title: Configurations of a two-tiered amplified gene expression system in adenoviral vectors designed to improve the specificity of in vivo prostate cancer imaging.
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.
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1738, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: M L
authors.initials: ML
authors.lastname: Figueiredo
authors.forename: J B
authors.initials: JB
authors.lastname: Burton
authors.forename: M
authors.initials: M
authors.lastname: Johnson
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Powell
authors.forename: S S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: M
authors.initials: M
authors.lastname: Carey
authors.forename: L
authors.initials: L
authors.lastname: Wu
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017498:Adenovirus E1 Proteins / Q000235:genetics; D017503:Adenovirus E3 Proteins / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005784:Gene Amplification; D015870:Gene Expression; D017930:Genes, Reporter; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D016513:Mice, SCID; D049268:Positron-Emission Tomography; D017430:Prostate-Specific Antigen / Q000032:analysis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D017498:Adenovirus E1 Proteins; D017503:Adenovirus E3 Proteins; D013937:Thymidine Kinase; D017430:Prostate-Specific Antigen