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Blood, 15 January 2009, Vol. 113, No. 3, pp. 659-667. Prepublished online as a Blood First Edition Paper on October 17, 2008; DOI 10.1182/blood-2008-02-140038. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-02-140038v1 113/3/659    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Qin, T. Articles by Issa, J.-P. J. Search for Related Content PubMed PubMed Citation Articles by Qin, T. Articles by Issa, J.-P. J. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines Taichun Qin1, Jaroslav Jelinek1, Jiali Si1, Jingmin Shu1, and Jean-Pierre J. Issa1 1 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston 5-aza-2'-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes, but resistance to this agent is common. In search for mechanisms of resistance, we measured the half maximal (50%) inhibitory concentration (IC50) of DAC and found it differed 1000-fold among a panel of cancer cell lines. The IC50 was correlated with the doses of DAC that induced the most hypomethylation of long interspersed nuclear elements (LINE; R = 0.94, P < .001), but not with LINE methylation or DNA methyltransferase 1 (DNMT1), 3a, and 3b expression at baseline. Sensitivity to DAC showed a low correlation (R = 0.44, P = .11) to that of 5-azacytidine (AZA), but a good correlation to that of cytarabine (Ara-C; R = 0.89, P < .001). The 5 cell lines most resistant to DAC had a combination of low dCK, hENT1, and 2 transporters, and high cytosine deaminase. In an HL60 clone, resistance to DAC could be rapidly induced by drug exposure and was related to a switch from heterozygous to homozygous mutation of DCK. Transfection of wild-type DCK restored DAC sensitivity. DAC induced DNA breaks as evidenced by H2AX phosphorylation and increased homologous recombination rates by 7- to 10-fold. These results suggest that in vitro resistance to DAC can be explained by insufficient incorporation into DNA. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. D. Robertson and K. N. Bhalla Missteps in "tango" for epigenome targeting Blood, September 24, 2009; 114(13): 2569 - 2570. [Full Text] [PDF] V. Krishnan and O. A. MacDougald The Silent Wif of Death IBMS BoneKEy, September 1, 2009; 6(9): 339 - 341. [Full Text] [PDF] J.-P. J. Issa and H. M. Kantarjian Targeting DNA Methylation Clin. Cancer Res., June 15, 2009; 15(12): 3938 - 3946. [Abstract] [Full Text] [PDF] R. L. Piekarz and S. E. Bates Epigenetic Modifiers: Basic Understanding and Clinical Development Clin. Cancer Res., June 15, 2009; 15(12): 3918 - 3926. [Abstract] [Full Text] [PDF]

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