II levels during granulocytic maturation in vitro and in vivo. 164 69

Three patients with secondary acute leukaemia after treatment with topoisomerase II inhibitor agents are described. Two patients had acute myeloid leukaemia (AML). FAB M5a, one had pro-B-acute lymphoblastic leukaemia (ALL). The interval between initiation of chemotherapy and the onset of secondary acute leukaemia was 19-20 months. 11q23 rearrangements were detected in all cases. They were due to translocations t(11;19) (q23;p13.3), t(11;16)(q23;p13) and t(4;11)(q21;q23), respectively. Fluorescence in situ hybridization (FISH) with Yeast Artificial Chromosome (YAC) probe 13HH4 spanning the ALL-1 gene on 11q23 confirmed that in each case the ALL-1 gene had been disrupted by the translocations. The study underlined the relationship between the development of secondary acute leukaemias with 11q23 rearrangement and previous chemotherapy with topisomerase II inhibitor agents. So far, however, only six adult patients with secondary ALL with t(4;11) after treatment with topoisomerase II inhibitor agents have been reported. All with t(4;11) mostly occurs in infants or young children. Our patient received epirubicin continuously for >19 months. This indicates that both myeloid and lymphoid leukaemias with involvement of the ALL-1 gene can be induced by exogenous agents, especially topoisomerase II inhibitors. Thus they may have a common biological background. This hypothesis was substantiated by means of combined immunophenotyping and FISH (FICTION). In the case of AML M5a with t(11;19), the tumour cells with ALL-1 rearrangement expressed CD34. Moreover, the pro-B-ALL with t(4;11) was CD34 positive. These findings suggest that the cell of origin of secondary AML and ALL with 11q23 rearrangement is an immature haemopoietic progenitor cell.
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PMID:Secondary acute leukaemias with 11q23 rearrangement: clinical, cytogenetic, FISH and FICTION studies. 861 34

Lymphangioma (LA) and congenital pulmonary lymphangiectasis (CPL) are part of a spectrum of lymphatic disorders less well characterized than other vascular tumors and malformations. Recent studies showed proliferative and involutional growth phases for hemangiomas that distinguish them from malformations. We investigated immunohistochemical reactivity and proliferative activity to determine whether a similar diagnostically/prognostically useful pattern exists for LA, comparing LA with CPL as a malformative lesion. Immunohistochemical tests for vimentin, Factor VIII-related protein, CD31, CD34, CD45RO, smooth muscle actin, Type IV collagen, MIB-1, bcl-2, and topoisomerase IIalpha were performed on 20 LAs and 10 cases of CPL. Giemsa staining was also performed to quantitate mast cells. Clinicopathologic correlation was performed by medical record review. LA and CPL shared a similar immunohistochemical profile for vimentin, Factor VIII-related protein, CD31, CD34, smooth muscle actin, CD34, and, to a lesser extent, CD45RO. CD31 and CD34 displayed the most uniform pattern of endothelial reactivity, although CD34 had high background staining. bcl-2 was negative. Four LAs exhibited focal low reactivity for MIB-1 and topoisomerase IIalpha; recent infection and thrombosis were associated conditions. LAs displayed seven-fold more mast cells and more reactive T lymphocytes than did cases of CPL. LA and CPL had similar immunohistochemical profiles; LA resembled vascular malformations more than hemangiomas. CD31 and CD34 were useful for detection of small lymphatics at resection margins of LA, a feature associated with recurrence. MIB-1 and topoisomerase IIalpha expression were associated with inflammatory, thrombotic, or reactive processes and were not diagnostically useful. Abundant mast cells, which also were noted in other soft tissue neoplasms, prompt speculation concerning their role in the growth of LAs.
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PMID:Lymphangioma and congenital pulmonary lymphangiectasis: a histologic, immunohistochemical, and clinicopathologic comparison. 1039 31

This study investigates differences in expression of the cell cycle/growth activation markers p53, p16, and p27, and their relationship with nerve sheath cell and proliferation markers among plexiform neurofibromas (PNF), NF1-related and non-NF1 MPNSTs of different histologic grades and between benign-appearing and malignant areas in the MPNSTs associated with PNFs. Formalin-fixed, paraffin-embedded archival tissue from PNFs and MPNSTs were immunostained using the avidin-biotin-complex method with antibodies to S-100 protein (S-100), Leu7 (CD57), CD34, p16, p27, p53, Mib-1, and topoisomerase II-alpha (TopoIIalpha), with appropriate controls. All PNFs and most low-grade MPNSTs displayed diffuse or focal reactivity for S-100, Leu7, CD34, p16, and p27 and negative reactivity for p53, Mib-1, and TopoIIalpha. Most high-grade MPNSTs displayed decreased or negative reactivity to S-100, Leu7, CD34, p16, and p27 but increased reactivity to p53 (59%), Mib-1 (72%), and TopoIIalpha (72%). In addition, combined nuclear and cytoplasmic (nucleocytoplasmic) p27 staining, which was not seen in the PNF or low-grade MPNST, was observed in 33% of high-grade MPNSTs. These findings suggest that p53, p16, and p27 may be involved in tumor progression in the PNF-MPNST sequence. However, alterations in p53, p16, and p27 do not distinguish between low-grade MPNST and PNF, including PNF adjacent to high-grade MPNST. Although p53, p16, and p27 are unlikely to be reliable markers for early detection of tumor progression in MPNST, p53 reactivity was more frequent in NF1-associated high-grade MPNST and appeared to be a marker for high tumor grade. Combining immunohistochemical stains with histologic grading with careful examination of mitotic activity may provide insight into the progression of peripheral nerve sheath tumors.
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PMID:Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions. 1450 95

