Interferon Gamma and PSA-restricted Expression of FAS Ligand: A Novel Gene Therapy Strategy for Prostate Cancer

摘要

Introduction: Fas is a transmembrane receptor which mediates apoptosis when transactivated by FasL. Earlier studies illustrated the ability of IFN-gamma to increase Fas expression on RM-l mouse prostate cancer cells. To kill the remaining Fas positive cells, the potential of combining adenovirus- mediated expression of FasL (Ad.FasL) with IFN-gamma in vifro and Ad.lL-12 to stimulate host production of lFN-gamma in vivo was addressed. Results: Alone Ad. FasL resulted in killing equal to the degree of transduction. The addition of IFN-gamma enhanced killing to maintain maximal cell kill with only 6% of cells expressing FasL. In vivo with a constant Ad.IL-12 dose and increasing doses of Ad.FasL, tumors were 25% smaller at lower doses tumors, increasing to 66% smaller at 1x10(9) pfu,. In a dose controlled experiment with equal doses of each vector (1x10(9) pfu), individually Ad.FasL and Ad.IL-12 resulted in 27+1- 10% and 54+1-4% smaller tumors with combination therapy resulting tumors which were 72+1-6% smaller than controls. However, the combination of Ad.FasL and Ad. mIL- 12 resulted in a worse survival than for Ad.IL-12 alone. However, the injection of Ad.mIL-12 into the nonnal contralateral prostate combined with the injection of the tumor by Ad.FasL resulted in superior survival. Conclusions: These studies validate the concept of exploiting Fas upregulation for fasL transactivation. The ability to eradicate tumors is currently being addressed by sequenriual injection of Ad.FasL.