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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4659-4665. Prepublished online as a Blood First Edition Paper on March 9, 2004; DOI 10.1182/blood-2003-07-2527. This Article Full Text (PDF) All Versions of this Article: 2003-07-2527v1 103/12/4659    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Willmore, E. Articles by Durkacz, B. W Search for Related Content PubMed PubMed Citation Articles by Willmore, E. Articles by Durkacz, B. W Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 29, 2003 Accepted February 19, 2004 A novel DNA-dependent protein kinase inhibitor NU7026 potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia Elaine Willmore, Sarah de Caux, Nicola J Sunter, Michael J Tilby, Graham H Jackson, Caroline A Austin, and Barbara W Durkacz* School of Cell & Molecular Biosciences, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom Northern Institute for Cancer Research, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom Dept of Haematology, Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom * Corresponding author; email: B.W.Durkacz{at}ncl.ac.uk. We report for the first time the use of a selective small molecule inhibitor of DNA repair to potentiate topo II poisons, identifying DNA-PK as a potential target for leukemia therapy.Topoisomerase II (topo II) poisons form cleavable complexes that are processed to DNA double strand breaks (DSB). DNA-dependent protein kinase (DNA-PK) mediates non-homologous end joining (NHEJ). Inhibition of this DSB repair pathway may sensitize cells to topo II poisons. We investigated the effects of a novel DNA-PK inhibitor, NU7026, on the response to topo II poisons using K562 leukemia cells. NU7026 (10µM) potentiated the growth inhibition of idarubicin, daunorubicin, doxorubicin, etoposide, mAMSA and mitoxantrone with potentiation factors at 50% growth inhibition ranging from 19 for mAMSA to 2 for idarubicin (potentiation of etoposide was confirmed by clonogenic assay). In contrast, NU7026 did not potentiate camptothecin or araC. NU7026 did not affect the levels of etoposide-induced topo II or cleavable complexes. NU7026 alone had no effect on cell cycle distribution, but etoposide-induced accumulation in G2/M was increased by NU7026. A concentration-dependent increase in etoposide-induced DSB levels was enhanced by NU7026. Thus, NU7026 potentiates topo II poisons downstream of cleavable complex formation by a mechanism involving inhibition of NHEJ and G2/M checkpoint arrest. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Bauerschmidt, C. Arrichiello, S. Burdak-Rothkamm, M. Woodcock, M. A. Hill, D. L. Stevens, and K. Rothkamm Cohesin promotes the repair of ionizing radiation-induced DNA double-strand breaks in replicated chromatin Nucleic Acids Res., November 11, 2009; (2009) gkp976v1. [Abstract] [Full Text] [PDF] J. Dejmek, J. D. Iglehart, and J.-B. 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