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Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus.
- Source :
-
Gene therapy [Gene Ther] 2004 Nov; Vol. 11 (21), pp. 1559-67. - Publication Year :
- 2004
-
Abstract
- Gene-directed enzyme prodrug therapy (GDEPT) based on the Escherichia coli enzyme, purine nucleoside phosphorylase (PNP), provides a novel strategy for treating slowly growing tumors like prostate cancer (CaP). PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis. Reporter gene expression directed by a hybrid prostate-directed promoter and enhancer, PSMEPb, was assayed after plasmid transfection or viral transduction of prostate and non-CaP cell lines. Androgen-sensitive (AS) LNCaP-LN3 and androgen-independent (AI) PC3 human CaP xenografts in nude mice were injected intratumorally with an ovine atadenovirus vector, OAdV623, that carries the PNP gene under PSMEPb, formulated with cationic lipid for enhanced infectivity. Fludarabine phosphate was then given intraperitoneally for 5 days at 75 mg/m2/day. PNP expression was evaluated by enzymic conversion of its substrate using reverse phase HPLC. OAdV623 showed excellent in vitro transcriptional specificity for CaP cells. In vivo, expression of PNP persisted for > 6 days after OAdV623 injection and a single treatment provided 100% increase in tumor doubling time and > 50% inhibition of tumor growth for both LNCaP-LN3 and PC3 lines, with increased tumor necrosis and apoptosis and decreased tumor cell proliferation. OAdV623 significantly suppressed the growth of AS and AI human CaP xenografts in mice.
- Subjects :
- Adenine metabolism
Animals
Antineoplastic Agents metabolism
Apoptosis
Cell Line, Tumor
Cell Proliferation
DNA Replication drug effects
Drug Evaluation, Preclinical
Genetic Vectors administration & dosage
Humans
Male
Mice
Mice, Nude
Neoplasm Transplantation
Prostatic Neoplasms metabolism
Purine-Nucleoside Phosphorylase metabolism
Vidarabine Phosphate metabolism
Adenine analogs & derivatives
Antineoplastic Agents therapeutic use
Genetic Therapy methods
Prodrugs therapeutic use
Prostatic Neoplasms therapy
Purine-Nucleoside Phosphorylase genetics
Vidarabine Phosphate analogs & derivatives
Vidarabine Phosphate therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0969-7128
- Volume :
- 11
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Gene therapy
- Publication Type :
- Academic Journal
- Accession number :
- 15343359
- Full Text :
- https://doi.org/10.1038/sj.gt.3302308