Potential and caveats of TRAIL in cancer therapy

Induction of apoptosis in tumor cells is a major goal for chemotherapy and radiation treatment strategies. However, disordered gene expression often leads to apoptosis resistance rendering tumor cells insensitive to various conventional treatments. TNF-related apoptosis-inclucing ligand (TRAIL) is a recently identified cytokine of the TNF superfamily that induces apoptosis in tumor cells upon binding to different receptors. Remarkably, the majority of tumor cell lines are sensitive to TRAIL-induced apoptosis, while most nontransformed cell types are TRAIL-resistant. Furthermore, a combination treatment of TRAIL with ionizing irradiation or chemotherapeutic agents induces apoptosis in a highly synergistic manner, particularly in those cells that are otherwise resistant to a sole treatment. In contrast to other TNF members, TRAIL apparently does not exert overt systemic toxicity in murine and primate models, although unexpected concerns about a potential hepatotoxicity of TRAIL have been recently raised. While the molecular mechanisms of TRAIL sensitivity and resistance are poorly understood, TRAIL seems to be a promising biological agent for combination therapy with chemotherapeutic drugs or irradiation. (C) 2001 Harcourt Publishers Ltd.