Interferon Gamma and PSA-Restricted Expression of FAS Ligand: A Novel Gene Therapy Strategy for Prostate Cancer
Abstract
Preliminary studies and work during the past 2 years illustrated the ability of IFN-gamma to restore or enhance sensitivity to Fas transactivation in vitro. However, the combination of Ad.FasL and Ad.mIL-12 resulted in a worse survival than for Ad.IL-12 alone. Studies focused first on injection schemes to improve on these results and understand the mechanisms underlying the reversal of resistance to Fas transactivation by IFN-gamma. Secondly, studies addressed the block in the Fas-apoptotic pathway mediated by IFN-gamma. Based on the serum peaks of IL-12 (Days 2/8) and IFN-gamma (4/11) measured following IL-12 gene therapy, a staggered injection pattern was developed, injecting orthotopic tumors with Ad.mIL-12 on day 6 and Ad.FasL on days 8 and 11. This resulted in a near tripling of apoptosis in combination treated tumors and a doubling of mean survival. In the human prostate cancer cell lines, PC3 and LNCaP, studies with caspase substrates noted that the CPP32 family was activated and not the ICE family following exposure to IFN-gamma and sFasL. Cell death could be blocked by the general caspase inhibitor z-VAD-FMK and the CPP32 inhibitor, z-DEVD-FMK and not the ICE inhibitor, ac-YVAD-CMK. Conclusions: These studies validate the concept of exploiting Fas upregulation for FasL transactivation using a sequential injection scheme of Ad.mIL-12 and Ad.FasL. Thus far, in the Fas sensitive cell line, PC3, and resistant cell line, LNCaP, sFasL activates the CPP32 family of caspases to induce apoptosis following IFN-gamma treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2002
- Accession Number
- ADA407038
Entities
People
- Simon J. Hall
Organizations
- Icahn School of Medicine at Mount Sinai