The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Resistance varies. Although regulatory approval may require efficacy in as few as 20% of trial cohorts, a drug may subsequently be used in unselected patients displaying resistance to the treatment. Principal mechanisms may include altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered target enzyme (e.g. mutated topoisomerase II), decreased drug activation, increased drug degradation due to altered expression of drug-metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptose as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance mainly involve the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors and, in specific instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in abrogating or delaying onset of resistance. Gene knockout using antisense molecules may be another effective way of blocking drug resistance genes. Conversely, drug resistance may also be used to good purpose by transplanting retrovirally transformed CD34 cells expressing the MDR gene to protect the bone marrow during high-dose chemotherapy.
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PMID:Mechanisms of drug resistance in cancer chemotherapy. 1610 12

Genetic abnormalities leading to infant leukemias already occur during fetal development and often involve rearrangements of the mixed-lineage leukemia (MLL) gene. These rearrangements resemble the aberrations observed in therapy-related leukemias following treatment with topoisomerase II (topoII)-inhibiting agents such as etoposide. Since flavonoids are potent topoII inhibitors, we examined the role of three widely consumed dietary flavonoids (quercetin, genistein and kaempferol) on the development of MLL rearrangements in primary human CD34(+) cells. Using the neutral Comet assay, we demonstrated a dose-dependent double-strand break (DSB) formation after exposure to flavonoids. An incorrect repair of these DSBs resulted in chromosomal translocations that co-localized with those identified in infant leukemias. Most of these translocations were formed by microhomology-mediated end joining. Moreover, in all but one translocation, SINE/Alu or LINE/L1 repetitive elements were present in at least one side of the breakpoint junction. Beside MLL translocations, fluorescence in situ hybridization analysis demonstrated monosomy or trisomy of MLL in 8-10% of the quercetin-exposed CD34(+) cells. Our study demonstrates that biologically relevant concentrations of flavonoids can induce MLL abnormalities in primary hematopoietic progenitor cells. This is particularly alarming knowing that the differences in metabolism and excretion rate between mother and fetus can lead to a higher flavonoid concentration on the fetal side. Therefore, it is important to raise public awareness and set guidelines for marketing flavonoid supplements to reduce the risk of infant leukemias.
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PMID:Dietary flavonoids induce MLL translocations in primary human CD34+ cells. 1746 13

We report here a 73-year old female who was admitted for hematomas, dyspnea, and fever. Hematological data showed pancytopenia with 9% blast cells positive for CD13, CD33, CD34, HLAD2, and myeloperoxydase. A diagnosis of acute myeloid leukemia (AML) type 2 (FAB classification) was made. Banding cytogenetic techniques performed on bone marrow cells showed a 48,XX,+8,+9,del(9)(q22q33)x2 ,t(16;21)(q24;q22)[20]/46,XX[2] karyotype. Fluorescence in situ hybridization (FISH) with BACs covering the RUNX1 (alias AML1) (band 21q22) and MTG16 (band 16q24) gene showed a fusion of both genes. The t(16;21)(q24;q22) has been described in 16 AML cases, including ours. Eleven patients had received chemotherapy for a previous cancer, most of them were been treated with DNA-topoisomerase II inhibitors known to be associated with chromosomal translocations involving the RUNX1 gene. The significant homology between MGT16 and MTG8 suggests that the RUNX1-MTG16 fusion gene induced by the t(16;21)(q24;q22) is a variant of the RUNX1-MTG8 that shares similar activity.
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PMID:RUNX1-MTG16 fusion gene in acute myeloblastic leukemia with t(16;21)(q24;q22): case report and review of the literature. 1865 94

