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Numerical analysis of etoposide induced DNA breaks.

Artikel i vetenskaplig tidskrift
Författare Aida Muslimovic
Susanne Nyström
Yue Gao
Ola Hammarsten
Publicerad i PloS one
Volym 4
Nummer/häfte 6
Sidor e5859
ISSN 1932-6203
Publiceringsår 2009
Publicerad vid Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin
Sidor e5859
Språk en
Länkar dx.doi.org/10.1371/journal.pone.000...
Ämnesord Antineoplastic Agents, Phytogenic, pharmacology, Cell Line, Tumor, Cell Separation, Cell Survival, DNA Breaks, Double-Stranded, drug effects, DNA Damage, drug effects, Dose-Response Relationship, Drug, Etoposide, pharmacology, Flow Cytometry, Histones, metabolism, Humans, Models, Theoretical, Phosphorylation, Time Factors
Ämneskategorier Biofarmaci

Sammanfattning

BACKGROUND: Etoposide is a cancer drug that induces strand breaks in cellular DNA by inhibiting topoisomerase II (topoII) religation of cleaved DNA molecules. Although DNA cleavage by topoisomerase II always produces topoisomerase II-linked DNA double-strand breaks (DSBs), the action of etoposide also results in single-strand breaks (SSBs), since religation of the two strands are independently inhibited by etoposide. In addition, recent studies indicate that topoisomerase II-linked DSBs remain undetected unless topoisomerase II is removed to produce free DSBs. METHODOLOGY/PRINCIPAL FINDINGS: To examine etoposide-induced DNA damage in more detail we compared the relative amount of SSBs and DSBs, survival and H2AX phosphorylation in cells treated with etoposide or calicheamicin, a drug that produces free DSBs and SSBs. With this combination of methods we found that only 3% of the DNA strand breaks induced by etoposide were DSBs. By comparing the level of DSBs, H2AX phosphorylation and toxicity induced by etoposide and calicheamicin, we found that only 10% of etoposide-induced DSBs resulted in histone H2AX phosphorylation and toxicity. There was a close match between toxicity and histone H2AX phosphorylation for calicheamicin and etoposide suggesting that the few etoposide-induced DSBs that activated H2AX phosphorylation were responsible for toxicity. CONCLUSIONS/SIGNIFICANCE: These results show that only 0.3% of all strand breaks produced by etoposide activate H2AX phosphorylation and suggests that over 99% of the etoposide induced DNA damage does not contribute to its toxicity.

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