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Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus

Gene Therapy volume 11, pages 1559–1567 (2004)Cite this article

Abstract

Gene-directed enzyme prodrug therapy (GDEPT) based on the Escherichia coli enzyme, purine nucleoside phosphorylase (PNP), provides a novel strategy for treating slowly growing tumors like prostate cancer (CaP). PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis. Reporter gene expression directed by a hybrid prostate-directed promoter and enhancer, PSMEPb, was assayed after plasmid transfection or viral transduction of prostate and non-CaP cell lines. Androgen-sensitive (AS) LNCaP-LN3 and androgen-independent (AI) PC3 human CaP xenografts in nude mice were injected intratumorally with an ovine atadenovirus vector, OAdV623, that carries the PNP gene under PSMEPb, formulated with cationic lipid for enhanced infectivity. Fludarabine phosphate was then given intraperitoneally for 5 days at 75 mg/m2/day. PNP expression was evaluated by enzymic conversion of its substrate using reverse phase HPLC. OAdV623 showed excellent in vitro transcriptional specificity for CaP cells. In vivo, expression of PNP persisted for >6 days after OAdV623 injection and a single treatment provided 100% increase in tumor doubling time and >50% inhibition of tumor growth for both LNCaP-LN3 and PC3 lines, with increased tumor necrosis and apoptosis and decreased tumor cell proliferation. OAdV623 significantly suppressed the growth of AS and AI human CaP xenografts in mice.

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Acknowledgements

We thank Mayne Pharma Pty Ltd for funding the project, Kylie Smith and Emma Bennetts for technical assistance in the early phase of the project and Mila Sajinovic and Hnin Pwint for excellent animal husbandry.

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Authors and Affiliations

  1. Oncology Research Centre, Prince of Wales Hospital Clinical School of Medicine, The University of New South Wales, Randwick, NSW, Australia

    XY Wang, R Martiniello-Wilks & PJ Russell

  2. CSIRO Molecular Science, North Ryde, NSW, Australia

    JM Shaw, T Ho, N Coulston, PL Molloy, F Cameron, M Moghaddam, TJ Lockett & GW Both

  3. Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW, Australia

    C Cooke-Yarborough

  4. Mayne Pharma Pty Ltd, Mt Waverley, VIC, Australia

    LK Webster

  5. Mayne Pharma Pty Ltd, Salisbury South, Australia

    IK Smith

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  1. XY Wang
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Wang, X., Martiniello-Wilks, R., Shaw, J. et al. Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus. Gene Ther 11, 1559–1567 (2004). https://doi.org/10.1038/sj.gt.3302308

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  • DOI: https://doi.org/10.1038/sj.gt.3302308

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