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An oncolytic adenovirus controlled by a modified telomerase promoter is attenuated in telomerase-negative cells, but shows reduced activity in cancer cells

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Abstract

The promoter for human telomerase reverse transcriptase (hTERTp) is preferentially active in malignant cells. It was recently used to control the expression of the adenoviral E1A gene for the development of oncolytic adenoviruses. To ensure maximal repression in normal cells, the inclusion of additional E-boxes in the proximal region of the core promoter was described. We found that the transcriptional activity of this artificial sequence (T-255-4DEB) is minimal in normal cells, but it is also reduced in all the cancer cell lines tested. The cancer specificity of a new oncolytic adenovirus based in this promoter (AdTE1) was evaluated by direct comparison with wild-type adenovirus type 5 (AdWT) in vitro and in vivo. In all the parameters tested, AdTE1 was attenuated in normal cells, but the efficacy in cancer cells showed a parallel reduction, suggesting a lack of specificity. However, the cytotoxicity of AdTE1 was repressed in senescent cells compared to AdWT. Therefore, we conclude that AdTE1 is preferentially attenuated only in cells that are permanently devoid of telomerase expression such as senescent cells. Further modifications in the telomerase-based promoters should be introduced in order to combine maximal attenuation of oncolytic adenoviruses in normal tissues and enhanced activity in tumors.

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Acknowledgements

We thank Izumi Horikawa (National Cancer Institute, Bethesda, MD) for the pBT-255 and pBT-255-4DEB plasmids, Helena Villanueva for technical assistance, Javier Dotor for the FJD cells and Michel Centelles for assistance with flow cytometry. This work was supported by grant SAF2003-08385 from the Spanish Department of Science and Technology and the UTE project CIMA. RHA is a recipient of a Ramon y Cajal research contract. MGK is a recipient of a Fondo de Investigacion Sanitaria (FIS) research contract.

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Authors and Affiliations

  1. Padua University Surgical and Gastroenterological Sciences, Padua, 35128, Italy

    S. Bortolanza & F. Farinati

  2. Gene Therapy Unit, Center for Applied Medical Research, Pio XII, 55, Pamplona, 31008, Spain

    C. Qian, M. G. Kramer, C. Gomar, J. Prieto & R. Hernandez-Alcoceba

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  1. S. Bortolanza
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Correspondence to R. Hernandez-Alcoceba.

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Bortolanza, S., Qian, C., Kramer, M.G. et al. An oncolytic adenovirus controlled by a modified telomerase promoter is attenuated in telomerase-negative cells, but shows reduced activity in cancer cells. J Mol Med 83, 736–747 (2005). https://doi.org/10.1007/s00109-005-0681-1

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