The potential of TRAIL for cancer chemotherapy

Innate and acquired resistance to chemotherapy and radiation therapy has be en a major obstacle for clinical oncology. One potential adjunct to such co nventional treatments is direct induction of cell death by activation of de ath receptor-mediated apoptosis. TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand), a recently identified member of the growing TN F superfamily, binds to its cognate "death" receptors DR4 and DR5 as well a s "decoy" receptors DcR1 and DcR2. Upon binding, rapid apoptosis is enacted in a variety of human cancer cell lines independent of p53 status, but not in normal cell lines. TRAIL treatment results in significant growth suppre ssion of TRAIL-sensitive human cancer xenografts in mice. Furthermore, comb ination treatment of TRAIL with genotoxic chemotherapeutic agents synergist ically suppresses growth of tumor xenografts which are otherwise resistant to treatment with TRAIL or chemotherapy alone. Unlike the other death ligan ds TNF-alpha or FasL, systemic administration of soluble human TRAIL does n ot cause toxicity in mice and non-human primates. While further studies are needed to evaluate the possible cytotoxicity of TRAIL especially for human hepatocytes, indications are increasing that TRAIL may be a novel therapeu tic agent for human cancer.