Telomeres and telomerase: from discovery to clinical trials

Abstract

Telomeres are the ends of linear chromosomes. They cannot be fully replicated by standard polymerases and are maintained by the ribonucleoprotein telomerase. Telomeres and telomerase stand at a junction of critical processes underlying chromosome integrity, cancer, and aging, and their importance was recognized by the 2009 Nobel Prize in Physiology or Medicine to Elizabeth Blackburn, Jack Szostak, and Carol Greider. Where will the field go now? What are the prospects for antitelomerase agents as drugs? Nearly 30 years after Szostak and Blackburn's pioneering manuscript on telomere ends, the challenges of discovery remain.

Figure 1

The number of publications in PubMed citing the word “telomerase” and the year in which they were published. Data from 2009 is through October 20, 2009.

Figure 2

Typical data from assays of telomerase activity demonstrating the effects of inhibiting telomerase. (A) TRAP assay showing inhibition of telomerase activity in C4(2)b cells treated with complementary 2’-methoxyethyl RNA inhibitor ISIS24691 or noncomplementary oligomer ISIS125628 (Canales et al., 2006). Concentration of oligomer is µM and compound was delivered into cells in the absence of transfection reagent. Measurements were in duplicate or quadruplicate. The band at the bottom of the gel is the internal amplification standard used for quantitation. (B) Telomere shortening in LNCaP cells measured by the telomere restriction fragment (TRF) assay. Lane 1; no oligonucleotide added, cells were harvested after three passages. Lane 2; no oligonucleotide added, cells were harvested after 17 passages. Lane 3; match oligonucleotide ISIS 24691 added for 55 days. Lane 4; mismatch oligonucleotide ISIS 125628 added for 55 days. Lane 5; match oligonucleotide ISIS 24691 added for 70 days. Size markers are shown on the right (Chen et al., 2003). Signal is weaker in the lanes showing telomere shortening because shortened telomeres have less DNA available for probe hybridization. (C) Effect of telomerase inhibition on growth of xenograph tumors in mice (Chen et al., 2003). LNCaP cells that had been treated with match or mismatch oligonucleotide for 21 days prior to implantation. P <0.05 (*) and P <0.001 (**).

Figure 3

Structural features of PNA and chemically modified oligonucleotides used to inhibit human telomerase.