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 hepatocytes

Sorin Armeanu; Ulrich M Lauer; Irina Smirnow; Martin Schenk; Thomas S Weiss; Michael Gregor; Michael Bitzer

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 hepatocytes

Cancer Res. 2003 May 15;63(10):2369-72.

Authors

Sorin Armeanu¹, Ulrich M Lauer, Irina Smirnow, Martin Schenk, Thomas S Weiss, Michael Gregor, Michael Bitzer

Affiliation

¹ Medical University Clinic, Department of Internal Medicine I, Tübingen, Germany.

PMID: 12750253

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoviruses, Human / genetics
Apoptosis / genetics*
Apoptosis Regulatory Proteins
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / therapy
Caspases / metabolism
Drug Resistance, Neoplasm
Enzyme Activation
Gene Transfer Techniques
Genetic Therapy / adverse effects*
Genetic Therapy / methods
Hepatocytes / enzymology
Hepatocytes / metabolism
Hepatocytes / pathology*
Humans
Liver Neoplasms / genetics*
Liver Neoplasms / metabolism
Liver Neoplasms / therapy
Membrane Glycoproteins / adverse effects
Membrane Glycoproteins / biosynthesis
Membrane Glycoproteins / genetics*
Membrane Glycoproteins / pharmacology
TNF-Related Apoptosis-Inducing Ligand
Transduction, Genetic
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / adverse effects
Tumor Necrosis Factor-alpha / biosynthesis
Tumor Necrosis Factor-alpha / genetics*
Tumor Necrosis Factor-alpha / pharmacology

Substances

Apoptosis Regulatory Proteins
Membrane Glycoproteins
TNF-Related Apoptosis-Inducing Ligand
TNFSF10 protein, human
Tumor Necrosis Factor-alpha
Caspases