Targeted Therapy of Human Breast Cancer by 2-5A-Antisense Directed Against Telomerase RNA
Abstract
Targeting telomerase RNA (hTR) for degradation by RNAseL in breast cancer cells using antisense molecules linked to 2-5A has demonstrated high levels of cytotoxicity in vivo and in vitro. The antisense molecules used in preliminary studies carried a phosphodiester backbone which can be recognized by endogenous nucleases and so make the half-life of these molecules very short. Having demonstrated in vitro that breast cancer cells undergo apoptosis following this treatment, we now sought to improve the stability of the antisense molecules by modifying the backbone. The phosphodiester linkages were therefore replaced with thioate or 2'-0-methyl linkages in various combinations. Many of these modifications resulted in the loss of ability to induce apoptosis in breast cancer cells. Although some of the modified oligonucleotides showed reasonable degrees of cytotoxicity, none of these were as efficient as the original (H1) phophodiester version of the oligonucleotide. When new targets within hTR were challenged with 2-5A-linked molecules, none showed any improvement over H1. We conclude that the Hi antisense molecule has the greatest specificity but that its efficacy is less if the backbone structure is changed either because of a reduced affinity for the target sequence or a reduced ability to activate RnaseL.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA396572
Entities
People
- John K. Cowell