Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report 4 additional cases of therapy-related acute myelogenous leukemia (t-AML) with the translocation t(9;11)(p22q23). Chemotherapy for the primary malignancy (breast carcinoma in 2, non-Hodgkin's lymphoma in 2) included agents with topoisomerase II inhibitory activity (doxorubicin in 2; doxorubicin and etoposide in 1; doxorubicin, etoposide and mitoxantrone in 1) as well as alkylators. In agreement with previous reports, the leukemia was monoblastic (FAB M5 subtype) in all 4 patients, with only 1 having prior myelodysplasia, and the latency period from primary therapy was relatively short (24-48 months). All patients received potentially curative treatment for the leukemia which included allogeneic bone marrow transplantation in 3; however, all died (3 of t-AML and 1 of lymphoma). Therapy-related AML associated with exposure to agents with topoisomerase II inhibitory activity (epipodophyllotoxins and anthracyclines) is a distinct entity, the genetic basis and optimal treatment of which remain to be determined.
Leuk Lymphoma 1993 Sep
PMID:Therapy-related acute myelogenous leukemia associated with 11q23 chromosomal abnormalities and topoisomerase II inhibitors: report of four additional cases and brief commentary. 822 Jan 47

Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II-reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.
 ...
PMID:Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II. 826 Jul 7

We have studied the functional properties of topoisomerase II (Topo II) in a subclone of the HL-60 cell line, which is highly resistant to cytotoxic Topo II inhibitors, but does not express p-glycoprotein. The cells contain the two forms of human topo II with Mr 170 and 180 kDa in equal proportions. Two different states of both forms of the enzymes can be separated by anion-exchange chromatography and functionally discriminated on the basis of orthovanadate sensitivity. The EC50 of orthovanadate was 0.2 microM for the early eluting and 30 microM for the late eluting Topo II.
Leuk Lymphoma 1993 Mar
PMID:Different functional states of topoisomerase II can be discriminated by orthovanadate sensitivity in multi-drug resistant human leukemic cells. 839 70

DNA topoisomerase-targeting antitumor drugs are potent inducers of protein-concealed strand breaks in mammalian cells and act by trapping DNA topoisomerases on chromosomal DNA in the form of drug-enzyme-DNA cleavable complexes. It has been proposed that the cleavable complex is an unusual form of DNA damage that elicits cellular responses analogous to those caused by DNA damaging agents. The relationship between topoisomerase-targeting drug-induced damage and radiation-induced damage has been investigated by analyzing the properties of DNA topoisomerases in mouse L5178Y lymphoma strains that are cross-sensitive to topoisomerase I-II inhibitors and to UV light or X-ray irradiation. The strains are LY-R, isolated from L5178Y cells on the basis of increased resistance to ionizing radiation, and strain LY-S, isolated from LY-R cells following a spontaneous increase in the sensitivity to ionizing radiation. LY-S cells, deficient in the rejoining of DNA double-strand breaks, show enhanced sensitivity to topoisomerase II-targeting inhibitors, whereas LY-R cells have an increased sensitivity to UV radiation and to the topoisomerase I inhibitor, camptothecin. The cellular availability of DNA topoisomerase I and II and the sensitivity of the enzymes to their specific inhibitors have been measured in the two related strains. In the LY-R strain, we found a 30% decrease in topoisomerase I content but no difference in camptothecin sensitivity, while no quantitative or qualitative differences were observed for the topoisomerase II. The results indicate that variations in sensitivity of the L5178Y strains to topoisomerase inhibitors are unlikely to be related to primary defects of the target enzymes, and thus it is possible that common pathways exist for processing of topoisomerase- and radiation-induced damage.
 ...
PMID:The sensitivity to DNA topoisomerase inhibitors in L5178Y lymphoma strains is not related to a primary defect of DNA topoisomerases. 840 96

After failing to exhibit benefits in clinical studies with cancer patients in the early 1970s, camptothecin (CPT) and its water-insoluble analogues are re-emerging as promising drugs with multiple actions in the treatment of human haematological malignancies. CPT analogues interfere with the mechanism of action of the nuclear enzyme topoisomerase I, while the cells progress through the S-phase of the cell cycle and this results in cell death by apoptosis. Modulations of topoisomerase I phosphorylation may indirectly modulate the cytotoxic activity of CPT analogues. In vitro, CPT analogues have exhibited increased or unaltered killing activity against leukaemia cells resistant to epipodophyllotoxins, anthracyclines, anthracenediones, and Vinca alkaloids, while development of resistance to CPT analogues renders leukaemia and lymphoma cells more sensitive to topoisomerase II-directed drugs, inducers of cell differentiation, and immunotoxins. Oral administration of the CPT analogues has circumvented the inconvenience of solubility of these drugs. Metabolic conversion of the CPT analogue 9-nitro-CPT to equally or more potent 9-amino-CPT practically makes unnecessary treatment of the patient with 9-amino-CPT, which, in addition, is costlier to prepare than 9-nitro-CPT. Considering the therapeutic, economic and handling viewpoints, the overall conclusion is that the water-insoluble CPT analogues are very promising antileukaemia/antilymphoma agents that warrant further preclinical and clinical studies.
 ...
PMID:The water-insoluble camptothecin analogues: promising drugs for the effective treatment of haematological malignancies. 855 94

