The cytotoxic effects of single-stranded telomere mimics on OMA-BL1 cells

Telomerase is a ribonucleoprotein that adds 5'-d(T-TAGGG)-3' hexameric repe ats onto the 3' ends of chromosomes. High telomerase activity has been asso ciated with immortal cells, transformed cells, mitogenic stimulation, and p roliferative diseases. It is not clear what phenotype would be observed by transient inhibition of telomerase. Studies were designed to inhibit telome rase activity using a series of S-ODN telomere sequence motifs. The studies evaluated the length, hydrogen bonding, and sequence requirements of telom erase inhibition using the TRAP assay and a bioassay measuring cell viabili ty following exposure to the compounds. In addition, we have also studied t he role of the 3' end and secondary structure of telomere mimics on telomer ase inhibition. Observations reveal that sensitivity to the S-ODNs may not require hybridization to an antisense target but required guanine nucleotid es on the 3' end for cells in culture and telomerase inhibition in vitro. T he importance of H bonding and the requirement for a free 3' end for the ac tivity of these compounds has also been demonstrated. However, transient in hibition of telomerase is not cytotoxic to all immortal cells and is not su fficient to explain the mechanism of cytotoxicity of these short oligonucle otides. (C) 1999 Academic Press.