Telomerase as an anti-cancer drug target: will it fulfil its early promise?

The discovery that the ribonucleoprotein telomerase is responsible for the immortality of human cancer cells represents a major advance in our quest t o identify a distinguishing biochemical feature of the malignant phenotype that could be useful as a target for novel anti-cancer drug development. Ho wever, recent observations on telomere dynamics and cell lifespan using tel omerase 'knockout' mouse models together with improved techniques to assay telomerase in normal human tissues have raised certain questions regarding potential side effects of anti-telomerase treatments. More importantly, suc h work has also demonstrated the propensity of mouse cell populations, in w hich telomerase has been experimentally inactivated, to generate immortal v ariants capable of maintaining their telomeres by alternative mechanisms. T hese recent findings and their implications for the potential success of an ti-telomerase therapies are subjected to critical review, The wide differen ces between telomerase and telomere biology in mouse and human cells are hi ghlighted, and the urgent need to obtain direct experimental evidence conce rning the behaviour of a wide variety of human cancer cells under condition s of telomerase inhibition is stressed. It is concluded that, despite the c aveats, the development of small molecule drugs that powerfully inhibit tel omerase should remain a top priority area for those engaged in the rational design of novel cancer therapeutics.