The cytotoxic effect of etoposide (ETO), a topoisomerase II inhibitor, and staurosporine (STA), a non-selective protein kinase inhibitor, were studied on a human lymphoma cell line of B-cell origin (HT58). Apoptosis, induced dose dependently by both drugs, was accompanied with nucleosomal DNA fragmentation detected by flow cytometry. On the other hand, induction of cell death failed using phorbol ester (PMA), anti-IgM antibody (a-IgM) or dexamethasone (DEX), although, all of these agents arrested the cells in G1. Furthermore, PMA pretreatment retarded ETO-induced apoptosis, but enhanced STA cytotoxicity. DEX increased the sensitivity of cells to STA, but did not to ETO. Activity of STA or DEX was only slightly modified by a-IgM pretreatment. The results support the possibility that different apoptotic pathways exist in HT58 cells. The differences in pathways could be manifested either in the signaling routes, or in the molecular effectors of apoptosis.
 ...
PMID:Modulation of drug-induced apoptosis in a human B-lymphoma cell line (HT58). 884 85

Even though folate antimetabolites were introduced over forty years ago, they continue to be the backbone of many active chemotherapeutic regimens used by medical and pediatric oncologists. The recognition of polyglutamylation by folylpolyglutamate synthetase (FPGS) as an important metabolic step in the "activation" of classical antifolates and novel drugs aimed at thymidylate synthase (TS) and de novo purine synthesis, has resulted in renewed interest in this class of drugs. In addition, the emergence of secondary neoplasms in patients treated with alkylating agents and topoisomerase inhibitors in contrast to the exceptional safety record of antimetabolites, underscores the need for clinical trials that incorporate new strategies with known active antimetabolites and novel promising agents. In that context, FPGS is an important target for further laboratory and clinical investigations.
Leuk Lymphoma 1996 Mar
PMID:Role of folylpolygutamate synthetase (FPGS) in antifolate chemotherapy; a biochemical and clinical update. 890 63

Etoposide is a topoisomerase II inhibitor that induces DNA cleavable complex and has been used as an antitumor drug. We isolated two genes that were transcriptionally suppressed at an early stage of incubation in etoposide-treated RVC lymphoma cells, using modified PCR-based subtractive hybridization. Sequencing revealed that one of these genes, which was approximately 1.7 kb and which encoded a protein of 320 amino acids, was identical to hnRNP A1. The other was a novel gene of about 2.2 kb encoding a protein of 469 amino acids. These genes were also down-regulated in the cells incubated with camptothecin, a topoisomerase I inhibitor that induces DNA single strand breaks, but not in those exposed to ICRF-154, a topoisomerase II inhibitor that does not induce DNA cleavable complex formation. These results suggest that the early down-regulation of these genes contributes to the cytotoxicity of the topoisomerase inhibitors that induce DNA cleavage.
 ...
PMID:Molecular cloning of the genes suppressed in RVC lymphoma cells by topoisomerase inhibitors. 891 29

A feasibility study was carried out on the treatment for refractory and relapsed non-Hodgkin's lymphomas with a combination of two oral topoisomerase II inhibitors, MST-16 and VP-16. On the basis of the synergistic activity in preclinical studies and the schedule dependency in these drugs, low-dose and long-term administration was planned. For the anticipated myelosuppression, two different regimens were designed as an open label trial in this study. In Regimen I, 400 mg of MST-16 combined with 25 mg of VP-16 was administered daily. With this regimen, the response rate (RR)/median time to tumor progression (TTP) in all evaluable patients was 50% (2/4)8.5 months in low grade (indolent) lymphoma and 60% (6/10)/5.2 months in intermediate/high grade (aggressive) lymphomas. In Regimen II, 400 mg of MST-16 combined with 25 mg of VP-16 was administered intermittently (3 days a week or every other day). With this regimen, there was an RR/median TTP of 60% (3/5)/7.0 months in indolent lymphoma and 33.3% (4/12)/1.1 months in aggressive lymphoma. A major side effect in both of these regimens was myelosuppression, with the incidence of grades 3 and 4 toxicity being higher in Regimen I than in Regimen II. The other side effects were uncommon and not severe. These findings indicated that two regimens were tolerated well and were promising for refractory and relapsed aggressive non-Hodgkin's lymphomas. To define the anti-tumor activity and safety of these regimens precisely, large-scale prospective randomized trials are necessary.
 ...
PMID:Feasibility of salvage chemotherapy for refractory or relapsed non-Hodgkin's lymphoma with two topoisomerase II inhibitors, MST-16 and VP-16. MST-16 Study Group. 892 84

1,8-Dihydroxyanthraquinones are under debate as plant-derived carcinogens that are found in laxatives, food colors, and possibly vegetables. Published genotoxicity data are controversial, and so three of them (emodin, danthron and aloe-emodin) were tested in a number of in vitro assay systems. All three compounds induced tk-mutations in mouse lymphoma L5178Y cells. Induction of micronuclei also occurred in the same cell line, and was dose-dependent, with the potency ranking being danthron > aloe-emodin > emodin. In a DNA decatenation assay with a network of mitochondrial DNA of C. fasciulata, all three test compounds inhibited the topoisomerase II-mediated decatenation. Danthron and aloe-emodin, but not emodin, increased the fraction of DNA moving into comet tails when tested at concentrations around 50 microM in single-cell gel-electrophoresis assays (SCGE; comet assay). Comet assays were also used in modified form to determine whether pretreatment of the cells with the test compounds would reduce the effects of etoposide, a potent topoisomerase II inhibitor. All three test chemicals were effective in this pretreatment protocol, with danthron again being the most potent. Given clearcut evidence of their genotoxic activity, further research on the human cancer risk of these compounds may be warranted.
 ...
PMID:Genotoxicity of the laxative drug components emodin, aloe-emodin and danthron in mammalian cells: topoisomerase II mediated? 900 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>