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

Abstract:

: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 IC(50) values of 5-10 nM at 37 degrees C. IC(50) 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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Elayadi AN,Demieville A,Wancewicz EV,Monia BP,Corey DR

doi

10.1093/nar/29.8.1683

keywords:

subject

Has Abstract

pub_date

2001-04-15 00:00:00

pages

1683-9

issue

8

eissn

0305-1048

issn

1362-4962

journal_volume

29

pub_type

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