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Transcription-targeted gene therapy for androgen-independent prostate cancer

Cancer Gene Therapy volume 9, pages 443–452 (2002)Cite this article

Abstract

The Escherichia coli enzyme (purine nucleoside phosphorylase, PNP) gene is delivered directly into PC3 tumors by one injection of replication-deficient human type-5 adenovirus (Ad5). Expressed PNP converts the systemically administered prodrug, 6MPDR, to a toxic purine, 6MP, causing cell death. We sought to increase the specificity of recombinant Ad vectors by controlling PNP expression with the promoter region from the androgen-dependent, prostate-specific rat probasin (Pb) gene. To increase its activity, the promoter was combined with the SV40 enhancer (SVPb). Cell lines were transfected with plasmids containing both a reporter gene, under SVPb control, and a reference gene cassette to allow normalization of expression levels. Plasmids expressed ∼20-fold more reporter in prostate cancer than in other cells, but surprisingly, the SVPb element was both androgen-independent and retained substantial prostate specificity. Killing by Ad5-SVPb-PNP vector of cell lines cultured with 6MPDR for 6 days was 5- to 10-fold greater in prostate cancer than in liver or lung cells. In vivo, a single intratumoral injection of Ad5-SVPb-PNP (4×108 pfu), followed by 6MPDR administration twice daily for 6 days, significantly suppressed the growth of human prostate tumors in nude mice and increased their survival compared to control animals. Thus, the androgen-independent, prostate-targeting Ad5 vector reduces human prostate cancer growth significantly in vitro and in vivo. This first example of an androgen-independent vector points the way toward treatment of emerging androgen-independent prostate cancer in conjunction with hormone ablation therapy at a time when the tumor burden is low.

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Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia, Cancer Council of NSW, and the Rebecca L Cooper Foundation. We thank Darren Cundy for the 6MPDR synthesis and purification. We also thank Mila Sajinovic and Debbie Padroth for their excellent animal husbandry.

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Authors and Affiliations

  1. Oncology Research Centre, Prince of Wales Hospital, Randwick, 2031, New South Wales, Australia

    Rosetta Martiniello-Wilks, Tania Tsatralis & Pamela J Russell

  2. Department of Medicine, University of New South Wales, Sydney, 2052, New South Wales, Australia

    Rosetta Martiniello-Wilks, Tania Tsatralis & Pamela J Russell

  3. Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, 2050, New South Wales, Australia

    Peter Russell

  4. CSIRO Molecular Science, North Ryde, 2113, New South Wales, Australia

    Diana E Brookes, Dorethea Zandvliet, Linda J Lockett, Gerald W Both & Peter L Molloy

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  1. Rosetta Martiniello-Wilks
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Correspondence to Rosetta Martiniello-Wilks.

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Martiniello-Wilks, R., Tsatralis, T., Russell, P. et al. Transcription-targeted gene therapy for androgen-independent prostate cancer. Cancer Gene Ther 9, 443–452 (2002). https://doi.org/10.1038/sj.cgt.7700451

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