Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rearrangements of the MLL (Mixed Lineage Leukemia) gene in the human 11q23 cytogenetic locus have been detected in secondary (therapy-related) acute leukemias in patients who have received topoisomerase II inhibitors for prior, independent neoplasms. The topoisomerase II inhibitors implicated in MLL/11q23 secondary leukemias all inhibit the religation step of reaction catalyzed by topoisomerase II. This results in the stabilization of a 'cleavable complex' with double-strand DNA breaks at the point of topoisomerase II binding. This raises the possibility that the cleavable complex participates in the translocation process in MLL/11q23 secondary leukemias. Here we report that the MLL/11q23 breakpoints in 13/13 patients with secondary leukemia map to the same breakpoint cluster region (bcr) noted in de novo MLL/11q23 acute leukemias and the presence of in vivo topoisomerase II inhibitor-induced cleavage sites in MLL/11q23 bcr. We have also cloned and sequenced the breakpoint from a MLL/11q23 secondary acute leukemia. This analysis revealed sequences similar to the consensus sequence for vertebrate topoisomerase II binding and cleavage close to the 11q23 and 4q21 breakpoints. These results support a role for topoisomerase II in mechanism generating translocations in MLL/11q23 secondary acute leukemia.
Leukemia 1995 Aug
PMID:Molecular analysis of 13 cases of MLL/11q23 secondary acute leukemia and identification of topoisomerase II consensus-binding sequences near the chromosomal breakpoint of a secondary leukemia with the t(4;11). 764 17

Treatment of HL-60 with phorbol myristate acetate (PMA) for 30 min, or all-trans retinoic acid (RA) for 60 min, results in hyperphosphorylation (3-5x) of topoisomerase II (p170, topo II) in vivo. RA and PMA activate a coprecipitating kinase, respectively inducing 1.6 and 2.7-fold increases in phosphorylation of topo II in immunoprecipitates. The activity of the co-precipitating kinase is inhibited by heparin and unlabelled GTP suggesting that casein kinase II (CKII) is, at least in part, responsible for the topo II hyperphosphorylation in response to differentiation signals. Although following dephosphorylation of the enzyme with alkaline phosphatase there was virtual abrogation of activity, the differentiation associated hyperphosphorylation had little impact on the decatenation activity of topo II in nuclear extracts. There were, however detectable changes in topo II function in vivo which affected the formation of the etoposide stabilised cleavable complex, but only after PMA treatment. PMA resulted in a rapid reduction in etoposide induced cleavage, 30 min treatment with PMA reducing cleavage by 20%. However, treatment with RA for 1 or 2 h when hyperphosphorylation was maximal did not affect cleavage. Immunoband depletion assays suggested that differentiation associated changes in chromatin structure rather than alterations in the enzyme per se are responsible for the reduction in cleavable complex formation following PMA treatment. Etoposide cytotoxicity was significantly reduced following just 30 min PMA treatment, but not reduced and even possibly enhanced by retinoic acid treatment. These findings are relevant not only to the dissection of the role of topo II in differentiation but also to its exploitation as a therapeutic target.
Leukemia 1995 Aug
PMID:Retinoic acid and phorbol ester induced hyperphosphorylation of topoisomerase II-alpha is an early event in HL-60 human leukaemia cell differentiation: effect on topoisomerase activity and etoposide sensitivity. 764 27

We describe the occurrence of a variant Ph chromosome (v-Ph) in a therapy-related acute leukemia (s-AL), developed after 8-year treatment for a NHL with alkylating agents, anthracyclines and topoisomerase II inhibitors. The v-Ph originated from a complex t(2;9;22) translocation, expressed a p190bcr-abl fusion protein, and was associated to other specific changes, such as dup(3) (q21q26) and -7. The s-AL, apparently not preceded by a dysplastic phase, presented with signs of trilineage dysplasia with 10% micromegakaryocytes; it was classified as M5 according to FAB. The complex genetic changes observed in the present case may reflect distinct leukemogenic effects by different chemotherapeutic agents.
Leukemia 1995 Sep
PMID:Acute leukemia presenting a variant Ph chromosome with p190 expression, dup 3q and -7, developed after malignant lymphoma treated with alkylating agents and topoisomerase II inhibitors. 765 16

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.
Leukemia 1995 Sep
PMID:Therapy-related acute myelomonocytic leukemia following successful treatment for acute promyelocytic leukemia. 765 28

