1. ¹Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
2. ²Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
3. ³Department of Molecular Cellular & Integrative Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
4. ⁴Department of Radiology and the Bio-X Program, Stanford University, School of Medicine, Stanford, CA, USA
5. ⁵Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
6. ⁶Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
7. ⁷Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

Correspondence: Dr L Wu, Department of Urology, University of California, MRL 2210, Box 951738, Los Angeles, CA 90095-1738, USA. E-mail: lwu@mednet.ucla.edu

Received 1 November 2007; Revised 19 January 2008; Accepted 20 January 2008; Published online 28 February 2008.

Abstract

Effective treatment for recurrent, disseminated prostate cancer is notably limited. We have developed adenoviral vectors with a prostate-specific two-step transcriptional amplification (TSTA) system that would express therapeutic genes at a robust level to target metastatic disease. The TSTA system employs the prostate-specific antigen (PSA) promoter/enhancer to drive a potent synthetic activator, which in turn activates the expression of the therapeutic gene. In this study, we explored different configurations of this bipartite system and discovered that physical separation of the two TSTA components into E1 and E3 regions of adenovirus was able to enhance androgen regulation and cell-discriminatory expression. The TSTA vectors that express imaging reporter genes were assessed by noninvasive imaging technologies in animal models. The improved selectivity of the E1E3 configured vector was reflected in silenced ectopic expression in the lung. Significantly, the enhanced specificity of the E1E3 vector enabled the detection of lung metastasis of prostate cancer. An E1E3 TSTA vector that expresses the herpes simplex virus thymidine kinase gene can effectively direct positron emission tomography (PET) imaging of the tumor. The prostate-targeted gene delivery vectors with robust and cell-specific expression capability will advance the development of safe and effective imaging guided therapy for recurrent metastatic stages of prostate cancer.