In vivo gene therapy for prostate cancer: Preclinical evaluation of two different enzyme-directed prodrug therapy systems delivered by identical adenovirus vectors

Martiniello-Wilks, R; Garcia-Aragon, J; Daja, MM; Russell, P; Both, GW; Molloy, PL; Lockett, LJ; Russell, PJ

In vivo gene therapy for prostate cancer: Preclinical evaluation of two different enzyme-directed prodrug therapy systems delivered by identical adenovirus vectors

Martiniello-Wilks, R

Garcia-Aragon, J Daja, MM Russell, P Both, GW Molloy, PL Lockett, LJ Russell, PJ

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Publication Type:: Journal Article
Citation:: Human Gene Therapy, 1998, 9 (11), pp. 1617 - 1626
Issue Date:: 1998-07-20

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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	Garcia-Aragon, J	en_US
dc.contributor.author	Daja, MM	en_US
dc.contributor.author	Russell, P	en_US
dc.contributor.author	Both, GW	en_US
dc.contributor.author	Molloy, PL	en_US
dc.contributor.author	Lockett, LJ	en_US
dc.contributor.author	Russell, PJ	en_US
dc.date.issued	1998-07-20	en_US
dc.identifier.citation	Human Gene Therapy, 1998, 9 (11), pp. 1617 - 1626	en_US
dc.identifier.issn	1043-0342	en_US
dc.identifier.uri	http://hdl.handle.net/10453/15519
dc.description.abstract	Advanced prostate cancer is invariably lethal once it becomes androgen independent (AI). With the aim of developing a new treatment we have used the human androgen-independent prostate cancer cell line, PC-3, to evaluate the effectiveness of two enzyme-directed prodrug therapy (EPT) systems as a novel means for promoting tumor cell destruction in vivo. We have confined our study to the use of a PSA promoter, in a preliminary attempt to achieve prostate specificity. The two EPT systems used were the HSVTK/GCV and PNP/6MPDR systems. These were chosen for their differential dependence on DNA replication for their mechanism of action. In the present work, either the HSVTK or PNP gene, each controlled by a PSA promoter fragment, was delivered by an E1-, replication-deficient human adenovirus (Ad5) into PC-3 tumors growing subcutaneously in BALB/c nude mice. Tumors were injected with a single dose of recombinant Ad5 and mice were treated intraperitoneally with the appropriate prodrug, twice daily, for 6 days thereafter. The growth of established PC-3 tumors was significantly suppressed and host survival increased with a single course of HSVTK/GCV or PNP/6MPDR treatment. HSVTK/GCV-treated PC-3 tumor growth was 80% less than that of control treatments on day 33, while PNP/6MPDR-treated tumor growth was ~ 75% less than that of control treatments on day 52. Survival data showed that 20% of HSVTK/GCV- or PNP/6MPDR-treated animals lived > 45 and > 448 days, respectively, longer than control animals. These results demonstrate that both HSVTK/GCV and PNP/6MPDR therapies interrupt the growth of an aggressive human prostate cancer cell line in vivo.	en_US
dc.relation.ispartof	Human Gene Therapy	en_US
dc.relation.isbasedon	10.1089/hum.1998.9.11-1617	en_US
dc.subject.classification	Biotechnology	en_US
dc.subject.mesh	Tumor Cells, Cultured	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred BALB C	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Mice, Nude	en_US
dc.subject.mesh	Escherichia coli	en_US
dc.subject.mesh	Adenoviridae	en_US
dc.subject.mesh	Simplexvirus	en_US
dc.subject.mesh	Adenocarcinoma	en_US
dc.subject.mesh	Prostatic Neoplasms	en_US
dc.subject.mesh	Ganciclovir	en_US
dc.subject.mesh	Purine-Nucleoside Phosphorylase	en_US
dc.subject.mesh	Thymidine Kinase	en_US
dc.subject.mesh	Prodrugs	en_US
dc.subject.mesh	Gene Therapy	en_US
dc.subject.mesh	Genetic Vectors	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Genetic Therapy	en_US
dc.title	In vivo gene therapy for prostate cancer: Preclinical evaluation of two different enzyme-directed prodrug therapy systems delivered by identical adenovirus vectors	en_US
dc.type	Journal Article
utslib.citation.volume	11	en_US
utslib.citation.volume	9	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1004 Medical Biotechnology	en_US
dc.location.activity	ISI:000075157700011	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	11	en_US
pubs.publication-status	Published	en_US
pubs.volume	9	en_US

Abstract:

Advanced prostate cancer is invariably lethal once it becomes androgen independent (AI). With the aim of developing a new treatment we have used the human androgen-independent prostate cancer cell line, PC-3, to evaluate the effectiveness of two enzyme-directed prodrug therapy (EPT) systems as a novel means for promoting tumor cell destruction in vivo. We have confined our study to the use of a PSA promoter, in a preliminary attempt to achieve prostate specificity. The two EPT systems used were the HSVTK/GCV and PNP/6MPDR systems. These were chosen for their differential dependence on DNA replication for their mechanism of action. In the present work, either the HSVTK or PNP gene, each controlled by a PSA promoter fragment, was delivered by an E1-, replication-deficient human adenovirus (Ad5) into PC-3 tumors growing subcutaneously in BALB/c nude mice. Tumors were injected with a single dose of recombinant Ad5 and mice were treated intraperitoneally with the appropriate prodrug, twice daily, for 6 days thereafter. The growth of established PC-3 tumors was significantly suppressed and host survival increased with a single course of HSVTK/GCV or PNP/6MPDR treatment. HSVTK/GCV-treated PC-3 tumor growth was 80% less than that of control treatments on day 33, while PNP/6MPDR-treated tumor growth was ~ 75% less than that of control treatments on day 52. Survival data showed that 20% of HSVTK/GCV- or PNP/6MPDR-treated animals lived > 45 and > 448 days, respectively, longer than control animals. These results demonstrate that both HSVTK/GCV and PNP/6MPDR therapies interrupt the growth of an aggressive human prostate cancer cell line in vivo.

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http://hdl.handle.net/10453/15519