Transcription-targeted gene therapy for androgen-independent prostate cancer

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� 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. Cancer Gene Therapy (2002 ) 9, 443– 452 DOI: 10.1038 /sj/cgt/7700451