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Nucleic Acids Research, 2001, Vol. 29, No. 8 1683-1689
© 2001 Oxford University Press

Inhibition of telomerase by 2'-O-(2-methoxyethyl) RNA oligomers: effect of length, phosphorothioate substitution and time inside cells

Anissa N. Elayadi, Andrea Demieville, Edward V. Wancewicz1, Brett P. Monia1 and David R. Corey*

Department of Pharmacology and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9041, USA and 1ISIS Pharmaceuticals Inc., Carlsbad Research Center, 2292 Faraday Avenue, Carlsbad, CA 92008, USA

2'-O-(2-methoxyethyl) (2'-MOE) RNA possesses favorable pharmocokinetic properties that make it a promising option for the design of oligonucleotide drugs. Telomerase is a ribonucleoprotein that is up-regulated in many types of cancer, but its potential as a target for chemotherapy awaits the development of potent and selective inhibitors. Here we report inhibition of human telomerase by 2'-MOE RNA oligomers that are complementary to the RNA template region. Fully complementary oligomers inhibited telomerase in a cell extract with IC50 values of 5–10 nM at 37°C. IC50 values for mismatch-containing oligomers varied with length and phosphorothioate substitution. After introduction into DU 145 prostate cancer cells inhibition of telomerase activity persisted for up to 7 days, equivalent to six population doublings. Inside cells discrimination between complementary and mismatch-containing oligomers increased over time. Our results reveal two oligomers as especially promising candidates for initiation of in vivo preclinical trials and emphasize that conclusions regarding oligonucleotide efficacy and specificity in cell extracts do not necessarily offer accurate predictions of activity inside cells.

* To whom correspondence should be addressed. Tel: +1 214 648 5096; Fax: +1 214 648 5095; Email: corey{at}chop.swmed.edu


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