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Published on: September 14, 2010
Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses effectively suppress growth
Akiko Harada1, Junji Uchino2,3, Taishi Harada1
1Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
A novel oncolytic virus, vascular endothelial growth factor conditionally replicative adenovirus (VEGF-CRAd), shows promise for treating malignant pleural mesothelioma (MPM). Intrapleural delivery of VEGF-CRAd effectively targets and destroys MPM cells, offering a potential new therapy for this asbestos-related cancer.
Area of Science:
- Oncology
- Virology
- Gene Therapy
Background:
- Malignant mesothelioma (MM) incidence is rising globally, primarily due to asbestos exposure.
- Advanced-stage MM lacks curative treatments, necessitating novel therapeutic strategies.
- Malignant pleural mesothelioma (MPM) spreads along the pleural surface, making it amenable to intrapleural therapies.
Purpose of the Study:
- To investigate the efficacy of intrapleural instillation of a replication-competent adenovirus as an oncolytic agent against MPM.
- To develop and evaluate a vascular endothelial growth factor (VEGF) promoter-based conditionally replicative adenovirus (VEGF-CRAd) for selective replication in VEGF-expressing MM cells.
Main Methods:
- Construction of VEGF-CRAd designed to replicate exclusively in VEGF-expressing cells.
- In vitro assessment of VEGF-CRAd's selective replication and oncolytic effect on MM cell lines.
- In vivo evaluation of intrapleural VEGF-CRAd instillation in a nude mouse model of MPM, assessing tumor suppression and survival.
Main Results:
- All tested MM cell lines expressed VEGF mRNA.
- VEGF-CRAd selectively replicated in MM cells, demonstrating a direct, concentration-dependent oncolytic effect in vitro.
- Intrapleural VEGF-CRAd administration potently suppressed MPM tumor formation and prolonged survival in tumor-bearing mice.
Conclusions:
- VEGF-CRAd exhibits a significant oncolytic effect against MM cells.
- Intrapleural instillation of VEGF-CRAd is a safe and potentially promising therapeutic strategy for MPM.