A growth factor-dependent cell line (TF-1) was treated with interleukin-3 (IL-3) or medium in combination with variable doses of VP-16 to test whether the latter's cytotoxicity can be modulated by IL-3. The results demonstrated that an augmented cell death occurred with TF-1 cells when pre-incubated for 24 h with IL-3 followed by treatment with VP-16 (10 micrograms/ml) for 1 h. The increased cell death could not be ascribed to an increased number of apoptotic cells as measured with the acridine orange method. However, the IL-3 treatment coincided with an upregulation of DNA topoisomerase II alpha (Topo II alpha) at mRNA and protein level after 24 h, which was preceded by an upregulation of c-myc mRNA. In contrast, Topo II beta did not demonstrate an upregulation at mRNA level in response to IL-3 stimulation. In addition, it was shown that cells treated with IL-3 followed by VP-16 demonstrated a higher number of cleavable DNA complexes which was not due to an increased uptake of VP-16, since cellular concentrations of VP-16 in the presence of IL-3 or medium were 16.8 +/- 7.8 ng/10(6) cells and 19.8 +/- 7.8 ng/10(6) cells (mean +/- SD, n = 3), respectively. These data indicate that IL-3 pretreatment followed by VP-16 results in an increased cell death due to cytotoxicity which may be ascribed to an upregulation of Topo II alpha.
Leukemia 1994 Dec
PMID:VP-16-mediated cytotoxicity is modulated by interleukin-3 in a growth factor-dependent leukemic cell line. 780 95

Leukemias with abnormalities in chromosome 11q23 occur frequently after exposure to topoisomerase II-reactive drugs. We investigated the characteristics and outcome of patients with de novo or secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) with abnormalities in chromosome 11q. Sixty-one patients had 11q abnormalities. Alterations involved 11q23 in 38 patients and other 11q abnormalities in 23. Sixteen patients had secondary disease, 12 involving 11q23, and four with other 11q abnormalities; 26 patients with de novo disease had 11q23 abnormalities and 19 other 11q abnormalities. The most common 11q23 abnormality was t(9;11), significantly more common in secondary (9/12) than in de novo (6/26) leukemias (p = 0.003). There were no significant differences in clinical characteristics between de novo and secondary groups involving 11q23. Five of 12 patients (42%) with secondary and 20/26 (77%) with de novo disease achieved complete remission (p = 0.05). Median survival was 6 weeks in the secondary group and 71 weeks in the de novo group (p = 0.001). There were no long-term survivors in either group. Results are similar when other 11q abnormalities are included. Adults with AML or MDS with 11q abnormalities secondary to prior chemotherapy have a worse prognosis than patients presenting de novo. However, 11q abnormalities define a population with a poor prognosis even when presenting de novo.
Leukemia 1994 Dec
PMID:Abnormalities in the long arm of chromosome 11 (11q) in patients with de novo and secondary acute myelogenous leukemias and myelodysplastic syndromes. 780 7

We used a recently established stroma-supported tissue culture technique that allows long-term culture of acute lymphoblastic leukemia (ALL) cells to study 2-chloro-2'-deoxyadenosine (2CdA) cytotoxicity to leukemic lymphoblasts. In the 20 cases of ALL studied, the number of cells recovered after 7 days of culture on allogeneic stromal layers were 58-192% (median, 95.5%) of those originally seeded. In parallel cultures with 2CdA (100 nM), 74- > 99% (median, 97.5%) of leukemic lymphoblasts were killed. The cytotoxicity of 2CdA extended to all ten samples with either the t(9;22) (q34;q11) or 11q23 chromosomal abnormalities, karyotypes associated with an extremely poor outcome, as well as to two samples collected at the time of relapse. The effects of 2CdA were dose-dependent, and were due to triggering of apoptosis as shown by typical morphologic changes and occurrence of DNA fragmentation. Stromal layers were apparently not affected by 2CdA treatment, even when used at 1000 nM. We also tested 2CdA cytotoxicity to multidrug resistant subclones of the CCRF-CEM ALL cell line. CEM/VLB100 expresses P-glycoprotein, whereas CEM/VM-1 and CEM/VM-1-5 have topoisomerase II mutations that are associated with resistance to topoisomerase II inhibitors. Overexpression of P-glycoprotein or alterations in topoisomerase II did not protect cells from 2CdA cytotoxicity. We conclude that 2CdA is cytotoxic in most cases of ALL. The method used in this study may be applied to evaluate leukemic blast cell sensitivity to compounds with potential anti-leukemic activity, and to select patients for entry into clinical trials.
Leukemia 1994 Jul
PMID:Use of stroma-supported cultures of leukemic cells to assess antileukemic drugs. II. Potent cytotoxicity of 2-chloro-deoxyadenosine in acute lymphoblastic leukemia. 791 12

