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Adenoviral Gene Transfer of Tumor Necrosis Factor-related Apoptosis-Inducing Ligand Overcomes an Impaired Response of Hepatoma Cells but Causes Severe Apoptosis in Primary Human Hepatocytes¹

Medical University Clinic, Department of Internal Medicine I [S. A., U. M. L., I. S., M. G., M. B], Surgical University Clinic, Department of General Surgery [M. S.], 72076 Tübingen, and Center for Liver Cell Research, University Hospital, 93042 Regensburg [T. S. W.], Germany

Ligands of the tumor necrosis factor family play key roles in liver pathogenesis. The ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is unique, because it is thought to be nontoxic to normal cells while killing a broad range of tumor cells. However, hepatocellular carcinoma is considered resistant to soluble TRAIL treatment. Therefore, a direct gene transfer of TRAIL to malignant cells is part of an alternative delivery strategy. We show that an adenoviral gene transfer (Ad-TRAIL) overcomes an impaired response of hepatocellular carcinoma cell lines to soluble TRAIL, but the transduction of primary human hepatocytes revealed a high number of apoptotic cells. Our data imply that Ad-TRAIL administration in vivo must either be restricted to tumor tissue or controlled by a tumor-specific promoter to avoid severe liver damage in human trials.

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