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. Wancewicz, Brett P. Monia, David R. Corey

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Abstract

2′-O-(2-methoxyethyl) (2′-MOE) RNA possesses favorable pharmacokinetic properties that make it a promising option for the design of oligonucleotide drugs. Telomerase is a ribonucleoprotein that is upregulated 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.

Original languageEnglish (US)
Pages (from-to)1683-1689
Number of pages7
JournalNucleic Acids Research
Volume29
Issue number8
StatePublished - Apr 15 2001

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Telomerase
Cell Extracts
Oligonucleotides
Inhibitory Concentration 50
Complementary RNA
Ribonucleoproteins
Drug Design
Prostatic Neoplasms
Pharmacokinetics
Drug Therapy
2'-O-(2-methoxyethyl)-RNA
Population
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

Inhibition of telomerase by 2′-O-(2-methoxyethyl) RNA oligomers : Effect of length, phosphorothioate substitution and time inside cells. / Elayadi, Anissa N.; Demieville, Andrea; Wancewicz, Edward V.; Monia, Brett P.; Corey, David R.

In: Nucleic Acids Research, Vol. 29, No. 8, 15.04.2001, p. 1683-1689.

Research output: Contribution to journalArticle

Elayadi, Anissa N. ; Demieville, Andrea ; Wancewicz, Edward V. ; Monia, Brett P. ; Corey, David R. / Inhibition of telomerase by 2′-O-(2-methoxyethyl) RNA oligomers : Effect of length, phosphorothioate substitution and time inside cells. In: Nucleic Acids Research. 2001 ; Vol. 29, No. 8. pp. 1683-1689.
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