In Situ Prostate Cancer Gene Therapy Using a Novel Adenoviral Vector Regulated by the Caveolin-1 Promoter

• Published in: Clinical cancer research 2001-12, Vol.7 (12), p.4272-4279
• Main Authors: Pramudji, C, Shimura, S, Ebara, S, Yang, G, Wang, J, Ren, C, Yuan, Y, Tahir, S A, Timme, T L, Thompson, T C
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Caveolin 1; Caveolins - genetics; Cell Survival; Genetic Therapy - methods; Genetic Vectors; Humans; Male; Mice; Mice, Inbred C57BL; Promoter Regions, Genetic; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Simplexvirus - genetics; Thymidine Kinase - genetics; Tumor Cells, Cultured
• ISSN: 1078-0432; 1557-3265

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-1 tk ) and compared with a cytomegalovirus (CMV) or Rous sarcoma virus (RSV) promoter-driven HSV- tk , AdCMV tk and AdRSV tk vectors, respectively. Mouse and human prostate cancer cells and mouse endothelial cells were infected with Adcav–1 tk , AdCMV tk 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-1 tk vector was comparable to that for AdCMV tk in multiple mouse and human prostate cancer cell lines. To evaluate the activity of Adcav-1 tk in vivo , orthotopic mouse prostate cancer tumors were generated with RM-9 cells and injected in situ with Adcav-1 tk , AdCMV tk , AdRSV tk , or AdCMVβgal (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-1 tk produced significant necrosis, and only Adcav-1 tk and AdRSV tk caused significant decreases in microvessel density. In conclusion, Adcav-1 tk 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.