Prostate-Specific Gene Therapy Using a "Gutless" Adeno-Vector Expressing Antisense TGF-Beta and PSA Promoter-Controlled TNF-Alpha Gene
Abstract
The goal of this research has been to develop an immune-based gene therapy that combines targeted cytotoxicity with reversal of local tumor immune suppression to eradicate prostate cancer cells. Reversal of local tumor immune suppression was achieved in vitro by blocking the over expression of TGF-beta2 produced by prostate cancer cells using TGF-beta2 phosphorothinate oligonucleotide antisense. We have been developing a gutless adenovector with extended transgene expression that we think will have enhanced safety for pre-clinical and clinical use. Our gutless adenovector DNA backbone contains the cytotoxic gene under the control of an improved prostate specific promoter and a marker GFP gene for detection in in vivo studies. Our improved PSA promoter/enhancer presents 19-fold higher transcriptional activity compared to native PSA promoter/enhancer and has no loss of tissue specificity. Using Apo2L/TRAlL, a TNF-a related cytokine with less systemic toxicity, we have demonstrated selective cytotoxicity in our highly aggressive androgen-independent prostate cancer cell line (CL1). Further in vivo studies are being conducted to evaluate the overall efficacy and safety of Apo2L/TRAIL gene therapy in combination with TGF-beta2 antisense for prostate cancer treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2002
- Accession Number
- ADA406173
Entities
People
- Arie S. Belldegrun
Organizations
- University of California, Los Angeles