The occurrence of this type of mesothelioma is increasing worldwide as a result of widespread exposure to asbestos, which was widely used in industrialized countries until approximately 1970. The median survival time of patients with mesothelioma from date of diagnosis ranges between 1 and 2 years (Antman et. al. J Clin Oncol. 1988, Aisner et al. Chest. 1995). Mortality is expected to increase, at least until 2020 mainly due to the long latency of the disease (30-50 years) (Robinson et al. N Engl J Med. 2005). Despite considerable advances in the understanding of its pathogenesis and etiology, malignant mesothelioma remains largely unresponsive to standard modalities of cancer therapy (Nowak et al. Semin Oncol. 2002). Gene therapy is one of the approaches currently being tried to treat malignant pleural mesothelioma. However, present tumor gene therapies have had limited success because they are prone to side effects due to the lack of tissue and tumor specificity. To address this problem we have developed a method of gene therapy specifically targeting malignant mesothelioma. We evaluated the tumor specificity of five different promoters from mesothelioma markers. A luciferase reporter assay demonstrated that the promoter region -2586/+87 of the human CRI1 (CREBBP/EP300 inhibitory protein 1) gene is highly active in malignant pleural mesothelioma cells (H2542, H2052, MSTO-211H) but not in normal mesothelial and pleural cells. In contrast, all the other promoters of mesothelioma markers (e.g., Mesothelin, WT1, Calretinin) showed significantly high promoter activity not only in malignant pleural mesothelioma cells but also in normal mesothelial and pleural cells. Flow cytometric analysis demonstrated that the recombinant adenoviral Ad-CRI1-2586/BID vector that expressed the CRI1 promoter-driven proapoptotic BID (BH3 interacting death agonist) induced BID expression and apoptosis in malignant mesothelioma MSTO-211H cells, whereas little apoptosis was detected in normal pleural cells. Here we report a novel strategy to target malignant mesothelioma using the pro-apoptotic BID gene and the CRI1 promoter.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA