Hormone binding and localization of the c-erb-A protein suggest that it is a receptor for thyroid hormone, a nuclear protein that binds to DNA and activates transcription. In contrast, the product of the viral oncogene v-erb-A is defective in binding the hormone but is still located in the nucleus.

The thyroid-hormone receptor can, in the absence of its ligand, suppress activity of a responsive promoter. Addition of thyroid hormone, however, results in the stimulation of expression. The oncogenic derivative of the thyroid-hormone receptor, v-erbA, acts as a constitutive repressor and, when coexpressed with the receptor, blocks activation by thyroid hormone. Thus, v-erbA may be the first example of a dominant negative oncogene.

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities.

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