p53 Adenoviral vector (Ad-CMV-p53) induced prostatic growth inhibition of primary cultures of human prostate and an experimental rat model

• Published in: The journal of gene medicine 2000-11, Vol.2 (6), p.426-432
• Main Authors: Shirakawa, Toshiro, Gotoh, Akinobu, Gardner, Thomas A., Kao, Chinghai, Zhang, Zhu-Jun, Matsubara, Shigeji, Wada, Yoshitaka, Hinata, Nobuyuki, Fujisawa, Masato, Hanioka, Keisuke, Matsuo, Masafumi, Kamidono, Sadao
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; adenovirus; Animals; Apoptosis - genetics; bcl-2-Associated X Protein; benign prostatic hyperplasia (BPH); Cell Division - genetics; Cells, Cultured; Cytomegalovirus - genetics; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation; Gene therapy; Gene Transfer Techniques; Genetic Vectors - genetics; Humans; Male; Models, Animal; Muscle, Smooth - cytology; Muscle, Smooth - metabolism; Organ Size - genetics; p53; p53 protein; Promoter Regions, Genetic; Prostate - cytology; Prostate - growth & development; Prostate - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stromal Cells - cytology; Stromal Cells - metabolism; Transfection; Tumor Suppressor Protein p53 - genetics
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/1521-2254(200011/12)2:6<426::AID-JGM140>3.0.CO;2-2

Background Benign prostatic hyperplasia (BPH) is the most common proliferative disease affecting men. Numerous minimally invasive technologies are being developed or are currently in use to obviate the need for transurethral surgery. The goal of the present study was to develop a novel molecular based approach for the treatment of BPH using recombinant p53 adenoviral vector. The over‐expression of wt‐p53 can cause cell apoptosis or cell growth arrest, thus preventing the uncontrolled cell proliferation underlying BPH pathophysiology. Methods Ad‐CMV‐p53, a replication‐deficient recombinant adenovirus containing cytomegalovirus promoter driving p53 gene, was used. Human prostate stromal (PS) cells were evaluated for apoptosis (TUNEL assay), mRNA levels of key cell cycle regulators influencing apoptosis (p‐53, Bax and Bcl‐2) using quantitative RT‐PCR and cytotoxicity after Ad‐CMV‐p53. Ad‐CMV‐p53 was unilaterally injected into rat ventral prostates and growth inhibition was measured by prostate weight 3 weeks after injection. Results In vitro exposure to Ad‐CMV‐p53 significantly inhibited the proliferation of PS cells, induced mRNA over‐expression of both wt‐p53 and Bax, and increased the proportion of apoptotic cells. A 30% decrease in average prostate weight was demonstrated in rodents after Ad‐CMV‐p53 injection. Conclusions The results suggest that further investigation of molecular gene therapy with recombinant wt‐p53 adenovirus for the treatment of BPH is warranted. Copyright © 2000 John Wiley & Sons, Ltd.