title: Purine nucleoside phosphorylase and fludarabine phosphate gene-directed enzyme prodrug therapy suppresses primary tumour growth and pseudo-metastases in a mouse model of prostate cancer.
abstract: Gene-directed enzyme prodrug therapy based on the E. coli purine nucleoside phosphorylase (PNP) gene produces efficient tumour cell killing. PNP converts adenosine analogs into toxic metabolites that diffuse across cell membranes to kill neighbouring untransduced cells (PNP-GDEPT). Interference with DNA, RNA and protein synthesis kills dividing and non-dividing cells, an important consideration for slow-growing prostate tumours. This study examined the impact of administering PNP-GDEPT into orthotopically grown RM1 prostate cancers (PCas) on the growth of lung pseudo-metastases of immunocompetent mice. C57BL/6 mice bearing orthotopic RM1 PCas received a single intraprostatic injection of OAdV220 (10(10) particles), a recombinant ovine atadenovirus containing the PNP gene controlled by the Rous Sarcoma virus promoter, followed by fludarabine phosphate (approximately 600 mg/m(2)/day) administered intraperitoneally (ip) once daily for 5 days. Pseudo-metastases were induced 2 days after intraprostatic vector administration by tail-vein injection of untransduced RM1 cells. Mice given PNP-GDEPT showed a significant reduction both in prostate volume (approximately 50%) and in lung colony counts (approximately 60%). Apoptosis was increased two-fold in GDEPT-treated prostates compared with controls (P < 0.01), but was absent in the lungs. Staining for proliferating cell nuclear antigen (PCNA) indicated that proliferation of both RM1 prostate tumours (P < 0.01) and lung colonies (P < 0.01) was significantly suppressed after GDEPT. Although prostate tumour immune cell infiltration did not differ significantly between treatments, immunostaining for Thy-1.2 (CD90) showed that GDEPT promoted Thy-1.2(+) cell infiltration into the prostate tumour site. This study showed that a single course of PNP-GDEPT significantly suppressed local PCa growth and reduced lung colony formation in the aggressive RM1 tumour model.
authors.affiliation: Oncology Research Centre, Prince of Wales Hospital Clinical School of Medicine, Faculty of Medicine, The University of New South Wales, Level 2, Clinical Sciences Building, Barker Street, Randwick, NSW 2031, Australia. r.martiniello@centenary.usyd.edu.au
authors.forename: Rosetta
authors.initials: R
authors.lastname: Martiniello-Wilks
authors.forename: Xiao Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Voeks
authors.forename: Allison
authors.initials: A
authors.lastname: Dane
authors.forename: Jan M
authors.initials: JM
authors.lastname: Shaw
authors.forename: Elin
authors.initials: E
authors.lastname: Mortensen
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Both
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002417:Cattle; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary* / Q000628:therapy / Q000662:veterinary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D011355:Prodrugs; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000628:therapy* / Q000662:veterinary; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000494:pharmacology*; D014161:Transduction, Genetic; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D018809:Proliferating Cell Nuclear Antigen; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D011683:Purine-Nucleoside Phosphorylase