Suppression of pancreatic tumor growth in the liver by systemic administration of the TRAIL gene driven by the hTERT promoter

摘要

Local and locoregional administration of adenovectors expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been demonstrated to be useful in treating established tumors in animals. Moreover, expression of the TRAIL gene from the human telomerase reverse transcriptase (hTERT) promoter can be used to prevent possible liver toxicity of the TRAIL gene. However, it remains unknown whether systemic administration of the TRAIL-expressing adenovector can be used for cancer therapy. Here, we showed that a combination of TRAIL gene therapy and gemcitabine, the first-line chemotheraphy agent for pancreatic cancer, had a synergistic effect on the induction of apoptosis in human pancreatic cancer cell lines in vitro. Systemic administration of an adenovector that contains an insertion of integrin-binding motif argine-glycine-aspartate (RGD) in the HI loop of the adenoviral fiber protein and expresses the human TRAIL gene from the hTERT promoter (designated Ad/TRAIL-F/RGD) suppressed the growth of human pancreatic tumor cells inoculated in the liver of nuu nude mice. Furthermore, Ad/TRAIL-F/RGD in combination with gemcitabine suppressed the tumor growth of pancreatic cancer in the liver more than did treatments consisting of each agent alone. No obvious liver toxicity was detected in any of the treatment groups. Our results suggest that TRAIL gene therapy in combination with gemcitabine might be a useful therapeutic approach for treating metastatic pancreatic cancers.