1. ¹Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School, Chinese Academy of Sciences, Shanghai, China
2. ²Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
3. ³Division of Hepatology and Gene Therapy, School of Medicine, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain
4. ⁴Lab of Gene and virus therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China

Correspondence: Professor X Liu, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. E-mail: xyliu@sibs.ac.cn

⁵These authors contributed equally to this work.

Received 21 October 2005; Revised 22 January 2006; Accepted 22 April 2006; Published online 23 June 2006.

Abstract

Melanoma differentiation associated gene-7 (Mda-7)/IL-24 was previously cloned into ZD55 (an adenovirus with E1B55 deleted) to form ZD55-IL-24, which had much better antitumor effect than Ad-IL-24. According to its good antitumor properties, ZD55-IL-24 has been used in preclinical studies. But ZD55-IL-24 alone still could not completely eradicate established tumors in all nude mice. It was reported that IL-24 could induce and enhance the activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (a member of tumor necrosis factor (TNF) superfamily). Accordingly, the combined use of ZD55-IL-24 and ZD55-TRAIL was carried out in this study. Treatment with both ZD55-IL-24 and ZD55-TRAIL could induce more significant apoptosis in cancer cells in vitro compared with ZD55-IL-24 or ZD55-TRAIL alone. The combination of the two replicative adenoviruses had better antitumor activity in vivo than that of single oncolytic adenovirus and led to complete eradication of xenograft tumors in all treated mice. Upregulation of TRAIL was observed in tumor cells infected with ZD55-IL-24 and studies of the apoptotic cascade regulators indicate that ZD55-IL-24 could further enhance the activation of apoptosis through the TNF family of death receptors. We demonstrated for the first time the potential therapeutic effect of combined ZD55-IL-24 with ZD55-TRAIL for the targeted therapy of cancer.