Gene-directed enzyme prodrug therapy for prostate cancer in a mouse model that imitates the development of human disease.
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 ( approximately 600 mg/m(2)/day) once daily for 5 consecutive days. Treated mice received a single intraprostatic injection containing 10(10) 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.


CONCLUSIONS
A single course of GDEPT based on OAdV-delivered PNP and fludarabine produced highly significant suppression of PCa progression in immune-competent TRAMP mice.
Martiniello-Wilks
Rosetta
R
Oncology Research Centre, Prince of Wales Hospital Clinical School of Medicine, Faculty of Medicine, The University of New South Wales, Prince of Wales Hospital, Randwick, NSW 2031, Australia. r.martiniello@centenary.usyd.edu.au
Dane
Allison
A
Voeks
Dale J
DJ
Jeyakumar
Geetha
G
Mortensen
Elin
E
Shaw
Jan M
JM
Wang
Xiao Yang
XY
Both
Gerald W
GW
Russell
Pamela J
PJ
D000230:Adenocarcinoma / Q000235:genetics* / Q000662:veterinary; D000256:Adenoviridae; D000818:Animals; D030801:Animals, Genetically Modified; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs; D011467:Prostate / Q000033:anatomy & histology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000662:veterinary; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000494:pharmacology*; D016019:Survival Analysis; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D011683:Purine-Nucleoside Phosphorylase