Tumor necrosis factor (
TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, is a type II transmembrane
cytokine molecule. Soluble TRAIL has been shown to induce apoptosis in a wide variety of
cancer cells in vitro and to suppress
tumor growth specifically without damaging normal cells and tissues in vivo. In our previous report, we have demonstrated that an artificial gene encoding the
polypeptide composed of the three functional elements (a secretion signal, a trimerization domain and an apoptosis-inducing moiety of TRAIL gene sequence) expresses and secretes highly apoptotic trimeric TRAIL into the culture supernatant. Here, as an approach to TRAIL-based cancer gene
therapy, we developed an adenoviral vector delivering the gene that encodes our secretable trimeric TRAIL (stTRAIL). This adenovirus (Ad-stTRAIL) potently induced apoptosis in vitro in
cancer cell lines such as HeLa, MDA-MB-231, A549, HCT116 and U-87MG. In an animal xenograft
tumor model bearing a human
glioma cell line U-87MG, intratumoral delivery of Ad-stTRAIL dramatically suppressed
tumor growth without showing detectable adverse side effects. Histological analysis revealed that Ad-stTRAIL suppresses
tumor growth by inducing apoptotic cell death. Contrary to the known rapid clearance of systemically delivered
TRAIL protein from the blood circulation, stTRAIL expressed by Ad-stTRAIL in
tumor tissues persisted for more than 4 days. In a comparison of
tumor suppressor activity between Ad-stTRAIL and Ad-flTRAIL (delivering the full-length TRAIL gene) after mixing infected cells with uninfected cells and implanting these mixed cells in nude mice, Ad-stTRAIL showed higher
tumor suppressor activity than that of Ad-flTRAIL. Our data reveal that a gene
therapy using Ad-stTRAIL has a promising potential to treat human
cancers including
gliomas.