A novel telomerase-specific gene therapy: Gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter

Apoptosis is a genetically encoded cell death process and is a pathway that may be disrupted in tumor cells. Therefore, therapies that restore the abi lity to undergo apoptosis are promising for the treatment of tumor cells. W e have demonstrated that the transfer of apoptosis-inducible genes inhibits the growth of tumors in vitro and in vivo through induction of apoptosis. However, to restrict induction of apoptosis to tumor cells, we need to expl ore a tumor-specific expression system of these genes. In the present study , we developed the telomerase-specific transfer system of apoptosis-inducib le genes, utilizing the promoter of the human telomerase catalytic subunit (hTERT) gene. Approximately 90% of tumors have telomerase activity whereas most normal cells do not express the activity. These observations indicate that telomerase is a particularly attractive target for the tumor-specific expression system of vectors. We demonstrate here that by using the hTERT p romoter-driven caspase-8 expression vector (hTERT/caspase-8), apoptosis is restricted to telomerase-positive tumor cells of wide range, and is not see n in normal fibroblast cells without telomerase activity. Furthermore, trea tment of subcutaneous tumors in nude mice with the hTERT/caspase-8 construc t inhibited tumor growth significantly because of induction of apoptosis (p < 0.01). The telomerase-specific expression of apoptosis-inducible genes a fforded by the hTERT promoter, therefore, may be a novel and promising targ eting approach for the treatment of tumors with telomerase activity.