Skip Navigation


Nucleic Acids Research Advance Access originally published online on January 30, 2007
Nucleic Acids Research 2007 35(4):1064-1074; doi:10.1093/nar/gkl1126
This Article
Right arrow Full Text Freely available
Right arrow Print PDF (1082K) Freely available
Right arrow Screen PDF (277K) Freely available
Right arrow Supplementary Material
Right arrowOA All Versions of this Article:
35/4/1064    most recent
gkl1126v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrow Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Right arrow Articles by Fisher, M.
Right arrow Articles by Herdewijn, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fisher, M.
Right arrow Articles by Herdewijn, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Nucleic Acids Research, 2007, Vol. 35, No. 4 1064-1074
© 2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Inhibition of MDR1 expression with altritol-modified siRNAs

Michael Fisher1, Mikhail Abramov2, Arthur Van Aerschot2, Dong Xu1, Rudolph L. Juliano1 and Piet Herdewijn2

1Department of Pharmacology, School of Medicine, University of North Carolina Chapel Hill NC 27599, USA and 2Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium

Received September 8, 2006. Revised December 5, 2006. Accepted December 11, 2006.

Altritol-modified nucleic acids (ANAs) support RNA-like A-form structures when included in oligonucleotide duplexes. Thus altritol residues seem suitable as candidates for the chemical modification of siRNAs. Here we report that ANA-modified siRNAs targeting the MDR1 gene can exhibit improved efficacy as compared to unmodified controls. This was particularly true of ANA modifications at or near the 3' end of the sense or antisense strands, while modification at the 5' end of the antisense strand resulted in complete loss of activity. Multiple ANA modifications within the sense strand were also well tolerated. Duplexes with ANA modifications at appropriate positions in both strands were generally more effective than duplexes with one modified and one unmodified strand. Initial evidence suggests that the loss of activity associated with ANA modification of the 5'-antisense strand may be due to reduced phosphorylation at this site by cellular kinases. Treatment of drug resistant cells with MDR1-targeted siRNAs resulted in reduction of P-glycoprotein (Pgp) expression, parallel reduction in MDR1 message levels, increased accumulation of the Pgp substrate rhodamine 123, and reduced resistance to anti-tumor drugs. Interestingly, the duration of action of some of the ANA-modified siRNAs was substantially greater than that of unmodified controls. These observations suggest that altritol modifications may be helpful in developing siRNAs with enhanced pharmacological effectiveness.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
R. Juliano, Md. R. Alam, V. Dixit, and H. Kang
Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides
Nucleic Acids Res., July 1, 2008; 36(12): 4158 - 4171.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. R. Alam, V. Dixit, H. Kang, Z.-B. Li, X. Chen, J. Trejo, M. Fisher, and R. L. Juliano
Intracellular delivery of an anionic antisense oligonucleotide via receptor-mediated endocytosis
Nucleic Acids Res., May 1, 2008; 36(8): 2764 - 2776.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.