1. ¹Department of Urology, Indiana University, Indianapolis, IN 46202, USA
2. ²Department of Microbiology and Immunology, Indiana University, Indianapolis, IN 46202, USA
3. ³Walther Oncology Cancer Center, Indianapolis, IN 46202, USA
4. ⁴Department of Medicine, Indiana University, Indianapolis, IN 46202, USA

Correspondence: Chinghai Kao, Department of Urology, Indiana University, Room OPW320, 1001 W. 10th Street, Wishard Hospital, Indianapolis, IN 46202, USA. Fax: (317) 278 3432. E-mail: chkao@iupui.edu

Received 10 May 2004; Accepted 30 August 2004.

Abstract

Prostate cancer is the second most commonly diagnosed cancer in men and accounts for significant mortality and morbidity in the United States. Initially androgen-dependent, prostate cancer ultimately becomes androgen-independent, which makes the disease extremely difficult to cure. In this study, we examined the use of conditionally replication-competent adenovirus for the treatment of hormone-independent prostate cancer. We utilized PSME, an enhancer element for prostate-specific PSMA expression, to control viral E1A protein expression and achieve exclusive virus replication in prostate. Western blotting confirmed that PSME mediated high E1A protein expression in PSMA-positive, androgen-independent prostate cancer cells (C4-2 and CWR22rv), but was much less active in PSMA-negative cancer cells (PC-3 and A549). Consistent with E1A protein expression, the recombinant adenovirus Ad5-PSME-E1a replicated in C4-2 and CWR22rv almost as efficiently as wild type with low levels of androgen, but its replication was significantly attenuated in PSMA-negative cells. In the in vitro killing assay, Ad5-PSME-E1a lysed all C4-2 and CWR22rv cells 5 days after infection, with minimal effect on PSMA-negative cells. In addition, injections of 1.7 10⁸ plaque-forming units in a CWR22rv xenograft model in nude mice induced significant tumor growth delay, with a substantial necrotic area. These studies suggest that PSME-driven replication-competent adenovirus may be a new therapeutic modality for prostate cancer patients after hormone ablation therapy.