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Preclinical evaluation of a gene therapy treatment for transitional cell carcinoma

Abstract

Three drugs were compared for their efficacy in treating murine transitional cell carcinoma (TCC) of the bladder. Intravesical gene therapy treatments utilizing expression-targeted plasmids, where the murine cyclooxygenase-2 (Cox-2) promoter was used to drive the expression of exogenously inducible forms of caspases 3 and 9, were compared with treatment modalities employing Bacille Calmette-Guérin (BCG) and celecoxib. When administered via lavage, only the gene therapy regimen was found to be effective at restricting tumor progression following a 7-day incubation of tumor tissues. Celecoxib was also administered via the diet to allow for systemic delivery of the drug. The most efficacious celecoxib use tested yielded tumors with masses of (18.3±8.4 mg) versus the gene delivery method, which yielded tumors with masses of (3.6±7.7 mg). The difference was significant (t-test, n4, P<0.025). The results showed that the Cox-2 expression-targeted gene therapy system could efficiently bypass the bladder permeability barrier and more effectively inhibit tumor growth and development than either BCG or celecoxib treatments. Long-term data further demonstrated that the gene therapy system could effectively inhibit tumor growth and elongate life expectancy.

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Acknowledgements

We would like to thank Sherri R Godbey, MD, for assistance with obtaining Celebrex, Carol Pilbeam, PhD, for originally providing the TIS10 (murine Cox-2) promoter, David Spencer, PhD, for originally providing the inducible caspase exons, and ARIAD (http://www.ariad.com/regulationkits) for providing significant amounts of AP20187. This work was funded by the National Science Foundation CAREER award (CBET-0846395).

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Correspondence to W T Godbey.

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Zhang, X., Godbey, W. Preclinical evaluation of a gene therapy treatment for transitional cell carcinoma. Cancer Gene Ther 18, 34–41 (2011). https://doi.org/10.1038/cgt.2010.50

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