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Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks
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2010 (English)In: ONCOTARGET, ISSN 1949-2553, Vol. 1, no 7, 606-619 p.Article in journal (Refereed) Published
Abstract [en]

Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality.

Place, publisher, year, edition, pages
2010. Vol. 1, no 7, 606-619 p.
Keyword [en]
DNA damage, homologous recombination, vosaroxin, topoisomerase II, cancer, subpopuations
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-66248ISI: 000293506100014OAI: oai:DiVA.org:su-66248DiVA: diva2:467390
Note
authorCount :6Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2011-12-19Bibliographically approved

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Helleday, Thomas
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Department of Genetics, Microbiology and Toxicology
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