Interferon Gamma and PSA-Restricted Expression of FAS Ligand: A Novel Gene Therapy Strategy for Prostate Cancer
Final rept. 1 Mar 2000-28 Feb 2003
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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Introduction Preliminary studies pointed to the ability for IFN-gamma to enhance sensitivity andor reverse resistance to Fas transactivation on prostate cancer cells and work during the past 2 years illustrated the ability of IFN-gamma to restore or enhance sensitivity to Fas transactivation in vitro. Studies exploded the usefulness of combining adenovirus mediated FasL expression with IFN-gamma, the mechanism underlying IFN-gamma effects on Fas sensitivity in human cells lines and the deivatgion of a better vector to deliver FasL. Results In vitro and in vivo, the combination of Ad.FasL and Ad.mIL-12-IFN-gamma resulted in powerful interactions to control growth. However, a staggered injection scheme was necessary to prevent the negative effects of FasL on IL-12IFN-gamma production. 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. Apoptosis was mediated through caspase 8. The enhancement of the delivery vector focused on vesicular stomatitis virus VSV. Studies noted the ability of VSV to rapidly kill human and mouse prostate cancer cells but not normal prostate epithelial cells. In addition infected cells expressed high levels of FasL. Conclusions These studies validate the concept of exploiting Fas upregulation for FasL transactivation through manipulation of the host to produce IFN-gamma through IL-12 gene therapy. The VSV vector is a powerful vector to kill prostate cancer cells and will be exploited further as a delivery vehicle for transgenes, such as FasL.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research