The treatment of acute myeloid leukaemia (AML) is often complicated by resistance to chemotherapeutic drugs. Many of the most effective drugs used to treat haematological malignancies target the nuclear enzyme topoisomerase II. Resistance to these drugs in vitro has been associated with quantitative and qualitative changes in the enzyme. In this study, we have investigated topoisomerase II mRNA expression in leukaemic blasts from 23 AML patients. Expression levels ranged from 1-47% relative to the haemopoietic cell line HL60 in 16 evaluable patients. Thirteen of 16 patients achieved complete remission (CR). We have therefore chosen ease of entry into CR as the most sensitive clinical correlate. Decreased topoisomerase II mRNA expression in vitro results in drug resistance. The clinical relevance of reduced expression is not known. All cases of AML and de novo AML have been studied separately. We are unable to identify a correlation between topoisomerase II mRNA levels and ease of entry into CR in either of these groups. Taking these findings into account, group size calculations have been undertaken and indicate that a multi-centre study of this question is warranted.
Leukemia 1994 Sep
PMID:Topoisomerase II alpha expression in acute myeloid leukaemia and its relationship to clinical outcome. 809 29

Rearrangements involving chromosome band 11q23 are very common in acute leukemia, both lymphoblastic and myeloid (monoblastic), and are less common in lymphoma. Although several different genes have been cloned from 11q23 translocation breakpoints, the great majority involve the MLL (myeloid-lymphoid leukemia) gene. The MLL gene has several different names, ALL1, Htrx, HRX; the central part of the gene codes for multiple zinc fingers which show strong homology to the Drosophila trithorax gene. MLL is involved in four common translocations as well as in 25 uncommon or rare translocations, insertions and deletions. The translocation breakpoints occur within an 8.3kb region which can be detected with a 0.7 kb cDNA probe. Twenty-five percent of patients have a deletion 3' of the breakpoint which includes the zinc finger region. Patients who previously received drugs that inhibit topoisomerase II often develop acute leukemia with translocations involving 11q23. These translocations break MLL in the same 8.3kb region. In the four breakpoints cloned to date, the translocation has led to a fusion gene on the derivative 11 chromosome with a chimeric transcript, consisting of 5' MLL and the 3' segment of the other gene. Although transcripts were also cloned from the other derivative chromosome, all the evidence indicates that the critical fusion gene is on the derivative 11 chromosome. The molecular dissection of these rearrangements will provide insights into the biology of MLL and into the interaction of MLL with topoisomerase II inhibitors. In addition, this research has provided DNA probes that will be important for diagnosis and for monitoring patients during the course of their disease.
Leukemia 1994 Apr
PMID:1993 Robert R. deVilliers Lecture. Chromosome translocations: dangerous liaisons. 815 72

Apoptotic cell death is physiological. Malignant cells often escape programmed cell death. Many genes that promote (p53) or antagonize (bcl-2, fes) apoptosis have been recognized. Apoptosis promoter genes can be activated by growth factor or hormone withdrawal in growth factor- or hormone-dependent tumor cells. Malignant cells acquiring apoptosis-resistance, still can be killed by cytotoxic lymphocytes releasing lymphotoxins. This phenomenon gives further support to the therapeutic use of activated and expanded lymphocyte populations and/or apoptosis-inducing cytokines. Chemotherapeutic agents (esp. topoisomerase inhibitors) frequently kill tumor cells by activating programmed cell death (PCD). Biologicals and chemotherapeutics may synergize in evoking apoptosis. We propose the cloning of apoptotic genes and their transfer by transfection in vivo into tumor cells. While transfection of genes into tumor cells in vitro is widely practiced, the lack of proper technology for transfection in vivo and the unknown aspects of apoptotic cell death are recognized.
Leukemia 1994 Apr
PMID:Apoptosis by genetic engineering. 815 15


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