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Malignant Pleural Mesothelioma–Targeted CREBBP/EP300 Inhibitory Protein 1 Promoter System for Gene Therapy and Virotherapy

¹ Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ² Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and ³ Department of Ecology and Evolutionary Biology, University of California, Irvine, California

Requests for reprints: Takuya Fukazawa, Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: 81-86-235-7257; Fax: 81-86-221-8775; E-mail: FukazawaT{at}aol.com.

Key Words: Mesothelioma • CRI1 • Gene therapy • Virotherapy

Gene therapy and virotherapy are one of the approaches used to treat malignant pleural mesothelioma. To improve the efficiency of targeting malignant mesothelioma cells, we designed a novel system using the promoter of the CREBBP/EP300 inhibitory protein 1 (CRI1), a gene specifically expressed in malignant pleural mesothelioma. Four tandem repeats of the CRI1 promoter (CRI1^{–138 4x}) caused significantly high promoter activity in malignant pleural mesothelioma cells but little promoter activity in normal mesothelial cells and normal fibroblasts. The recombinant adenoviral vector expressing proapoptotic BH3-interacting death agonist or early region 1A driven by the CRI1^{–138 4x} promoter induced cell death in malignant mesothelioma cells but not in normal cells. Moreover, these viruses showed antitumor effects in a mesothelioma xenograft mouse model. Here, we describe a novel strategy to target malignant mesothelioma using the CRI1^{–138 4x} promoter system. [Cancer Res 2008;68(17):7120–9]