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Cleavage of cellular DNA by calicheamicin γ1
Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
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2003 (English)In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 2, no 4, 363-374 p.Article in journal (Refereed) Published
Abstract [en]

It is assumed that the efficient antitumor activity of calicheamicin γ1 is mediated by its ability to introduce DNA double-strand breaks in cellular DNA. To test this assumption we have compared calicheamicin γ1-mediated cleavage of cellular DNA and purified plasmid DNA. Cleavage of purified plasmid DNA was not inhibited by excess tRNA or protein indicating that calicheamicin γ1 specifically targets DNA. Cleavage of plasmid DNA was not affected by incubation temperature. In contrast, cleavage of cellular DNA was 45-fold less efficient at 0°C as compared to 37° due to poor cell permeability at low temperatures. The ratio of DNA double-strand breaks (DSB) to single-stranded breaks (SSB) in cellular DNA was 1:3, close to the 1:2 ratio observed when calicheamicin γ1 cleaved purified plasmid DNA. DNA strand breaks introduced by calicheamicin γ1 were evenly distributed in the cell population as measured by the comet assay. Calicheamicin γ1-induced DSBs were repaired slowly but completely and resulted in high levels of H2AX phosphorylation and efficient cell cycle arrest. In addition, the DSB-repair deficient cell line Mo59J was hyper sensitive to calicheamicin γ. The data indicate that DSBs is the crucial damage after calicheamicin γ1 and that calicheamicin γ1-induced DSBs are recognized normally. The high DSB:SSB ratio, specificity for DNA and the even damage distribution makes calicheamicin γ1 a superior drug for studies of the DSB-response and emphasizes its usefulness in treatment of malignant disease.

Place, publisher, year, edition, pages
2003. Vol. 2, no 4, 363-374 p.
Keyword [en]
Bleomycin, Calicheamicin γ1, DNA damage, DNA double-strand break, DNA repair, DNA single-strand break, Ionizing radiation, calicheamicin gamma1, cell DNA, double stranded DNA, histone H2A, plasmid DNA, single stranded DNA, transfer RNA, article, cell membrane permeability, cell population, comet assay, comparative study, controlled study, DNA cleavage, DNA purification, DNA strand breakage, gene targeting, human, human cell, low temperature, mitosis inhibition, priority journal, protein phosphorylation, temperature dependence, Aminoglycosides, Anti-Bacterial Agents, DNA, Enediynes, Fibroblasts, Humans
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:sh:diva-23268DOI: 10.1016/S1568-7864(02)00235-5ISI: 000181649000001PubMedID: 12606118ScopusID: 2-s2.0-0037414347OAI: oai:DiVA.org:sh-23268DiVA: diva2:713638
Available from: 2014-04-23 Created: 2014-04-16 Last updated: 2014-04-23Bibliographically approved

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Nygren, Jonas
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