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A novel attenuated replication-competent adenovirus for melanoma therapy

Gene Therapy volume 10, pages 530–539 (2003)Cite this article

Abstract

To generate a replication-competent adenovirus (Ad) with specificity for melanoma, we constructed a tissue-specific promoter restricting E1A expression to melanoma cells. The combination of four copies of a mouse tyrosinase enhancer element (TE) fused to the human tyrosinase promoter (TP) yielded up to 2000-fold higher luciferase reporter activity in tyrosinase-expressing melanoma cells than in nonmelanoma cells. Insertion of the composite TETP construct upstream of the E1A gene was combined with deleting as far as possible the intertwined endogenous Ad enhancer/promoter (EP). The resulting AdΔEP–TETP vector, also deleted for the E3 region, was found to replicate in tyrosinase-positive melanoma cells, such as SK-Mel23 as efficiently as wild-type Ad5, but at a more than 50-fold reduced level in nonmelanoma tumour cells and primary human cells. Injection of AdΔEP–TETP into xenotransplanted melanomas, but not into HeLa-derived tumours led to long-lasting tumour regression in nude mice. This AdΔEP–TETP virus might be useful for the treatment of accessible lesions in advanced melanoma patients.

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Acknowledgements

We thank C Torres-de los Reyes, E Horvath, J Willers and P Selvam for excellent technical assistance and F Ochsenbein for the artwork. Statistical analysis was performed with the help of W Blanckenhorn, Museum of Zoology, University of Zürich. Isabelle Peter was supported by the Julius Klaus Foundation, Silvio Hemmi was supported by the Cancer Society of the Kanton Zürich and the University of Zürich, Reinhard Dummer and Urs Greber were supported by the Swiss National Science Foundation (3200-063704.00/1) and (31-55994.98), respectively.

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Authors and Affiliations

  1. Institute of Molecular Biology, University of Zürich, Zürich, Switzerland

    I Peter, C Graf, W Schaffner & S Hemmi

  2. Department of Dermatology, University Hospital, Zürich, Switzerland

    R Dummer

  3. Institute of Zoology, University of Zürich, Zürich, Switzerland

    U F Greber

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Peter, I., Graf, C., Dummer, R. et al. A novel attenuated replication-competent adenovirus for melanoma therapy. Gene Ther 10, 530–539 (2003). https://doi.org/10.1038/sj.gt.3301940

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