Philip J. Perry

Telomerase inhibitors for the treatment of cancer: the current perspective

Telomerase is a holoenzyme responsible for the maintenance of telomeres, the protein-nucleic acid complexes at the ends of eukaryotic chromosomes that serve to maintain chromosomal stability and integrity. Telomerase activity is essential for the sustained proliferation of most immortal cells, including cancer cells. Since the discovery that telomerase activity is detected in 85 - 90% of all human tumours and tumour-derived cell lines but not in most normal somatic cells, telomerase has become the focus of much attention as a novel and potentially highly-specific target for the development of new anticancer chemotherapeutics. Herein we review the current perspective for the development of telomerase inhibitors as cancer chemotherapeutics. These include antisense strategies, reverse transcriptase inhibitors and compounds capable of interacting with high-order telomeric DNA tetraplex (‘G-quadruplex’) structures, so as to prevent enzyme access to the necessary linear telomere substrate. Critical appraisal of each individual approach is provided together with highlighted areas of likely future development.

Telomeres and telomerase: targets for cancer chemotherapy?

Telomerase is a specialised ribonucleoprotein comprising of, at present, 3 known components: the human telomerase RNA component (hTR); the human telomerase reverse transcriptase catalytic subunit (hTERT), and TP1, a telomerase-associated protein. Applications involving telomerase have been proposed in the fields of cellular engineering, diagnostics/prognostics and therapeutics. In the diagnostics area, around 85% of human cancers have been shown to possess telomerase activity, while such activity is not detectable in most somatic cells. In some cases (notably neuroblastomas, gastric and breast tumours), higher levels of telomerase activity were associated with poor prognosis. Telomerase activity, which has generally been measured using a highly sensitive PCR-based TRAP assay, may also be assessed to monitor residual disease following surgery and/or chemotherapy. As telomerase appears to be selectively expressed in tumours versus normal cells, many have proposed that the enzyme represents a good target for...