Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo

The intractability of malignant gliomas to multimodality treatments plays a large part in their extremely poor prognosis. Tumor necrosis factor-relate d apoptosis-inducing ligand (TRAIL) is a novel member of the tumor necrosis factor (TNF) family that induces apoptosis preferentially in tumor cells t hrough binding to its cognate death receptors, DR4 and DR5. Here we show th at the DNA-damaging chemotherapeutic drugs, cis-diamminedichloroplatinum(II ) (CDDP) and etoposide, elicited increased expression of DR5 in human gliom a cells. Exposure of such cells in vitro to soluble human TRAIL in combinat ion with CDDP or etoposide resulted in synergistic cell death that could be blocked by soluble TRAIL-neutralizing DR5-Fc or the caspase inhibitors, Z- Asp-CH2-DCB and CrmA. Moreover, systemic in vivo administration of TRAIL wi th CDDP synergistically suppressed both tumor formation and growth of estab lished s.c human glioblastoma xenografts in nude mice by inducing apoptosis without causing significant general toxicity. The combination treatment re sulted in complete and durable remission in 29% of mice with the establishe d s.c, xenografts and also significantly extended the survival of mice bear ing intracerebral xenografts. These results provide preclinical proof-of-pr inciple for a novel therapeutic strategy in which the death ligand, TRAIL, is safely combined with conventional DNA-damaging chemotherapy.