Transcription-targeted gene therapy for androgen-independent prostate cancer.
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 approximately 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 x 10(8) 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.
Martiniello-Wilks
Rosetta
R
Oncology Research Centre, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia. r.martiniello@unsw.edu.au
Tsatralis
Tania
T
Russell
Peter
P
Brookes
Diana E
DE
Zandvliet
Dorethea
D
Lockett
Linda J
LJ
Both
Gerald W
GW
Molloy
Peter L
PL
Russell
Pamela J
PJ
D000256:Adenoviridae / Q000235:genetics; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010957:Plasmids / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000628:therapy*; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D000728:Androgens; D011355:Prodrugs