Telomerase: biology and phase I trials

In normal somatic cells, the ends of chromosomes (the telomeres) shorten with each cell division. By contrast, in tumour cells, telomere length is maintained, generally through the reactivation of the reverse transcriptase enzyme, telomerase. At least three applications relating to telomeres and telomerase have been proposed: in cancer diagnosis and prognosis (especially through measurements of the catalytic component of telomerase, hTERT) and as a means of monitoring tumour response to therapy; as an aid to tissue engineering; and inhibition as a cancer therapeutic strategy. Mouse knockout, hTERT dominant negative, and antisense experiments suggest that telomerase inhibitors will confer anticancer activity, especially in tumours with short telomeres. Inhibitory strategies have focused on antisense molecules, inhibitors of reverse transcriptases, and small molecules able to interact with and stabilise four-stranded (G-quadruplex) structures formed by telomeres. Clinical trials involving telomerase inhibitors require careful consideration compared to those looking at conventional anticancer cytotoxic drugs.