title: Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses effectively suppress growth of malignant pleural mesothelioma.
abstract: Malignant mesothelioma (MM) incidence is increasing drastically worldwide as an occupational disease resulting from asbestos exposure. However, no curative treatment for MM of advanced stage is available. Thus, new therapeutic approaches for MM are required. Because malignant pleural mesothelioma (MPM) cells spread along the pleural surface in most patients, MPM can be targeted using intrapleural therapeutic approaches. In this study, we investigated the effectiveness of the intrapleural instillation of a replication-competent adenovirus as an oncolytic agent against MPM. We constructed a vascular endothelial growth factor promoter-based conditionally replicative adenovirus (VEGF-CRAd) that replicates exclusively in VEGF-expressing cells. All of the MM cell lines that we tested expressed VEGF mRNA, and VEGF-CRAd selectively replicated in these MM cells and exerted a direct concentration-dependent oncolytic effect in vitro. Furthermore, our in vivo studies showed that pre-infection of MM cells with VEGF-CRAd potently suppressed MPM tumor formation in nude mice, and that intrapleural instillation of VEGF-CRAd prolonged the survival time of tumor-bearing mice. Our results indicate that VEGF-CRAd exerts an oncolytic effect on MM cells and that intrapleural instillation of VEGF-CRAd is safe and might represent a promising therapeutic strategy for MPM.
authors: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Akiko
authors: A
authors: Harada
authors: Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan.|Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Junji
authors: J
authors: Uchino
authors: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Taishi
authors: T
authors: Harada
authors: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Noriaki
authors: N
authors: Nakagaki
authors: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Junko
authors: J
authors: Hisasue
authors: Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan.
authors: Masaki
authors: M
authors: Fujita
authors: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Koichi
authors: K
authors: Takayama
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development*; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000628:therapy* / Q000821:virology; D008654:Mesothelioma / Q000473:pathology* / Q000628:therapy* / Q000821:virology; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D010997:Pleural Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019076:Transgenes / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: Conditionally replicative adenovirus; gene therapy; intrathoracic nude-mouse model; malignant mesothelioma; vascular endothelial growth factor