Prostate Specific Gene Therapy Using a 'Gutless' Adene-Vector Expressing Antisense TGF-B and PSA Promoter-Controlled TNF-A Gene

摘要

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 phosphorothioate oligonucleotide antisense. We have been developing a gutless adenovector with extended transgene expression that we think will have enhanced safety for preclinical and clinical use. Our gutless adenovector DNA backbone contains the cytotoxic gene under the control of an improved prostate specific promoter and a marker OFP gene for detection 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/TRAIL, a TNF-alpha 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/TRAlL gene therapy in combination with TGF-beta2 antisense for prostate cancer treatment.