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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
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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.


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