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)

Mitoxantrone, an anthracenedione derivative, has been used for preclinical and clinical studies from the end of the 1970s. Several working mechanisms are suggested such as intercalation and electrostatic interactions with DNA with or without involvement of topoisomerase II, immunosuppressive effects and inhibition of prostacyclin synthesis. Efficacy of mitoxantrone alone or in combination with other chemotherapeutic drugs has been especially demonstrated in patients with breast cancer, leukemia and lymphoma. Locoregional (but not intrathecal) therapy with this drug is possible because it is not a vesicant. It has an improved tolerability profile compared with doxorubicin. Dose-limiting toxicity is myelotoxicity and mucositis. Therefore this drug has recently also been used in high doses with bone marrow support and in combination with hematopoietic growth factors. Cardiotoxicity is less frequent than after doxorubicin and daunorubicin. However, cardiac function tests are warranted after cumulative doses greater than 160 mg/m2 or earlier if additional risk factors, namely previous mediastinal irradiation, anthracycline therapy or cardiovascular disease, are present.
Anticancer Drugs 1990 Dec
PMID:Mitoxantrone: bluebeard for malignancies. 215 49

We studied DNA repair by injecting plasmids containing random pyrimidine dimers into Xenopus oocytes. We demonstrated excision repair by recovering plasmids and analyzing them with T4 UV endonuclease treatment and alkaline agarose gel electrophoresis. The mechanism for excision repair of these plasmids appears to be processive, rather than distributive, since repair occurs in 'all or none' fashion. At less than 4-5 dimers/plasmid, nearly all repair occurs within 4-6 hours (approximately 10(10) dimers repaired per oocyte); the oocyte, therefore, has abundant repair activity. Specific antibodies and inhibitors were used to determine enzymes involved in repair. We conclude that DNA polymerase alpha (and/or delta) is required because repair is inhibited by antibodies to human DNA polymerase alpha, as well as by aphidicolin, an inhibitor of polymerases alpha (and/or delta). Repair was not inhibited by hydroxyurea, cytosine beta-D-arabinofuranoside, or inhibitors of topoisomerase II (novobiocin). Oocyte repair does not activate semi-conservative DNA replication, nor is protein synthesis required. Photoreactivation cannot account for repair because dimer removal is independent of exogenous light.
Nucleic Acids Res 1990 Dec 25
PMID:Excision repair of UV-damaged plasmid DNA in Xenopus oocytes is mediated by DNA polymerase alpha (and/or delta). 217 36

Cultured rat mesangial cells contain high affinity endothelin (ET) receptors at high densities. Exposure of these cells to ET resulted in a transient activation of topoisomerase I extractable activity, which reached its maximum value at approximately 2 min and returned to basal value after approximately 10 min of treatment. The activation of this enzyme was dependent upon the concentration of ET added. Incubation of the cells with pertussis toxin inhibited ET-induced increases in topoisomerase I activity in a concentration-dependent manner, suggesting that involvement of pertussis toxin-sensitive GTP-binding protein in ET-mediated action. Endothelin had no detectable effect upon extractable topoisomerase II activity.
FEBS Lett 1990 Dec 10
PMID:Inhibition of endothelin-mediated topoisomerase I activation by pertussis toxin. 217 62

Exposure of infected CV-1 cells to specific type I and type II topoisomerase poisons caused strong protein association with distinct subsets of simian virus 40 (SV40) DNA replication intermediates. On the basis of the known specificity and mechanisms of action of these drugs, the proteins involved are assumed to be the respective topoisomerases. Camptothecin, a topoisomerase I poison, caused strong protein association with form II (relaxed circular) and form III (linear) viral genomes and replication intermediates having broken DNA replication forks but not with form I (superhelical) viral DNA or normal late replication intermediates which were present. In contrast, type II topoisomerase poisons caused completely replicated forms and late viral replication forms to be tightly bound to protein--some to a greater extent than others. Different type II topoisomerase inhibitors caused distinctive patterns of protein association with the replication intermediates present. Both intercalating and nonintercalating type II topoisomerase poisons caused a small amount of form I (superhelical) SV40 DNA to be protein-associated in vivo. The protein complex with form I viral DNA was entirely drug-dependent and strong, but apparently noncovalent. The protein associated with form I DNA may represent a drug-stabilized "topological complex" between type II topoisomerase and SV40 DNA.
Biochemistry 1990 Dec 11
PMID:Patterns of strongly protein-associated simian virus 40 DNA replication intermediates resulting from exposures to specific topoisomerase poisons. 217 89

Interaction between tumor necrosis factor (TNF) and the DNA topoisomerase II inhibitor, etoposide VP-16, in cell killing has been studied. To accurately investigate the nature of DNA damage during the cell killing process, experiments were assessed using the highly TNF-sensitive WEHI164.13 murine fibrosarcoma clone and DNA filter elution methodology. Concomitant treatment of cells with combination of TNF/VP-16 resulted in marked enhancement of cell lysis. Using the alkaline elution technique, we show that TNF fails to induce DNA single-strand breaks as compared to those generated by VP-16. In addition, the potentiating effect of VP-16 on TNF-mediated WEHI164.13 cell killing was not associated with an increase in its intrinsic activity with respect to DNA single-strand break formation. While the 2 phospholipase A2 inhibitors, quinacrine and dexamethasone, were efficient in inhibiting TNF-mediated cell lysis, only quinacrine was efficient in selectively abrogating the TNF/VP-16 cell killing pathway. The inhibitory effect of quinacrine on VP-16/TNF-mediated cell lysis was accompanied by a marked decrease in VP-16-mediated DNA single-strand break generation. Taken together, our findings suggest that TNF and TNF/VP-16 treatments may involve different events during cell killing and support the hypothesis that 2 signals are required for optimal induction of cell lysis by the combination of VP-16/TNF: one signal provided by VP-16 resulting in topoisomerase II inhibition and subsequent DNA single-strand break generation, and a second signal involving TNF.
Int J Cancer 1990 Dec 15
PMID:Potentiation of TNF-mediated cell killing by VP-16: relationship to DNA single-strand break formation. 224 91

