title: Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy.
abstract: Alternative treatments for cancer using gene therapy approaches have shown promising results and some have even reached the marketplace. Even so, additional improvements are needed, such as employing a strategically chosen promoter to drive expression of the transgene in the target cell. Previously, we described viral vectors where high-level transgene expression was achieved using a p53-responsive promoter. Here we present an adenoviral vector (AdPGp53) where p53 is employed to regulate its own expression and which outperforms a traditional vector when tested in a model of gene therapy for prostate cancer. The functionality of AdPGp53 and AdCMVp53 were compared in human prostate carcinoma cell lines. AdPGp53 conferred greatly enhanced levels of p53 protein and induction of the p53 target gene, p21, as well as superior cell killing by a mechanism consistent with apoptosis. DU145 cells were susceptible to induction of death with AdPGp53, yet PC3 cells were quite resistant. Though AdCMVp53 was shown to be reliable, extremely high-level expression of p53 offered by AdPGp53 was necessary for tumor suppressor activity in PC3 and DU145. In situ gene therapy experiments revealed tumor inhibition and increased overall survival in response to AdPGp53, but not AdCMVp53. Upon histologic examination, only AdPGp53 treatment was correlated with the detection of both p53 and TUNEL-positive cells. This study points to the importance of improved vector performance for gene therapy of prostate cancer.
authors.affiliation: a Viral Vector Laboratory, Center for Translational Investigation in Oncology/LIM24 , Cancer Institute of São Paulo, School of Medicine, University of São Paulo , Brazil.
authors.forename: Rodrigo Esaki
authors.initials: RE
authors.lastname: Tamura
authors.affiliation: b Viral Vector Group, Laboratory of Genetics and Molecular Cardiology/LIM13 , Heart Institute, School of Medicine, University of São Paulo , Brazil.
authors.forename: Rafael Bento
authors.initials: RB
authors.lastname: da Silva Soares
authors.affiliation: c Gene Therapy Laboratory, Department of Cell and Developmental Biology , Biomedical Sciences Institute, University of São Paulo , Brazil.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Costanzi-Strauss
authors.affiliation: a Viral Vector Laboratory, Center for Translational Investigation in Oncology/LIM24 , Cancer Institute of São Paulo, School of Medicine, University of São Paulo , Brazil.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Strauss
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D011467:Prostate; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Adenovirus; apoptosis; gene therapy; p53; prostate cancer