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)

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation t(15;17). Recently, using molecular biology techniques, a number of laboratories have demonstrated that the gene coding for the retinoic acid receptor alpha (RARA), normally located on chromosome 17, is disrupted by the t(15;17) and fused with the PML gene on chromosome 15. The chromosome 17 breaks were mapped consistently within the second intron of the RARA gene while the chromosome 15 breaks were clustered in two limited regions within the PML gene. Molecular cloning and sequence analysis of the PML gene demonstrated a complex splicing pattern and this gene may encode a transcription factor. Different isoforms of the PML-RARA fusion transcripts were discovered which are produced as a result of distinct PML gene rearrangements. Sequence analysis of the reciprocal products of the translocation t(15;17) in some APL cases suggested the implication of topoisomerase II in mediating the DNA recombination. The RT/PCR procedure has been established to characterize the expression patterns of the PML-RARA fusion gene and to detect minimal residual disease (MRD). The biological activity of the PML-RARA fusion gene and its isoforms should be further explored.
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PMID:RARA and PML genes in acute promyelocytic leukemia. 133 47

Exposure of exponentially growing human promyelocytic of lymphocytic leukemic cells to the putative DNA topoisomerase II inhibitor fostriecin (FST), at a concentration of 1 microM, results in the suppression of their rate of progression through the S and G2 phases of the cell cycle. At concentrations between 5 microM and 0.5 mM, FST triggers endonucleolytic DNA degradation in human promyelocytic leukemia cells, resulting in apoptotic cell death; this effect is not selective for any particular phase of the cell cycle. Little or no apoptotic cell death is observed in lymphocytic leukemic cells at any FST concentration. Because FST, unlike other inhibitors of topoisomerase II, such as teniposide (TN) or amsacrine (m-AMSA), does not stabilize cleavable DNA-topoisomerase complexes, the observed differences between the effects of FST versus TN or m-AMSA on the cell cycle may provide clues regarding the role of such complexes in the kinetic effects of these inhibitors. The present results, therefore, are compared with our earlier data on the effects of TN and m-AMSA on the same cells. The only observed difference is the loss of cell cycle phase-specific triggering of DNA degradation by FST in human promyelocytic leukemia cells, compared to the S phase-specific effects of TN and m-AMSA. Therefore, stabilization of the DNA-topoisomerase cleavable complexes may be essential in the selectivity of cell kill during S phase. However, it appears that the presence of stabilized complexes is not essential to the suppression of cell progression through S or G2 or the induction of apoptotis or necrosis, in general, by topoisomerase II inhibitors.
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PMID:Cytostatic and cytotoxic effects of fostriecin on human promyelocytic HL-60 and lymphocytic MOLT-4 leukemic cells. 154 Sep 62

There is multiple evidence linking the inhibition of DNA topoisomerases I and II with the cytotoxic effects of antitumor drugs such as camptothecin and the DNA intercalators, 4-(9-acridinylamino)methanesulfon-m-anisidine) (mAMSA) and Adriamycin. We have assessed the effect of the DNA intercalator 3-nitrobenzothiazolo(3,2-a)quinolinium (NBQ) on the DNA topoisomerase I and II activities. NBQ has no effect on the activity of purified topoisomerase I, whereas it induced purified topoisomerase II binding to DNA without inducing DNA scission. Above 30 microM, NBQ stimulated formation of double- and single-strand breaks mediated by topoisomerase II in plasmid DNA. Using the alkaline elution technique we determined that NBQ induced single-strand and DNA-protein-associated breaks in the human promyelocytic leukemia cell line HL-60. At sublethal concentrations (less than or equal to 1 microM), NBQ induce HL-60 cells to differentiate. Topoisomerase II-mediated DNA cleavage induced by mAMSA was substantially reduced in NBQ-differentiated cells. Our data suggest that topoisomerase II could play a major role in the biological activity of NBQ in vivo.
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PMID:Interaction of DNA intercalator 3-nitrobenzothiazolo (3,2-a)quinolinium with DNA topoisomerases: a possible-mechanism for its biological activity. 215 51

Treatment of a human promyelocytic leukemia cell line (HL-60) with etoposide for 3-4 hrs produced an extensive degradation of DNA. Agarose gel electrophoresis showed DNA fragmentation in a nucleosomal ladder pattern. Simultaneous addition of zinc ion (ZnSO4, 1 mM) inhibited DNA fragmentation, although the amount of DNA strand breakage introduced initially by etoposide did not change significantly as measured by the DNA unwinding assay. Furthermore, zinc ion abrogated both the activation of poly(ADP-ribose) synthesis and the morphologic changes characteristic of apoptosis by etoposide. These results suggest that zinc ion inhibits a metabolic process somewhere between initial DNA cleavage through an interference with type II topoisomerase and delayed degradation of cellular DNA to a nucleosome-like pattern.
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PMID:Inhibition of both etoposide-induced DNA fragmentation and activation of poly(ADP-ribose) synthesis by zinc ion. 216 30

We report a case of therapy-related acute myeloid leukemia (t-AML), M4 FAB subtype, with t(10;11)(p14;q21) chromosome abnormality developed in a patient treated for acute promyelocytic leukemia (APL) after 4 years of continuous complete remission (CCR). Two distinct forms of t-AML have been described: the classical type and the second type. Our case has many characteristics in common with the second type of t-AML such as: exposure to topoisomerase II active agents (idarubicin (IDA), mitoxantrone (MITOX), etoposide (VP16)), M4 FAB subtype, a latency period of 39 months and absence of a preleukemic phase. However, it differs in the chromosome 11 breakpoint (band q21 instead of q23) and absence of ALL-1 (Hrx, MLL, Htrx) gene involvement. This can represent the second observation of t-AML occurring after treatment for APL.
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PMID:Therapy-related acute myelomonocytic leukemia following successful treatment for acute promyelocytic leukemia. 765 28

