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Overexpression of Soluble TRAIL Induces Apoptosis in Human Lung Adenocarcinoma and Inhibits Growth of Tumor Xenografts in Nude Mice

¹ Gene Therapy Laboratory, Genome Research Center, ² Department of Biochemistry, University of Hong Kong, Pokfulam, Hong Kong; ³ National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking, China; and ⁴ Department of Haematological and Molecular Medicine, GKT School of Medicine, King's College London, United Kingdom

Requests for reprints: Ruian Xu, Gene Therapy Laboratory, Genome Research Centre, University of Hong Kong, 8S-01, Kadoories BioScience Building, Pokfulam, Hong Kong. Phone: 852-2299-0757; Fax: 852-2817-9488; E-mail: rxua{at}hkucc.hku.hk.

Recombinant adeno-associated virus 2/5 (rAAV2/5), a hybrid rAAV-2 with AAV-5 capsid, seems to be a very efficient delivery vector for the transduction of the lung adenocarcinoma cell line A549. Infection of the A549 cell line with a rAAV2/5 vector encoding the extracellular domain of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, amino acids 114-281) resulted in secretion of soluble TRAIL (sTRAIL) and induction of apoptosis in these cells. rAAV2/5-sTRAIL mediated delivery and stable expression of sTRAIL resulted in the presence of the trimeric form of sTRAIL in sera of nude mice that were implanted with s.c. or orthotopic A549 tumors. The rAAV2/5-sTRAIL transduction of the tumors resulted in a statistically significant reduction in tumor growth and prolonged survival of the tumor-bearing animals. Primary cell culture, histologic examination of the tumors, and serum analyses showed the absence of detectable TRAIL-induced toxicity in normal tissues including the liver. The successful inhibition of lung cancer growth and the absence of detectable toxicity suggest a putative role for rAAV2/5-sTRAIL_114-281 in the therapy of lung cancer.

Key Words: TRAIL • AAV • NSCLC • cancer gene therapy • apoptosis

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