933. Adenovirus-Mediated Delivery of Secretable Trimeric TRAIL Enhances Apoptosis and Improves Survival Compared with Conventional Chemotherapy for Malignant Gliomas

Treatment of malignant gliomas is still a significant clinical challenge. The conventional therapies for malignant gliomas yield a median survival of only 9 months. TRAIL is a novel therapeutic candidate for treating a wide variety of cancer. In particular, a secreted, soluble trimeric TRAIL (stTRAIL) easily disseminates to nearby cancer cells and induces more extensive induction of apoptosis than that of full length transmembrane TRAIL. In this study, we compared tumor suppressive activity of adenovirus mediated delivery of stTRAIL (Ad-stTRAIL) with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment, the conventional therapy for malignant glioma. Treatment with either Ad-stTRAIL or BCNU alone induced tumor-killing effects in several malignant glioma cell lines. Furthermore, the combination of Ad-stTRAIL and BCNU had a synergistic effect in vitro. To examine the effects of stTRAIL and BCNU in vivo, a disease animal model was used where U87-MG cells were injected into the brain of nude mice. The median survival of xenografted mice was 40 days. The intratumoral treatment with Ad-stTRAIL produced a significantly increase in survival compared with BCNU. MR imaging allowed the precise localization of tumors in brain and showed the established tumors were suppressed more significantly with Ad-stTRAIL treatment group than with BCNU. In situ TRAIL immunohistochemical staining and TUNEL staining showed the regression of Ad-stTRAIL treated tumor mass was due to the apoptotic cell death induced by expressed stTRAIL from Ad- stTRAIL. Our results suggest that Ad-stTRAIL treatment is a promising alternative therapy for malignant glioma as compared with conventional brain tumor therapy.