Transcriptionally regulated adenoviruses for prostate-specific gene therapy.

Abstract

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.