Targeting of prostate cancer cells by a cytotoxic lentiviral vector containing a prostate stem cell antigen (PSCA) promoter.
BACKGROUND
The efficacy of prostate cancer gene therapy is limited by the inefficiency of prostate-specific promoters as compared to ubiquitous viral promoters. The purpose of this investigation was to evaluate the specificity and efficacy of a lentiviral vector driven by a PSCA promoter.


METHODS
Prostate cancer (LNCap, C42-B, and LAPC-4) and non-prostate cancer (HeLa, MB231, and MCF-7) cells were transduced with a lentiviral vector expressing either the luciferase or the HSV-TK suicide gene and driven by a short PSCA promoter. Specificity and efficacy were evaluated in vitro and in vivo.


RESULTS
Luciferase expression was only detected in prostate cancer cells and was comparable to the universal CMV promoter. Luciferase expression in prostate cancer cells cultured with androgen was higher than that in cells cultured without androgen. In subsequent cytotoxicity experiments in which the luciferase marker gene was replaced with the HSV-TK gene, the lentiviral vector harboring the PSCA promoter induced cytotoxicity in prostate cancer cell lines while demonstrating a minimal effect on non-prostate cells. Cellular toxicity was correlated to increasing concentrations of the prodrug ganciclovir. Androgen had a positive effect on the cytotoxicity of this lentiviral construct. Intratumoral injection of prostate cancer xenografts with the lentiviral construct induced tumor growth inhibition versus saline controls.


CONCLUSIONS
Our results indicate that a lentiviral gene therapy vector driven by a short PSCA promoter can induce prostate-specific cellular toxicity in vivo and in vitro and may provide a strategy to selectively treat local and advanced metastatic prostate cancer. Prostate 69: 1422-1434, 2009. (c) 2009 Wiley-Liss, Inc.
Petrigliano
Frank A
FA
Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. fpetrigliano@gmail.com
Virk
Mandeep S
MS
Liu
Nancy
N
Sugiyama
Osamu
O
Yu
Duan
D
Lieberman
Jay R
JR
D000728:Androgens / Q000502:physiology; D000818:Animals; D000951:Antigens, Neoplasm; D001943:Breast Neoplasms; D002470:Cell Survival; D005260:Female; D058851:GPI-Linked Proteins; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008156:Luciferases / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D008156:Luciferases; D013937:Thymidine Kinase