Transcriptionally regulated adenoviruses for prostate-specific gene therapy.
Most virally based vectors for gene therapy contain viral promoters that are tissue-nonspecific. Consequently, unintended expression of toxic therapeutic genes in normal tissues may potentially occur. We have constructed adenoviruses that contain a bacterial beta-galactosidase (beta-gal) gene (lacZ) under the control of three different prostate-specific promoters: prostate-specific antigen (PSA), probasin, and the mouse mammary-tumor-virus long terminal repeat (MMTV; prostate-specific Ad-lacZ). In general, these prostate-specific Ad-lacZ can effectively transduce and express beta-gal in prostate cells and display weak, if any, expression of beta-gal in nonprostate cells in vitro. In vivo, these adenoviruses showed a high level of beta-gal expression in canine prostate but also disseminated to tissues other than prostate after intraprostatic (i.p.) injection. However, none of the prostate-specific Ad-lacZ expressed beta-gal in these nonprostate tissues. Furthermore, prostate-specific Ad-lacZ expressed beta-gal only in xenograft tumors grown in nude mice, derived from human prostate-cancer cells DU145 and PPC-1, but showed no beta-gal expression in tumors derived from human bladder-cancer cells RT4. These results indicate that adenoviruses containing prostate-specific promoters may express intended transgenes specifically in prostate in vivo.
Lu
Y
Y
Department of Urology, College of Medicine, University of Tennessee, Memphis 38163, USA. ylu@utmem1.utmem.edu
Steiner
M S
MS
D000256:Adenoviridae / Q000235:genetics*; D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007763:Lac Operon; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000628:therapy*; D014158:Transcription, Genetic / Q000235:genetics*; D019076:Transgenes / Q000235:genetics; D014407:Tumor Cells, Cultured
D000727:Androgen-Binding Protein; C027519:probasin; D017430:Prostate-Specific Antigen