1. ¹Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan
2. ²Department of Urology, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
3. ³Department of Urology, National Cheng Kung University Medical College, Tainan, Taiwan
4. ⁴Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan
5. ⁵Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

Correspondence: Professor T-S Tzai, Department of Urology, National Cheng Kung University Medical College, 1, Dashiue Road, Tainan 70101, Taiwan. E-mail: tts777@mail.ncku.edu.tw; Professor C-L Wu, Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, 1, Dashiue Road, Tainan 70101, Taiwan. E-mail: wumolbio@mail.ncku.edu.tw

Received 3 July 2008; Revised 14 December 2008; Accepted 24 January 2009; Published online 19 June 2009.

Abstract

The objective of this study was to develop an HER2-targeted, envelope-modified Moloney murine leukemia virus (MoMLV)-based gammaretroviral vector carrying interleukin (IL)-12 gene for bladder cancer therapy. It displayed a chimeric envelope protein containing a single-chain variable fragment (scFv) antibody to the HER2 receptor and carried the mouse IL-12 gene. The fragment of anti-erbB2scFv was constructed into the proline-rich region of the viral envelope of the packaging vector lacking a transmembrane subunit of the carboxyl terminal region of surface subunit. As compared with envelope-unmodified gammaretroviruses, envelope-modified ones had extended viral tropism to human HER2-expressing bladder cancer cell lines, induced apoptosis, and affected cell cycle progression despite lower viral titers. Moreover, animal studies showed that envelope-modified gammaretroviruses carrying IL-12 gene exerted higher antitumor activity in terms of retarding tumor growth and prolonging the survival of tumor-bearing mice than unmodified ones, which were associated with enhanced tumor cell apoptosis as well as increased intratumoral levels of IL-12, interferon-, IL-1, and tumor necrosis factor- proteins. Therefore, the antitumor activity of gammaretroviruses carrying the IL-12 gene was enhanced through genetic modification of the envelope targeting HER2 receptor, which may be a promising strategy for bladder cancer therapy.