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Cancer Research 67, 6400-6408, July 1, 2007. doi: 10.1158/0008-5472.CAN-07-0251
© 2007 American Association for Cancer Research

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Experimental Therapeutics, Molecular Targets, and Chemical Biology

Delivery of 5-Aza-2'-Deoxycytidine to Cells Using Oligodeoxynucleotides

Christine B. Yoo1, Shinwu Jeong3, Gerda Egger3, Gangning Liang2,3, Pasit Phiasivongsa4, Chunlin Tang4, Sanjeev Redkar4 and Peter A. Jones1,2,3

Departments of 1 Biochemistry and Molecular Biology and 2 Urology and 3 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California and 4 SuperGen, Inc., Pleasanton, California

Requests for reprints: Peter A. Jones, University of Southern California/Norris Comprehensive Cancer Center and Hospital, 1441 Eastlake Avenue, Room 8302L, Mail Stop 83, Los Angeles, CA 90033-9181. Phone: 323-865-0816; Fax: 323-865-0102; E-mail: jones_p{at}ccnt.hsc.usc.edu.

The major goal of epigenetic therapy is to reverse aberrant promoter hypermethylation and restore normal function of tumor suppressor genes by the use of chromatin-modifying drugs. Decitabine, or 5-aza-2'-deoxycytidine (5-aza-CdR), is a well-characterized drug that is now Food and Drug Administration approved for the treatment of myelodysplastic syndrome. Although 5-aza-CdR is an extremely potent inhibitor of DNA methylation, it is subject to degradation by hydrolytic cleavage and deamination by cytidine deaminase. We show that short oligonucleotides containing a 5-aza-CdR can also inhibit DNA methylation in cancer cells at concentrations comparable with 5-aza-CdR. Detailed studies with S110, a dinucleotide, showed that it works via a mechanism similar to that of 5-aza-CdR after incorporation of its aza-moiety into DNA. Stability of the triazine ring in aqueous solution was not improved in the S110 dinucleotide; however, deamination by cytidine deaminase was dramatically decreased. This is the first demonstration of the use of short oligonucleotides to provide effective delivery and cellular uptake of a nucleotide drug and protection from enzymatic degradation. This approach may pave the way for more stable and potent inhibitors of DNA methylation as well as provide means for improving existing therapeutics. [Cancer Res 2007;67(13):6400–8]







HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
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Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2007 by the American Association for Cancer Research.