FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo

Gene transfer vectors will dramatically increase the safety and effectivene ss of cancer gene therapy, if they could restrict expression of the therape utic products to the target tumors. To realize such a tumor-targeting syste m, telomerase is one of the most promising candidates. It is because telome rase activity is detected in the vast majority of tumors, but not in most n ormal cells. Activation of telomerase is tightly regulated at the transcrip tional level of the telomerase catalytic subunit (hTERT). Therefore, the us e of the hTERT promoter-driven vector system could restrict the expression of therapeutic products to telomerase positive tumors. In this study, we co nstructed the expression vector of FADD gene with death domain afforded by the hTERT promoter (hTERT/FADD) and investigated its effect on tumors in vi tro and in vivo. Transient transfection with the hTERT/FADD construct induc ed apoptosis in telomerase-positive tumor cells of wide range. In contrast, normal fibroblast cells without telomerase did not undergo apoptosis follo wing the hTERT/FADD transfer. Furthermore, the growth of subcutaneous tumor s in nude mice was significantly suppressed by the intratumoral injection o f the hTERT/FADD construct (every day for one week) compared to the control (P <0.0005). The findings described here indicate the high potentiality of a novel telomerase-specific gene therapy of tumors with telomerase.