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 rumours), 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 rumours versus normal cells, many have proposed that the enzyme represents a good target for inhibition. Efforts are underway to target various components of the telomerase/telomere machinery including the hTR template region using antisense oligonucleotides and peptide nucleic acids (PNAs), some of which inhibit at the nanomolar level, hTERT, and the telomere/telomerase interaction. Small-molecule inhibitors of telomerase have recently been described. These include a series of regioisomeric diamidoanthracene-9,10-diones (the best of which inhibit telomerase in cell-free assays with IC50 values of 1 - 5 mu M) and porphyrin-based molecules. These molecules have been proposed to act via stabilisation of telomerase. Reverse transcriptase inhibitors, such as AZT triphosphate,and guanine-quadruplexes, structures associated with telomeres have also been shown to inhibit telomerase. This will clearly be an area where, in the near future, potent inhibitors will be developed thus permitting further target validation experiments to be performed in tumour-bearing mice and ultimately in cancer patients.