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To evaluate the tumoricidal activity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on disseminated liver metastatic tumors, we constructed a recombinant adeno-associated virus (rAAV) expressing the extracellular domain (95–281aa) of human TRAIL (TRAIL95–281, and the recombinant virus was designated as rAAV-TRAIL) using the 3-plasmid, helper-virus-free, packaging system. Transduction of mouse lymphoma EL-4 cells and Jurkat T cells lead to the expression of TRAIL95–281 protein in both virus-transduced cells and the culture media, along with apoptosis of these cellsin vitro. The therapeutic potential of rAAV-TRAIL was then evaluated in an orthotopic transplanted mouse model mimicking liver cancer metastasis, which was established by injection of EL-4 cells into the liver of C57BL/6 miceviathe hepatic portal veins. Subsequent intraportal vein injection of rAAV-TRAIL, not the control virus, into the liver of these mice resulted in significant suppression of tumor growth and prolonged survival, while normal hepatocyte toxicity is undetectable. Histological and biochemical analysis in tumor tissue and serum confirmed that TRAIL95–281 was stably expressed in relatively high level in hepatocytes and was secreted into the serum in active trimeric form. Futhermore, the mechanism for rAAV-TRAIL to inhibit tumor growth was by inducing apoptosis of the tumor cells metastasizing to the livers. These results strongly suggest that the rAAV-TRAIL-mediated gene delivery could be a promising approach for the treatment of liver metastasis cancer.