Targeted Therapy of Human Breast Cancer by 2-5A-Antisense Directed Against Telomerase RNA

摘要

The telomerase enzyme consists of an RNA template and a reverse transcriptase which ensures replication of the termini of chromosomes. Normal somatic cells do not express telomerase and progressively lose telomeric repeat units at each cell division which ultimately results in celluar senescence. Rapidly growing tumor cells overcome this handicap by reexpressiong the telomerase enzyme making it a potential target for therapy. We have demonstrated using anti sense oligonuclotides that targeting the RNA component of telomerase (hTR) for degradation commits tumor cells to rapid apoptosis in vitro and in vivo. Normal cells are unaffected a tumor cells treated with oligonucleotides carrying mismatched bases do not illicit this response. The same apoptotic response was induced in breast cancer cells in vitro using small interfering RNA molecules (siRNA) targeting hTR. In these approaches only a single treatment over a seven day period was sufficient to reduce cell viability significantly. This is in contrast to the need for daily administration of the antisense molecules. These observations provide strong support for the possibility that targeting the telomerase RNA could be developed as a rational therapeutic approach if limitations of delivery and specificity can be overcome.