Abstract
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.
Highlights
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family [1,2]
This homotrimeric structure of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is stabilized by a cysteine residue at position 230 that coordinates with a divalent zinc ion [4,5,6]
To develop a biologically active form of soluble TRAIL produced in mammalian cells, we manipulated the apoptosis-inducing moiety of TRAIL to be secreted through fusion with a secretion signal sequence
Summary
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family [1,2]. In tests using various glioma cells (Figure 2A), Ad-stTRAIL induced cell death in all except U373-MG and ACBRI371, both of which showed significant resistance to recombinant TRAIL protein. Doi:10.1371/journal.pone.0004545.g002 (recombinant TRAIL protein or Ad-stTRAIL), U373-MG and ACBRI371 cells expressed TRAIL receptors DR4 and DR5 (data not shown).
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