Gene-directed enzyme prodrug therapy for prostate cancer in a mouse model that imitates the development of human disease

Martiniello-Wilks, R; Dane, A; Voeks, DJ; Jeyakumar, G; Mortensen, E; Shaw, JM; Wang, XY; Both, GW; Russell, PJ

Gene-directed enzyme prodrug therapy for prostate cancer in a mouse model that imitates the development of human disease

Martiniello-Wilks, R

Dane, A Voeks, DJ Jeyakumar, G Mortensen, E Shaw, JM Wang, XY Both, GW Russell, PJ

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Publication Type:: Journal Article
Citation:: Journal of Gene Medicine, 2004, 6 (1), pp. 43 - 54
Issue Date:: 2004-01-01

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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	Dane, A	en_US
dc.contributor.author	Voeks, DJ	en_US
dc.contributor.author	Jeyakumar, G	en_US
dc.contributor.author	Mortensen, E	en_US
dc.contributor.author	Shaw, JM	en_US
dc.contributor.author	Wang, XY	en_US
dc.contributor.author	Both, GW	en_US
dc.contributor.author	Russell, PJ	en_US
dc.date.issued	2004-01-01	en_US
dc.identifier.citation	Journal of Gene Medicine, 2004, 6 (1), pp. 43 - 54	en_US
dc.identifier.issn	1099-498X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/15553
dc.description.abstract	Background. Gene-directed enzyme prodrug therapy (GDEPT) based on the E. coli enzyme purine nucleoside phosphorylase (PNP) represents a new approach for treating slow growing tumours like prostate cancer (PCa). Expressed enzyme converts a systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine. Infected and neighbouring cells are killed by a bystander effect that results from the inhibition of DNA and RNA synthesis. Methods. These studies were carried out using the transgenic adenocarcinoma of the prostate (TRAMP) model that mimics human PCa development and progression. Control TRAMP mice were injected intraprostatically with vector vehicle and thereafter intraperitoneally with saline or fludarabine phosphate (∼600 mg/m2/day) once daily for 5 consecutive days. Treated mice received a single intraprostatic injection containing 1010 particles of OAdV220, an ovine atadenovirus which expresses the E. coli PNP gene under the control of the Rous sarcoma virus promoter, followed by systemic fludarabine treatment. The weight of the genitourinary tract, seminal vesicles and the prostate as well as animal survival were monitored. Tumours were also analysed histologically. Results. Preliminary studies showed that fludarabine alone caused no significant change in genitourinary (GU) tract weight in TRAMP mice. Animals injected with vector and prodrug showed a significant reduction (36-47%) in GU tract weight (ANOVA p = 0.0002) and a 35-50% reduction in seminal vesicle weight (ANOVA p = 0.0007). In particular, the target organ showed a significant 57% reduction in prostate weight (ANOVA p = 0.0007). PNP-GDEPT mice also showed a survival advantage over control mice. Histological analysis suggested that the cancer progression was slowed in GDEPT-treated animals. Conclusion. A single course of GDEPT based on OAdV-delivered PNP and fludarabine produced highly significant suppression of PCa progression in immune-competent TRAMP mice. Copyright © 2004 John Wiley & Sons, Ltd.	en_US
dc.relation.ispartof	Journal of Gene Medicine	en_US
dc.relation.isbasedon	10.1002/jgm.474	en_US
dc.subject.classification	Biotechnology	en_US
dc.subject.mesh	Prostate	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Animals, Genetically Modified	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Escherichia coli	en_US
dc.subject.mesh	Adenoviridae	en_US
dc.subject.mesh	Adenocarcinoma	en_US
dc.subject.mesh	Prostatic Neoplasms	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Purine-Nucleoside Phosphorylase	en_US
dc.subject.mesh	Vidarabine Phosphate	en_US
dc.subject.mesh	Antimetabolites, Antineoplastic	en_US
dc.subject.mesh	Prodrugs	en_US
dc.subject.mesh	Infusions, Parenteral	en_US
dc.subject.mesh	Survival Analysis	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Genetic Therapy	en_US
dc.title	Gene-directed enzyme prodrug therapy for prostate cancer in a mouse model that imitates the development of human disease	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	6	en_US
utslib.for	1103 Clinical Sciences	en_US
dc.location.activity	ISI:000188661900005	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	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	6	en_US

Abstract:

Background. Gene-directed enzyme prodrug therapy (GDEPT) based on the E. coli enzyme purine nucleoside phosphorylase (PNP) represents a new approach for treating slow growing tumours like prostate cancer (PCa). Expressed enzyme converts a systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine. Infected and neighbouring cells are killed by a bystander effect that results from the inhibition of DNA and RNA synthesis. Methods. These studies were carried out using the transgenic adenocarcinoma of the prostate (TRAMP) model that mimics human PCa development and progression. Control TRAMP mice were injected intraprostatically with vector vehicle and thereafter intraperitoneally with saline or fludarabine phosphate (∼600 mg/m2/day) once daily for 5 consecutive days. Treated mice received a single intraprostatic injection containing 1010 particles of OAdV220, an ovine atadenovirus which expresses the E. coli PNP gene under the control of the Rous sarcoma virus promoter, followed by systemic fludarabine treatment. The weight of the genitourinary tract, seminal vesicles and the prostate as well as animal survival were monitored. Tumours were also analysed histologically. Results. Preliminary studies showed that fludarabine alone caused no significant change in genitourinary (GU) tract weight in TRAMP mice. Animals injected with vector and prodrug showed a significant reduction (36-47%) in GU tract weight (ANOVA p = 0.0002) and a 35-50% reduction in seminal vesicle weight (ANOVA p = 0.0007). In particular, the target organ showed a significant 57% reduction in prostate weight (ANOVA p = 0.0007). PNP-GDEPT mice also showed a survival advantage over control mice. Histological analysis suggested that the cancer progression was slowed in GDEPT-treated animals. Conclusion. A single course of GDEPT based on OAdV-delivered PNP and fludarabine produced highly significant suppression of PCa progression in immune-competent TRAMP mice. Copyright © 2004 John Wiley & Sons, Ltd.

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http://hdl.handle.net/10453/15553