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...

Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sit...

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...

Doxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects o...

Topoisomerase I cleavage complexes can be induced by a variety of DNA damages and by the anticancer drug camptothecin. We have developed a ligation-mediated PCR (LM-PCR) assay to analyze replication-mediated DNA double-strand breaks induced by topoisomerase I cleavage complexes in human colon carcinoma HT29 cells at the nucleotide level. We found that conversion of topoisomerase I cleavage comp...

Topoisomerase II has been suggested to play a major role in chromosome organization based on its DNA decatenating activity and its ability to mediate direct binding interactions between DNA and nuclear matrix. However, this latter point remains controversial. Here we address the question of whether the chromatin binding activity of Topoisomerase II is sufficient to modify chromosome form using ...

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...

Merbarone has previously been shown to have antitumor activity of unknown mechanism in P388 and L1210 tumor models (A. D. Brewer et al., Biochem. Pharmacol., 34:2047-2050, 1985) and is currently undergoing Phase I clinical trials. Here we report that merbarone is an inhibitor of topoisomerase II. Merbarone inhibited purified mammalian topoisomerase II with a 50% inhibitory concentration of 20 m...

.        . Transporting one DNA double helix through another  . The clamp model: a type II DNA topoisomerase as an ATP-modulated protein clamp  . The number of gates in the protein clamp  . Three-dimensional structures of type II DNA topoisomerase fragments  . How are the various subfragments connected?  . A molecular model of DNA...

Escherichia coli expressing SOS-inducing mutant topoisomerase I was utilized to demonstrate that covalent protein-DNA complex accumulation results in oxidative damage. Hydroxyl radicals were detected following mutant topoisomerase induction. The presence of the Fe(2+) chelator 2,2'-dipyridyl and an iscS mutation affecting Fe-S cluster formation protect against topoisomerase I cleavage complex-m...