title: Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks.
abstract: 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.
authors.affiliation: Sunesis Pharmaceuticals, Inc. 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Rachael Elizabeth
authors.initials: RE
authors.lastname: Hawtin
authors.affiliation: Sunesis Pharmaceuticals, Inc. 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: David Elliot
authors.initials: DE
authors.lastname: Stockett
authors.affiliation: Sunesis Pharmaceuticals, Inc. 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Oi Kwan
authors.initials: OK
authors.lastname: Wong
authors.affiliation: Gray Institute for Radiation Oncology & Biology, University of Oxford. Old Road Campus Research Building, Roosevelt Drive. Oxford, OX3 7DQ, UK.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lundin
authors.affiliation: Gray Institute for Radiation Oncology & Biology, University of Oxford. Old Road Campus Research Building, Roosevelt Drive. Oxford, OX3 7DQ, UK.|Dept. of Genetics Microbiology and Toxicology, Stockholm University. Arrhenius Laboratory, Svante Arrhenius väg 16 E4. S-106 91 Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.affiliation: Sunesis Pharmaceuticals, Inc. 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Judith Ann
authors.initials: JA
authors.lastname: Fox
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D024522:Genes, BRCA2 / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009287:Naphthyridines / Q000494:pharmacology*; D011995:Recombination, Genetic / Q000502:physiology*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines; D013844:Thiazoles; D004317:Doxorubicin; C485113:vosaroxin