A novel telomerase template antagonist (GRN163) as a potential anticancer agent.

Abstract

Telomerase, the enzyme responsible for proliferative immortality, is expressed in essentially all cancer cells, but not in most normal human cells. Thus, specific telomerase inhibition is potentially a universal anticancer therapy with few side effects. We designed N3'-->P5' thio-phosphoramidate (NPS) oligonucleotides as telomerase template antagonists and found that their ability to form stable duplexes with the telomerase RNA subunit was the key factor for antitelomerase activity. In biochemical assays 11-13-mer NPS oligonucleotides demonstrated sequence- and dose-dependent inhibition of telomerase with IC(50) values <1 nM. Optimization of the sequence, length, and bioavailability resulted in the selection of a 13-mer NPS oligonucleotide, GRN163, as a drug development candidate. GRN163 inhibited telomerase in a cell-free assay at 45 +/- 7 pM, and in various tumor cell lines at approximately 1 nM and approximately 0.3-1.0 micro M in the presence and absence of carriers, respectively. GRN163 was competitive with telomeric primer binding, primarily because of hybridization to human telomerase RNA (hTR) component. Tumor cells treated with GRN163 in culture underwent telomere shortening, followed by cellular senescence or apoptosis after a period of time that generally correlated with initial telomere length. In a flank DU145 (prostate cancer) xenograft model, parenterally administered GRN163 caused suppression of tumor growth in the absence of gross toxicity. These data demonstrate that GRN163 has significant potential for additional development as an anticancer agent.

• Authors: Akira Asai, Yuko Oshima, Yoshihiro Yamamoto, Taka-aki Uochi, Hideaki Kusaka, Shiro Akinaga, Yoshinori Yamashita, Krisztina Pongracz, Ronald Pruzan, Ellen Wunder, Mieczyslaw Piatyszek, Shihong Li, Allison C Chin, Calvin B Harley, Sergei Gryaznov
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 14 Pg. 3931-9 (Jul 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 12873987 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amides
• Oligonucleotides
• Phosphoric Acids
• RNA
• phosphoramidic acid
• Telomerase

Topics

• Amides (metabolism, pharmacology)
• Biological Availability
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Oligonucleotides (genetics, metabolism, pharmacokinetics, pharmacology)
• Phosphoric Acids (metabolism, pharmacology)
• RNA (genetics, metabolism)
• Telomerase (antagonists & inhibitors, genetics, metabolism)