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Abstract
The prognosis and response to conventional therapies of malignant melanoma inversely correlate with disease progression. With increasing thickness, melanomas acquire metastatic potential and become inherently resistant to radiotherapy and chemotherapy. These harsh realities mandate the design of improved therapeutic modalities, especially those targeting metastases. To develop an approach to effectively treat this aggressive disease, we constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV produces large quantities of MDA-7/IL-24 protein as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal human immortal melanocytes and human melanoma cells demonstrates cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 CTV into xenografts derived from MeWo human metastatic melanoma cells in athymic nude mice completely eliminated not only primary treated tumors but also distant non-treated tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for treating patients with advanced melanomas with metastases.
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1 Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, Department of Urology, New York, USA; Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, Department of Pathology, New York, USA; 6Current address: Dr Department of Human and Molecular Genetics and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA, (GRID:grid.224260.0) (ISNI:0000 0004 0458 8737)
2 Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, Department of Urology, New York, USA (GRID:grid.224260.0); 6Current address: Dr Department of Human and Molecular Genetics and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA, (GRID:grid.224260.0) (ISNI:0000 0004 0458 8737)
3 Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, Department of Urology, New York, USA (GRID:grid.224260.0)
4 and the Massey Cancer Center, Virginia Commonwealth University, Departments of Biochemistry and Radiation Oncology, Richmond, USA (GRID:grid.224260.0) (ISNI:0000 0004 0458 8737)
5 Pathology and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Division of Human Gene Therapy, Departments of Medicine, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
6 Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, Department of Urology, New York, USA (GRID:grid.265892.2); Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, Department of Pathology, New York, USA (GRID:grid.265892.2); Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, Department of Neurosurgery, New York, USA (GRID:grid.265892.2); 6Current address: Dr Department of Human and Molecular Genetics and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA, (GRID:grid.224260.0) (ISNI:0000 0004 0458 8737)