Recent progress in the understanding of drug resistance has led to the discovery of new targets for chemotherapy. By attacking the molecules that make cancer cells insensitive to chemotherapy, it is hoped that drug-resistant disease will respond to treatment. This review describes some of the latest advances in understanding of the biochemistry of drug resistance. Following a general introduction four areas of topical interest are discussed: (1) multidrug resistance and P-glycoprotein, (2) glutathione and its related enzymes, (3) topoisomerase II and (4) DNA repair.
Radiother Oncol 1990 Dec
PMID:Biochemical basis of resistance to chemotherapy. 228 41

Purified type I topoisomerase from calf thymus as well as nuclear and cytoplasmic extracts from EGF-stimulated human and mouse fibroblasts in cell culture efficiently convert supercoiled plasmid DNA to the relaxed form. The purified IgG fraction from the sera of Japanese patients with the rheumatic disease scleroderma were shown to inhibit this relaxation activity. Thus, these patients likely produce autoantibodies to topoisomerase I. In addition, the human, bovine and murine enzymes share antigenic determinants recognized by the antisera.
FEBS Lett 1986 Dec 15
PMID:Inhibition of topoisomerase I by antibodies in sera from scleroderma patients. 243 27

We have identified DNA fragments which bind specifically to the nuclear matrix in vitro, termed matrix association regions (MARs), in the first and fourth introns of rat alpha 2-macroglobulin gene. The MAR in the first intron is enriched with sequences closely related to the cleavage consensus of topoisomerase II, and contains the binding site of nuclear factor-alpha, a sequence-specific DNA binding protein reported previously.
Biochem Biophys Res Commun 1987 Dec 16
PMID:Nuclear matrix association regions of rat alpha 2-macroglobulin gene. 244 78

xrs-1 is an ionizing radiation sensitive Chinese hamster ovary (CHO) strain and has a defect in double strand break rejoining. It is also highly sensitive to topoisomerase II inhibiting anticancer drugs. Sensitivity is specific for those drugs that inhibit the breakage/reunion mechanism of topoisomerase II. xrs-1 and its parent strain CHO-K1 have equal levels of topoisomerase II activity, assayed by their ability to unknot complex knotted P4 head DNA. Drug stimulated protein-DNA complex formation was similar in xrs-1 and CHO-K1, showing that they accrued equal levels of drug induced lesions. Thus sensitivity most likely results from subsequent differences in the processing of these lesions rather than the rate of formation. Drug sensitivity is directly related to the xrs phenotype since drug and gamma-ray resistance are coordinately reactivated by azacytidine treatment. All six members of the xrs complementation group are hypersensitive to etoposide. Sensitivity is not a feature common to all X-ray sensitive mutants but is shown by another complementation group, which also has a defect in double strand break rejoining. These results thus demonstrate a correlation between an inability to rejoin double strand breaks and sensitivity to topoisomerase II targeting antitumor drugs.
Cancer Res 1989 Dec 15
PMID:Sensitivity of Chinese hamster ovary mutants defective in DNA double strand break repair to topoisomerase II inhibitors. 247 75

Previous studies have shown that DNA topoisomerase II enzyme activity and protein levels are reduced in cloned lines of Adriamycin-resistant P388 leukemia cells relative to drug-sensitive cells (Deffie et al., Cancer Res., 49: 58-62, 1989). The molecular basis of the reduced topoisomerase II levels in these resistant cells has been investigated. Northern blot analysis of total cellular RNA from drug-sensitive and -resistant cells using a 1.8-kilobase human topoisomerase II complementary DNA revealed the presence of two mRNA species: a 6.6-kilobase transcript that was strongly expressed in drug-sensitive cells but reduced 7- to 8-fold in resistant cells; and a 5.5-kilobase transcript detected only in drug-resistant cells. Southern blot analysis of genomic DNA digested with BamHI, StuI, or PvuII and probed with the 1.8-kilobase complementary DNA for human topoisomerase II showed that, in Adriamycin-resistant cells, there were two different alleles for topoisomerase II, one identical to the native allele but with a lower gene copy number than that found in sensitive cells, and a second allele containing a mutation present only in resistant cells. These findings suggest that the reduced levels of topo II protein in drug-resistant cells may be due to reduced amounts of the native 6.6-kilobase mRNA. The unique 5.5-kilobase mRNA in resistant cells may represent a shortened transcript of the mutated topoisomerase II allele.
Cancer Res 1989 Dec 15
PMID:Evidence for a mutant allele of the gene for DNA topoisomerase II in adriamycin-resistant P388 murine leukemia cells. 255 55


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