title: In situ prostate cancer gene therapy using a novel adenoviral vector regulated by the caveolin-1 promoter.
abstract: Caveolin-1, a structural component of caveolae, is overexpressed in metastatic and androgen-resistant prostate cancer and highly expressed in tumor-associated endothelial cells. The mouse cav-1 promoter was cloned and placed upstream of the HSV-tk gene in an adenoviral vector (Adcav-1tk) and compared with a cytomegalovirus (CMV) or Rous sarcoma virus (RSV) promoter-driven HSV-tk, AdCMVtk and AdRSVtk vectors, respectively. Mouse and human prostate cancer cells and mouse endothelial cells were infected with Adcav-1tk, AdCMVtk or control vectors without the HSV-tk gene (Adcav-1 and AdCMV) and subsequently treated with ganciclovir (GCV). GCV-mediated in vitro cytotoxicity induced by the Adcav-1tk vector was comparable to that for AdCMVtk in multiple mouse and human prostate cancer cell lines. To evaluate the activity of Adcav-1tk in vivo, orthotopic mouse prostate cancer tumors were generated with RM-9 cells and injected in situ with Adcav-1tk, AdCMVtk, AdRSVtk, or AdCMVbetagal (control) and treated with GCV. All three HSV-tk transducing vectors produced statistically significant reductions in wet weight and increased apoptotic indices compared with the control vector. However, only Adcav-1tk produced significant necrosis, and only Adcav-1tk and AdRSVtk caused significant decreases in microvessel density. In conclusion, Adcav-1tk demonstrated efficacy in vitro and in vivo in preclinical models of prostate cancer. Our results suggest that the cav-1 promoter may have unique benefits in targeting gene therapy to prostate cancer and its associated vasculature.
authors.affiliation: Matsunaga-Conte Prostate Cancer Research Center and Scott Department of Urology, Baylor College of Medicine, 6560 Fannin Street, Houston, TX 77030, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pramudji
authors.forename: S
authors.initials: S
authors.lastname: Shimura
authors.forename: S
authors.initials: S
authors.lastname: Ebara
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Ren
authors.forename: Y
authors.initials: Y
authors.lastname: Yuan
authors.forename: S A
authors.initials: SA
authors.lastname: Tahir
authors.forename: T L
authors.initials: TL
authors.lastname: Timme
authors.forename: T C
authors.initials: TC
authors.lastname: Thompson
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics*; D002470:Cell Survival; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D013937:Thymidine Kinase