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Formation and longevity of idarubicin-induced DNA topoisomerase II cleavable complexes in K562 human leukaemia cells

Lookup NU author(s): Dr Elaine Willmore, Fiona Errington, Dr Michael Tilby, Professor Caroline Austin

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Abstract

Idarubicin (IDA) is an anthracycline used during treatment of acute myelogenous leukaemia (AML) and is clinically important because of its potency and lipophilicity (compared to the related compounds daunorubicin and doxorubicin). These drugs target DNA topoisomerase II (topo II), a nuclear enzyme that regulates DNA topology. Topo II poisoning leads to the trapping of an intermediate in the enzyme's cycle termed the "cleavable complex." This study aims to increase understanding of drug interactions by use of the 'TARDIS' (trapped in agarose DNA immunostaining) assay to measure drug-induced topo II cleavable complexes in individual cells treated with anthracyclines. Mammalian cells contain two isoforms of topo II (α and β) and the TARDIS assay enables visualisation of isoform-specific complexes. Drug-treated cells were embedded in agarose, lysed and incubated with anti-topo II antibodies to microscopically detect topo IIα or β complexes. Results for K562 cells (at clinically relevant concentrations) showed that IDA and idarubicinol, its metabolite, formed mainly topo IIα cleavable complexes, the level of which decreases at doses >1μM for IDA. Our data suggest that this decrease is due to catalytic inhibition by IDA at these doses. Doxorubicin formed low levels of topo IIα complexes and negligible topo IIβ complexes. In cytotoxicity studies, IDA and idarubicinol were equipotent, but both were more potent than daunorubicin and doxorubicin. We showed for the first time that there was a persistent increase in levels of topo IIα cleavable complexes after removal of IDA, suggesting that its greater effectiveness may be associated with both the longevity and high levels of these complexes. © 2002 Elsevier Science Inc. All rights reserved.


Publication metadata

Author(s): Willmore, E., Errington, F., Tilby, M.J., Austin, C.A.

Publication type: Article

Publication status: Published

Journal: Biochemical Pharmacology

Year: 2002

Volume: 63

Issue: 10

Pages: 1807-1815

Print publication date: 15/05/2002

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968

URL: http://dx.doi.org/10.1016/S0006-2952(02)00920-6

DOI: 10.1016/S0006-2952(02)00920-6

PubMed id: 12034365


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