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Modulation of Telomerase Promoter Tumor Selectivity in the Context of Oncolytic Adenoviruses

¹ Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Glasgow, United Kingdom and ² Centre for Molecular Oncology, Institute of Cancer and the Cancer Research UK Clinical Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom

Requests for reprints: W. Nicol Keith, Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Alexander Stone Building, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom. Phone: 44-141-330-4811; Fax: 44-141-330-4127; E-mail: n.keith{at}beatson.gla.ac.uk.

The telomerase RNA (hTR) and reverse transcriptase (hTERT) promoters are active in most cancer cells, but not in normal cells, and are useful for transcriptional targeting in gene therapy models. Telomerase-specific conditionally replicating adenoviruses (CRAd) are attractive vectors because they should selectively lyse tumor cells. Here, we compare CRAds, in which either the hTR or hTERT promoter controls expression of the adenovirus E1A gene. In replication-defective reporter adenoviruses, the hTR promoter was up to 57-fold stronger in cancer cells than normal cells and up to 49-fold stronger than hTERT. In normal cells, hTERT promoter activity was essentially absent. Doses of telomerase-specific CRAds between 1.8 and 28 infectious units per cell efficiently killed cancer cells, but normal cells required higher doses. However, CRAd DNA replication and E1A expression were detected in both cancer and normal cells. Overall, tumor specificity of the CRAds was limited compared with nonreplicating vectors. Surprisingly, both CRAds expressed similar E1A levels and functional behavior, despite known differentials between hTR and hTERT promoter activities, suggesting that the promoters are deregulated. Rapid amplification of cDNA ends analysis of hTR-/hTERT-E1A transcripts ruled out cryptic transcription from the vector backbone. Blocking E1A translation partially restored the hTR-/hTERT-E1A mRNA differential, evidencing feedback regulation by E1A. [Cancer Res 2007;67(3):1299–307]

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