During development, renal stem cells reside in the nephrogenic blastema. Wilms' tumour (WT), a common childhood malignancy, is suggested to arise from the nephrogenic blastema that undergoes partial differentiation and as such is an attractive model to study renal stem cells leading to cancer initiation and maintenance. Previously we have made use of blastema-enriched WT stem-like xenografts propagated in vivo to define a 'WT-stem' signature set, which includes cell surface markers convenient for cell isolation (frizzled homolog 2 [Drosophila] - FZD2, FZD7, G-protein coupled receptor 39, activin receptor type 2B, neural cell adhesion molecule - NCAM). We show by fluorescenceactivated cell sorting analysis of sphere-forming heterogeneous primary WT cultures that most of these markers and other stem cell surface antigens (haematopoietic, CD133, CD34, c-Kit; mesenchymal, CD105, CD90, CD44; cancer, CD133, MDR1; hESC, CD24 and putative renal, cadherin 11), are expressed in WT cell sub-populations in varying levels. Of all markers, NCAM, CD133 and FZD7 were constantly detected in low-to-moderate portions likely to contain the stem cell fraction. Sorting according to FZD7 resulted in extensive cell death, while sorted NCAM and CD133 cell fractions were subjected to clonogenicity assays and quantitative RT-PCR analysis, exclusively demonstrating the NCAM fraction as highly clonogenic, overexpressing the WT 'stemness' genes and topoisomerase2A (TOP2A), a bad prognostic marker for WT. Moreover, treatment of WT cells with the topoisomerase inhibitors, Etoposide and Irinotecan resulted in down-regulation of TOP2A along with NCAM and WT1. Thus, we suggest NCAM as a marker for the WT progenitor cell population. These findings provide novel insights into the cellular hierarchy of WT, having possible implications for future therapeutic options.
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PMID:Developmental tumourigenesis: NCAM as a putative marker for the malignant renal stem/progenitor cell population. 2018 2

Infant acute lymphoblastic leukemia (ALL) involving mixed-lineage leukemia (MLL) fusions has attracted a huge interest in basic and clinical research because of its prenatal origin, mixed-lineage phenotype, dismal prognosis and extremely short latency. Over 90% of infant ALLs are pro-B ALL harboring the leukemic fusion MLL-AF4. Despite the fact that major achievements have provided a better understanding about the etiology of infant MLL-AF4+ ALL over the last two decades, key questions remain unanswered. Epidemiological and genetic studies suggest that the in utero origin of MLL rearrangements in infant leukemia may be the result of prenatal exposure to genotoxic compounds. In fact, chronic exposure of human embryonic stem cells (hESCs) to etoposide induces MLL rearrangements and makes hESC more prone to acquire subsequent chromosomal abnormalities than postnatal CD34(+) cells, linking embryonic exposure to topoisomerase II inhibitors to genomic instability and MLL rearrangements. Unfortunately, very little is known about the nature of the target cell for transformation. Neuron-glial antigen 2 expression was initially claimed to be specifically associated with MLL rearrangements and was recently shown to be readily expressed in CD34+CD38+, but not CD34+CD38- cells suggesting that progenitors rather than stem cells may be the target cell for transformation. Importantly, the recent findings showing that MLL-AF4 rearrangement is present and expressed in mesenchymal stem cells from infant patients with MLLAF4+ ALL challenged our current view of the etiology and cellular origin of this leukemia. It becomes therefore crucial to determine where the leukemia relapses come from and how the tumor-stroma relationship is defined at the molecular level. Finally, MLL-AF4 leukemogenesis has been particularly difficult to model and bona fide MLL-AF4 disease models do not exist so far. It is likely that the current disease models are missing some essential ingredients of leukemogenesis in the human embryo/fetus. We thus propose modeling MLL-AF4+ infant pro-B ALL using prenatal hESCs.
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PMID:Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement. 2113 58

Yes-associated protein 1 (YAP1), a downstream effector of the Hippo pathway, plays an important role in the development and progression of multiple malignancies, including human gastric cancer (GC). However, the clinical significance of YAP1 expression in GC needs to be comprehensively explored. Based on the pivotal role of YAP1 in the hippo pathway, we explored the clinicopathologic characteristics of YAP1 overexpression and its relationship to some tumor biomarkers in GC. Ninety cases of GC, chronic gastritis (CG) and CG with dysplasia samples were collected, and clinical data of all patients with GC were analyzed. The expression of YAP1 was assessed using immunohistochemical assay in biopsy samples. As a result, almost all the GC samples, but few CG and dysplasia samples showed YAP1 positive staining mainly in the nucleus. The expression of YAP1 was found in GC tissues with higher strong reactivity rate, compared with dysplasia and CG tissues (79.2 percent vs 47.1 percent and 15 percent, each P<0.001), and its expression level was elevated with the ascending order of GC malignancy. However, no significant correlation was found between the expression of YAP1 and epidermal growth factor receptor (EGFR) with gender, age, gross stage, degree of differentiation, tumor size, TNM staging, perineural infiltration, vascular invasion, lymphatic vessel invasion and lymph node metastases in patients with GC (each P>0.05). Furthermore, Spearman rank correlation analysis also showed no correlation of YAP1 with EGFR, Ki-67, CD34 and topoisomerase II (TOP II). Taken together, YAP1 is highly expressed in GC tissues compared with the dysplasia and CG tissues and its expression level is elevated with the ascending order of tumor malignancy; but, YAP1 expression does not correlate with the clinicopathologic characteristics and the expression of EGFR, Ki-67, CD34 and TOP II in GC.
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PMID:Clinicopathologic characteristics of YES-associated protein 1 overexpression and its relationship to tumor biomarkers in gastric cancer. 2329 88


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