Transcription-targeted gene therapy for androgen-independent prostate cancer

Martiniello-Wilks, R; Tsatralis, T; Russell, P; Brookes, DE; Zandvliet, D; Lockett, LJ; Both, GW; Molloy, PL; Russell, PJ

Transcription-targeted gene therapy for androgen-independent prostate cancer

Martiniello-Wilks, R

Tsatralis, T Russell, P Brookes, DE Zandvliet, D Lockett, LJ Both, GW Molloy, PL Russell, PJ

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Publication Type:: Journal Article
Citation:: Cancer Gene Therapy, 2002, 9 (5), pp. 443 - 452
Issue Date:: 2002-01-01

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Field	Value	Language
dc.contributor.author	Martiniello-Wilks, R https://orcid.org/0000-0002-0038-3430	en_US
dc.contributor.author	Tsatralis, T	en_US
dc.contributor.author	Russell, P	en_US
dc.contributor.author	Brookes, DE	en_US
dc.contributor.author	Zandvliet, D	en_US
dc.contributor.author	Lockett, LJ	en_US
dc.contributor.author	Both, GW	en_US
dc.contributor.author	Molloy, PL	en_US
dc.contributor.author	Russell, PJ	en_US
dc.date.issued	2002-01-01	en_US
dc.identifier.citation	Cancer Gene Therapy, 2002, 9 (5), pp. 443 - 452	en_US
dc.identifier.issn	0929-1903	en_US
dc.identifier.uri	http://hdl.handle.net/10453/17074
dc.description.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.	en_US
dc.relation.ispartof	Cancer Gene Therapy	en_US
dc.relation.isbasedon	10.1038/sj.cgt.7700451	en_US
dc.subject.classification	Oncology & Carcinogenesis	en_US
dc.subject.mesh	Tumor Cells, Cultured	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	Adenoviridae	en_US
dc.subject.mesh	Prostatic Neoplasms	en_US
dc.subject.mesh	Prodrugs	en_US
dc.subject.mesh	Androgens	en_US
dc.subject.mesh	Transfection	en_US
dc.subject.mesh	Transcription, Genetic	en_US
dc.subject.mesh	Tissue Distribution	en_US
dc.subject.mesh	Genetic Vectors	en_US
dc.subject.mesh	Plasmids	en_US
dc.subject.mesh	Time Factors	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Genetic Therapy	en_US
dc.title	Transcription-targeted gene therapy for androgen-independent prostate cancer	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	9	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
dc.location.activity	ISI:000175228700005	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	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	9	en_US

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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http://hdl.handle.net/10453/17074