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Originally published In Press as doi:10.1074/jbc.M203347200 on April 10, 2002

J. Biol. Chem., Vol. 277, Issue 25, 22980-22984, June 21, 2002
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Evaluating the Specificity of Antisense Oligonucleotide Conjugates
A DNA ARRAY ANALYSIS*

Anna Astriab FisherDagger , Dongjiu YeDagger , Dimitri S. Sergueev§, Michael H. FisherDagger , Barbara Ramsay Shaw§, and Rudolph L. JulianoDagger

From the Dagger  Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 and § Department of Chemistry, Duke University, Durham, North Carolina 27708

Antisense oligonucleotides are potentially powerful tools for selective control of cellular and viral gene expression. Crucial to successful application of this approach is the specificity of the oligonucleotide for the chosen RNA target. Here we apply DNA array technology to examine the specificity of antisense oligonucleotide treatments. The molecules used in these studies consisted of phosphorothioate oligomers linked to the Antennapedia (Ant) delivery peptide. The antisense oligonucleotide component was complementary to a site flanking the AUG of the MDR1 message, which codes for P-glycoprotein, a membrane ATPase associated with multidrug resistance in tumor cells. Using a DNA array of 2059 genes, we analyzed cellular responses to molecules comprised of Ant peptide-oligonucleotide conjugates, as well as to the Ant peptide alone. Besides the expected reduction in MDR1 message level, 37 other genes (~2% of those tested) showed changes of comparable magnitude. The validity of the array results was confirmed for selected genes using Northern blots to assess messenger RNA levels. These results suggest that studies using antisense oligonucleotide technology to modulate gene expression need to be interpreted with caution.

* This work was supported by National Institutes of Health Grant PO1 GM59299.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: CB 7365, 1106 Jones Bldg., Dept. of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7365. Tel.: 919-966-4383; Fax: 919-966-5640; E-mail: arjay@med.unc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.