Recent advances in the development of telomerase inhibitors for the treatment of cancer.
Telomerase is an holoenzyme responsible for the maintenance of telomeres, the protein-nucleic acid structures which exist at the ends of eukaryotic chromosomes that serve to protect 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 expressed 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 recent advances in the development of telomerase inhibitors for the treatment of cancer. To date, these have included antisense strategies, reverse transcriptase inhibitors and compounds capable of interacting with high-order telomeric DNA tetraplex ('G-quadruplex') structures to prevent enzyme access to the necessary linear telomere substrate. In addition, a number of telomerase-inhibitory therapies have been shown to synergistically enhance the effects of clinically-established anticancer drugs. Critical appraisal of each individual approach is provided, together with highlighted areas of likely future development. We also review recent developments in telomere and telomerase biology, of which a more detailed understanding would be essential in order to further develop the present classes of telomerase inhibitors into viable, clinically applicable therapies.
Perry
PJ
School of Pharmacy and Pharmaceutical Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK. pperry@dmu.ac.uk
Jenkins
TC