Abstract
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.
Highlights
Malignant pleural mesothelioma is an aggressive tumor of mesenchymal origin and is increasing worldwide as a result of widespread exposure to asbestos that was widely used in industrialized countries until approximately 1970
To design a system for specific gene therapy and virotherapy to treat malignant mesothelioma, we evaluated the specificity of the promoters of four different mesothelioma-specific genes: calretinin [14], Wilms’ tumor suppressor gene (WT1; ref. 15), mesothelin [16], and CREBBP/EP300 inhibitory protein 1
The expression of calretinin, WT1, and mesothelin was detectable in normal human mesothelial cells and extracts of normal human pleura and lung, whereas the expression of CREBBP/ EP300 inhibitory protein 1 (CRI1) was not seen in these normal human cells and tissues
Summary
Malignant pleural mesothelioma is an aggressive tumor of mesenchymal origin and is increasing worldwide as a result of widespread exposure to asbestos that was widely used in industrialized countries until approximately 1970. There is substantial interest in this disease because millions of people have been exposed to asbestos fibers, and there are more than 3,000 cases of mesothelioma seen annually in the United States [1]. The median survival of patients with mesothelioma from time of diagnosis ranges between 1 and 2 years [2, 3]. The mortality is expected to increase, at least until 2020, which is mainly due to the long latency (30–50 years) of the disease [4]. Extrapleural pneumonectomy can prolong the median survival time of more than 2 years; this approach is suitable for only a few patients. Chemotherapy can ameliorate the symptoms of the disease, including pain and breathlessness with pleural effusion, no regimen for mesothe-
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