Possible novel therapy for malignant gliomas with secretable trimeric TRAIL

• Published in: PloS one Vol. 4; no. 2; p. e4545
• Main Authors: Jeong, Moonsup, Kwon, Yong-Sam, Park, Soon-Hye, Kim, Chae-Young, Jeun, Sin-Soo, Song, Kang-Won, Ko, Yong, Robbins, Paul D, Billiar, Timothy R, Kim, Byong-Moon, Seol, Dai-Wu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.02.2009; Public Library of Science (PLoS)
• Subjects: Adenoviridae - genetics; Adenoviruses; Advertising executives; Animals; Antineoplastic agents; Apoptosis; Brain; Brain cancer; Brain research; Brain tumors; Carmustine - therapeutic use; Cell Biology/Cellular Death and Stress Responses; Cytotoxicity; Drug Therapy, Combination; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Genetics and Genomics/Gene Therapy; Glioma; Glioma - drug therapy; Gliomas; Health aspects; Humans; Killing; Laboratories; Ligands; Magnetic resonance; Magnetic Resonance Imaging; Mice; Neoplasm Transplantation; Neuroimaging; Neurosurgery; Oncology/Neuro-Oncology; Pharmaceuticals; Pharmacology/Drug Development; Proteins; Side effects; Skull; Survival; Survival Rate; TNF-Related Apoptosis-Inducing Ligand - administration & dosage; Toxicity; TRAIL protein; Treatment Outcome; Tumor Burden; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor suppressor genes; Tumors; United States > US; Pittsburgh Pennsylvania; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0004545

Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL) and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL) delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI). Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.