The concept that TRAIL can be used to treat human cancers without inducing hepatotoxicity in vivo remains a tantalizing hope. Current data that suggest that TRAIL might be toxic to hepatocytes is subject to alternative interpretations but cannot be ignored. These data should be used to generate additional preclinical studies and to prompt the inclusion of appropriate safeguards into the design of early clinical trials. Given the limitations of the recent data on TRAIL hepatotoxicity, however, it is also important that preclinical and clinical development of this agent not be abandoned prematurely. In addition, it might be feasible to begin searching for selective agonists capable of binding TRAIL-R1 or -R2 selectively in hopes that these agents might induce apoptosis in cancer cells but not normal, healthy hepatocytes. Finally, TRAIL needs more attention as a potential mediator of liver injury in disease states (Fig. 2). It is likely that drugs and pathophysiologic perturbations in hepatocyte function may induce TRAIL-R2 and/or render the hepatocyte susceptible to toxicity by its ligand. Additional studies using a variety of cellular and animal models are required to address these issues.
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