Vaccinia DNA topoisomerase, a eukaryotic type I enzyme, has unique pharmacological properties, including sensitivity to the coumarin drugs novobiocin and coumermycin, which are classical inhibitors of DNA gyrase, a type II enzyme. Whereas coumarins inhibit gyrase by binding the GyrB subunit and thereby blocking the ATP-binding site, they inhibit vaccinia topoisomerase by binding to the protein ...

Topoisomerase II is the only enzyme able to cleave and religate double-stranded DNA; this makes it essential for many vital functions during normal cell growth. Increased expression of topoisomerase II is a common occurrence in neoplasia, and different topoisomerase II inhibitors have indeed been proven to be powerful anticancer drugs. For this reason, the topoisomerase II catalytic cycle has a...

Several recently developed derivatives of bis(2,6-dioxopiperazine) have been shown to be new antitumor agents and are currently under clinical trials. We found that the mother compound of the bis(2,6-dioxopiperazine)s, ICRF-154, and its derivatives, ICRF-159, ICRF-193, and MST-16, are all inhibitors of mammalian type II DNA topoisomerase. By decatenation assay using kinetoplast DNA from Crithid...

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 promyelocyti...

We have isolated a Chinese hamster ovary cell line, designated ADR-1, which exhibits hypersensitivity to a range of drugs which are thought to inhibit the action of the enzyme topoisomerase II. These include anthracyclines, other classes of intercalating agents, and the epipodophyllotoxin, etoposide. No significant sensitivity to radiation, or to mono- and bifunctional alkylating agents was see...

Topoisomerase II catalyzes the passage of one DNA helix through another via a transient double-stranded break. The essential nature of this enzyme in cell proliferation and its mechanism of action make it an ideal target for cytotoxic agents. Saccharomyces cerevisiae topoisomerase II has been frequently used as a model for testing potential inhibitors of eukaryotic topoisomerase II as antitumor...

Maleimide, N-ethyl-maleimide (NEM), and N-methyl-maleimide (NMM) were identified as potent catalytic inhibitors of purified human topoisomerase IIalpha, whereas the ring-saturated analog succinimide was completely inactive. Catalytic inhibition was not abrogated by topoisomerase II mutations that totally abolish the effect of bisdioxopiperazine compounds on catalytic inhibition, suggesting a di...

Two trends are apparent in current early-stage drug discovery settings, firstly a revival of phenotypic screening strategies [1], and secondly the increasing acceptance that drugs modulate multiple targets in parallel (‘multi-target drugs’) [2].The work presented here combines those aspects by integrating experimental phenotypic screening for cytotoxic compounds with an experimental validation ...

Most chemotherapy regimens contain at least one DNA-damaging agent that preferentially affects the growth of cancer cells. This strategy takes advantage of the differences in cell proliferation between normal and cancer cells. Chemotherapeutic drugs are usually designed to target rapid-dividing cells because sustained proliferation is a common feature of cancer [1,2]. Rapid DNA replication is e...

A series of new benzimidazole derivatives with potential anticancer activity were tested as a new topoisomerase I inhibitors. The fluorometric method was used to determine in vitro the quantitative level of plasmid DNA relaxation by these compounds. Optimization of the fluorometric system and validation of the established analytical method were performed. Out of benzimidazole derivatives which ...