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Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo

Gene Therapy volume 10, pages 172–179 (2003)Cite this article

Abstract

Existing local therapies for superficial transitional cell carcinoma (TCC) of the bladder have limited success in preventing progression to life-threatening, muscle-invasive disease, and novel therapies are needed. Recent studies have raised doubts concerning the feasibility of adenovirus-mediated gene therapy for bladder cancer. We have therefore investigated adenoviral transduction of normal and malignant human urothelial cells, both as primary cultures and in intact epithelium.

All 15 primary normal human urothelial cell lines tested were transduced in vitro by Adv-cmv-β-gal at high efficiency, and better than most human TCC cell lines. Eight primary human TCC explants were also successfully transduced. In contrast, in intact normal urothelium, transduction efficiency was lower, and occurred only in superficial epithelial layers. Expression of the hCAR adenovirus receptor, however, occurred throughout the full thickness of urothelium. Transduction of human TCC biopsy specimens was at least as efficient as intact normal urothelium.

We demonstrate for the first time that adenoviral transduction of both normal and malignant human urothelial cells is feasible. A physical barrier, rather than hCAR status, may be the main determinant of transduction of intact epithelium. Clinical trials of adenovirus-mediated gene therapy for superficial bladder cancer are warranted.

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Acknowledgements

We thank our surgical colleagues in the Pyrah Department of Urology at St. James's Hospital and the patients who consented to provide bladder tumour biopsy samples. Our thanks are also due to Jon Laye for specimen collection and processing, Eva Pitt for advice on organ culture techniques, Pat Harnden for expert histological staging of tumour specimens, and Christine Gascoigne and Ailsa Rose for processing of wax-embedded specimens. We are grateful to Poulam Patel, Andrew Jackson, Mick Brown and Susan Hedley for critical reading of the manuscript. Monoclonal antibody RmcB was a gift from J Bergelson, Children's Hospital of Philadelphia, PA, USA. These data were presented in poster form at a poster discussion session at ECCO 11, Lisbon, Portugal, October 2001.

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  1. Cancer Research UK Clinical Centre in Leeds, St. James's University Hospital, Leeds, UK

    J D Chester, W Kennedy, G D Hall, P J Selby & M A Knowles

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  1. J D Chester
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Chester, J., Kennedy, W., Hall, G. et al. Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo. Gene Ther 10, 172–179 (2003). https://doi.org/10.1038/sj.gt.3301851

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