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- Title
Transcription-targeted gene therapy for androgen-independent prostate cancer.
- Authors
Martiniello-Wilks, Rosetta; Tsatralis, Tania; Russell, Peter; Brookes, Diana E; Zandvliet, Dorethea; Lockett, Linda J; Both, Gerald W; Molloy, Peter L; Russell, Pamela J
- Abstract
The Escherichia coli enzyme (purine nucleoside phosphorylase, PNP) gene is delivered directly into PC3 tumors by one injection of replication-deficient human type-5 adenovirus (Ad5). Expressed PNP converts the systemically administered prodrug, 6MPDR, to a toxic purine, 6MP, causing cell death. We sought to increase the specificity of recombinant Ad vectors by controlling PNP expression with the promoter region from the androgen-dependent, prostate-specific rat probasin (Pb) gene. To increase its activity, the promoter was combined with the SV40 enhancer (SVPb). Cell lines were transfected with plasmids containing both a reporter gene, under SVPb control, and a reference gene cassette to allow normalization of expression levels. Plasmids expressed ∼20-fold more reporter in prostate cancer than in other cells, but surprisingly, the SVPb element was both androgen-independent and retained substantial prostate specificity. Killing by Ad5-SVPb-PNP vector of cell lines cultured with 6MPDR for 6 days was 5- to 10-fold greater in prostate cancer than in liver or lung cells. In vivo, a single intratumoral injection of Ad5-SVPb-PNP (4×108 pfu), followed by 6MPDR administration twice daily for 6 days, significantly suppressed the growth of human prostate tumors in nude mice and increased their survival compared to control animals. Thus, the androgen-independent, prostate-targeting Ad5 vector reduces human prostate cancer growth significantly in vitro and in vivo. This first example of an androgen-independent vector points the way toward treatment of emerging androgen-independent prostate cancer in conjunction with hormone ablation therapy at a time when the tumor burden is low. Cancer Gene Therapy (2002) 9, 443–452 DOI: 10.1038/sj/cgt/7700451
- Subjects
ADENOVIRUS diseases; PROSTATE cancer; PURINES; PROSTATE-specific antigen; THERAPEUTICS
- Publication
Cancer Gene Therapy, 2002, Vol 9, Issue 5, p443
- ISSN
0929-1903
- Publication type
Article
- DOI
10.1038/sj.cgt.7700451