Topoisomerases are ubiquitous enzymes necessary for controlling the interlinking and twisting of DNA molecules. Among the four topoisomerases identified in eubacteria, two, DNA gyrase and topoisomerase IV have been exploited by nature and the pharmaceutical industry as antibacterial targets. Natural products that are inhibitors of one or both of these topoisomerases include the coumarin and cyc...

Thiopurines and topoisomerase II-targeted drugs (e.g., etoposide) are widely used anticancer drugs. However, topoisomerase II-targeted drugs can cause acute myeloid leukemia, with the risk of this secondary leukemia linked to a genetic defect in thiopurine catabolism. Chronic thiopurines result in thioguanine substitution in DNA. The effect of these substitutions on DNA topoisomerase II activit...

Bisdioxopiperazines such as ICRF-159 and ICRF-193 have been shown to inhibit DNA topoisomerase II. To determine the molecular target of these compounds in vivo, we utilized a yeast genetic system in which the topoisomerase II activity can be modulated. To reduce topoisomerase II activity, we used top2-1 mutant yeast cells that have normal DNA topoisomerase II activity at 25 degrees C but greatl...

AIMS To study the patterns of expression of topoisomerase II-alpha in primary invasive ductal breast carcinomas; to correlate this expression with clinicopathological data and prognosis. METHODS Cryostat sections from 63 primary invasive ductal breast carcinomas were stained immunohistochemically for topoisomerase II-alpha. Nuclear immunoreactivity was quantified by counting at least 500 cell...

The antitumor drugs camptothecin and an anilinoacridine, 4'-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA), which act on DNA topoisomerase I and II, respectively, are shown to inhibit the growth of Saccharomyces cerevisiae mutants selected for their permeability to other inhibitors. In addition to growth inhibition, these drugs induce high levels of homologous recombination and induce the...

Topoisomerase inhibitors have been developed in a variety of clinical applications. We investigated the inhibitory effect of evodiamine on E. coli topoisomerase I, which may lead to an anti-bacterial effect. Evodiamine inhibits the supercoiled plasmid DNA relaxation that is catalyzed by E. coli topoisomerase I, and computer-aided docking has shown that the Arg161 and Asp551 residues of topoisom...

Introduction: Fluoroquinolones are potent inhibitors of bacterial topoisomerase II. They can also inhibit eukaryotic topoisomerase, and may confer antitumoral properties. Method: In this study the antitumoral activity of a new series of N-substituted piperazinylfluoroquinolones against a panel of human tumor cell lines was determined by MTT assays. Results: Among the tested compounds N-[2- (5-b...

Doxorubicin has become one of the most effective chemotherapeutic agents, but its use was complicated by development heart failure. Proposed mechanisms for antitumor effects included intercalation into DNA that caused prevention micro molecule synthesis, cross-linkage and binding, damage due to topoisomerase 2b suppression, reactive oxygen species production, induction apoptosis. Several drugs ...

Several classes of antitumor drugs are known to stabilize topoisomerase complexes in which the enzyme is covalently bound to a terminus of a DNA strand break. The DNA cleavage sites generally are different for each class of drugs. We have determined the DNA sequence locations of a large number of drug-stimulated cleavage sites of topoisomerase II, and find that the results provide a clue to the...

We have isolated two Chinese hamster ovary cell lines, designated ADR-4 and ADR-5, which exhibit hypersensitivity to intercalating agents and epipodophyllotoxins. These drugs are thought to exert their cytotoxicity via an interaction with the enzyme topoisomerase II. However, there is no apparent change in the level or catalytic activity of topoisomerase II in the mutant cells. Drug sensitivity...