DNA studies of the translocation t(15;17) in acute promyelocytic leukemia (APL) have shown that the retinoic acid receptor alpha (RARA) gene on chromosome 17 is juxtaposed to the promyelocytic leukemia (PML) gene on chromosome 15. The PML breakpoints have been mapped to 3 clusters: bcr1, bcr2, and bcr3. We have examined the PML breakpoint distribution in a series of 33 Chinese patients with APL. Twenty-two patients fell within bcr1, 2 within bcr2, and 9 within bcr3. The primary structure of the reciprocal chromosome translocation joints of one patient and that of their normal counterparts have been determined and compared to those of 2 previously reported cases. These studies revealed possible topoisomerase II cleavage sites close to the breakpoints and suggested implications of DNA attachment sites to nuclear matrix. We propose that these features are relevant to the process of illegitimate recombination generating the translocation.
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PMID:Breakpoint clusters of the PML gene in acute promyelocytic leukemia: primary structure of the reciprocal products of the PML-RARA gene in a patient with t(15;17). 768 97

We performed cytogenetic studies in a patient with treatment-related acute leukemia (t-AL) to identify the associated chromosomal changes. Metaphase analysis revealed a t(3;21)(q26;q22) translocation. Acute promyelocytic leukemia (APL) had been diagnosed 4 years earlier and the patient had received intensive induction chemotherapy and sequential post-induction therapy that included agents that targeted DNA-topoisomerase II (topo II). This case suggests an association between previous therapy with topo II inhibitors and development of t-AL associated with a balanced aberration involving the 3q26 and 21q22 bands.
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PMID:Translocation (3;21)(q26;q22) in treatment-related acute leukemia secondary to acute promyelocytic leukemia. 801 66

The apoptosis-associated DNA strand breaks were detected in situ, in individual leukemic cells in peripheral blood and bone marrow of over 110 patients with different types of leukemia (ALL, AML, CML in blastic crisis, APL), prior to and during routine chemotherapy. The DNA strand breaks were labeled with digoxigenin- or biotin-conjugated dUTP in the reaction catalyzed by exogenous terminal deoxynucleotidyl transferase, and the cells, counterstained for DNA, were analyzed by bivariate flow cytometry. The proportion of cells with DNA strand breaks prior to therapy, most likely reflecting spontaneous apoptosis, varied from 0.1 to 16%, but in the large majority of cases was below 3%. Administration of drugs of different classes, which included DNA topoisomerase I (Topotecan) and II (mitoxantrone, VP-16) inhibitors, antimetabolite (ara-C) or microtubule poison (Taxol), all triggered the appearance of cells with extensive DNA breakage, typical of apoptosis, to up to 80%. The peak of the response, measured as maximal percent of cells with DNA strand breaks, which varied between individual patients by as much as factor 10, was generally seen between 8 to 24 h after the initial administration of DNA topoisomerase inhibitors, and somewhat later (48-72 h) during the response to Taxol or ara-C. Thus, the data show that the response to treatment with a variety of drugs, in terms of induction of apoptosis, can be conveniently measured by the present method. The prognostic value of the apoptotic index, before, as well as during treatment, is being estimated for each type of leukemia, in the ongoing prospective studies.
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PMID:Apoptotic cell death during treatment of leukemias. 807 83

Molecular studies of chromosomal translocation (15;17) in acute promyelocytic leukemia (APL) have shown that retinoic acid receptor A (RARA) gene on chromosome 17 is juxtaposed to the PML gene on chromosome 15. This results in a PML-RARA chimeric gene. Our work has demonstrated that the PML breakpoints in APL patients are clustered in two limited regions, PML-bcr1 and PML-bcr2, separated from each other by about 10 kb. DNA sequence of PML-bcr1 and primary structure of the junctional region of reciprocal chromosomal translocation in a patient have been determined in this paper. Compared to those of two previously reported cases abroad, we found that the breakpoint may be situated in the topoisomerase II cleavage site. A working model has been proposed for the mechanism of DNA illegitimate recombination in t (15;17).
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PMID:[Molecular study of the mechanism of chromosomal translocation (15;17) in acute promyelocytic leukemia (APL)]. 816 69

We have investigated the effect of mAMSA, a potent topoisomerase II inhibitor, on the c-myc proto-oncogene of the acute promyelocytic leukemia HL60 cell line during its differentiation. When HL60 cells were induced by dimethylsulfoxide (DMSO) to terminally differentiate, a rapid drop in the level of c-myc mRNA was observed, followed by an arrest of cell proliferation. In contrast, the level of topoisomerase II mRNA was transiently increased with a maximum at 6 h after DMSO addition and was then completely abolished after 48 h, indicating that topoisomerase II is activated during the onset of HL60 differentiation. In exponentially growing cells, treatment by mAMSA results in the formation of topoisomerase II-mediated double strand DNA breaks in the c-myc gene at positions where topoisomerase II would normally nick and reseal the two strands. In HL60 cells treated with both mAMSA and DMSO, the sites in the c-myc gene at which mAMSA had induced cleavage were not altered. However, a DNA cleavage site located at the end of the first c-myc exon (position +3100), was strongly stimulated by mAMSA and DMSO treatment. This site fell within a DNase I hypersensitive region encompassing the MYC intron factor 1 (MIF1) binding site, where transcription elongation is normally blocked during differentiation. These data indicate that a change of topoisomerase II binding to critical regulatory region of the c-myc gene is associated with the downregulation of this gene during differentiation.
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PMID:Analysis of topoisomerase II-mediated DNA cleavage of the c-myc gene during HL60 differentiation. 824 49


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