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

Wang, XY; Martiniello-Wilks, R; Shaw, JM; Ho, T; Coulston, N; Cooke-Yarborough, C; Molloy, PL; Cameron, F; Moghaddam, M; Lockett, TJ; Webster, LK; Smith, IK; Both, GW; Russel, PJ

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

Wang, XY Martiniello-Wilks, R

Shaw, JM Ho, T Coulston, N Cooke-Yarborough, C Molloy, PL Cameron, F Moghaddam, M Lockett, TJ Webster, LK Smith, IK Both, GW Russel, PJ

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Publication Type:: Journal Article
Citation:: Gene Therapy, 2004, 11 (21), pp. 1559 - 1567
Issue Date:: 2004-11-01

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Field	Value	Language
dc.contributor.author	Wang, XY	en_US
dc.contributor.author	Martiniello-Wilks, R https://orcid.org/0000-0002-0038-3430	en_US
dc.contributor.author	Shaw, JM	en_US
dc.contributor.author	Ho, T	en_US
dc.contributor.author	Coulston, N	en_US
dc.contributor.author	Cooke-Yarborough, C	en_US
dc.contributor.author	Molloy, PL	en_US
dc.contributor.author	Cameron, F	en_US
dc.contributor.author	Moghaddam, M	en_US
dc.contributor.author	Lockett, TJ	en_US
dc.contributor.author	Webster, LK	en_US
dc.contributor.author	Smith, IK	en_US
dc.contributor.author	Both, GW	en_US
dc.contributor.author	Russel, PJ	en_US
dc.date.issued	2004-11-01	en_US
dc.identifier.citation	Gene Therapy, 2004, 11 (21), pp. 1559 - 1567	en_US
dc.identifier.issn	0969-7128	en_US
dc.identifier.uri	http://hdl.handle.net/10453/14947
dc.description.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. © 2004 Nature Publishing Group. All rights reserved.	en_US
dc.relation.ispartof	Gene Therapy	en_US
dc.relation.isbasedon	10.1038/sj.gt.3302308	en_US
dc.subject.classification	Biotechnology	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Mice, Nude	en_US
dc.subject.mesh	Prostatic Neoplasms	en_US
dc.subject.mesh	Adenine	en_US
dc.subject.mesh	Purine-Nucleoside Phosphorylase	en_US
dc.subject.mesh	Vidarabine Phosphate	en_US
dc.subject.mesh	Antineoplastic Agents	en_US
dc.subject.mesh	Prodrugs	en_US
dc.subject.mesh	Drug Evaluation, Preclinical	en_US
dc.subject.mesh	Neoplasm Transplantation	en_US
dc.subject.mesh	Apoptosis	en_US
dc.subject.mesh	Cell Proliferation	en_US
dc.subject.mesh	DNA Replication	en_US
dc.subject.mesh	Genetic Vectors	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Genetic Therapy	en_US
dc.title	Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus	en_US
dc.type	Journal Article
utslib.citation.volume	21	en_US
utslib.citation.volume	11	en_US
utslib.for	0604 Genetics	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
dc.location.activity	ISI:000224457100003	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	21	en_US
pubs.publication-status	Published	en_US
pubs.volume	11	en_US

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. © 2004 Nature Publishing Group. All rights reserved.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/14947