期刊
GENE THERAPY
卷 16, 期 8, 页码 1009-1020出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2009.56
关键词
oncolytic adenovirus; renal cell cancer; antiangiogenic gene therapy; dual luciferase imaging
类别
资金
- European Research Council
- EU FP6 APOTHERAPY and THERADPOX
- HUCH Research Funds (EVO)
- Finnish Cancer Society
- Sigrid Juselius Foundation
- Academy of Finland
- Biocentrum Helsinki, University of Helsinki
- Helsinki Graduate School in Biotechnology and Molecular Biology
- Helsinki Biomedical Graduate School
- K Albin Johansson Foundation
- Orion-Farmos research foundation
- Finnish Cultural Foundation
Despite good safety data in clinical trials, oncolytic adenoviruses have not been efficient enough to make them a viable treatment alternative for cancers. As more potent viruses are being made, transcriptional and transductional targeting to tumor tissues becomes increasingly appealing. To improve antitumor efficacy, oncolytic adenoviruses can be armed with therapeutic transgenes, such as the antiangiogenic soluble vascular endothelial growth factor receptor 1-Ig fusion protein. We hypothesized that an infectivity enhanced, targeted, vascular endothelial growth factor receptor 1-Ig armed oncolytic adenovirus would exhibit improved specificity and antitumor effect in murine kidney cancer models. Two hypoxia inducible factor-sensitive promoters were evaluated for renal cancer specificity using a novel in vivo dual luciferase-imaging system. Earlier data had shown usefulness of the 5/3-serotype chimera capsid modification for kidney cancer. Therefore, we constructed Ad5/3-9HIF-Delta 24-VEGFR-1-Ig, which showed good specificity and oncolytic effect on renal cancer cells in vitro and resulted in antitumor efficacy in a subcutaneous in vivo model, in which vascular endothelial growth factor receptor 1-Ig expression and a concurrent antiangiogenic effect were confirmed. In an intraperitoneally disseminated kidney cancer model, significantly enhanced survival was observed when compared with control viruses. These results suggest that a targeted, antiangiogenic, oncolytic adenovirus might be a valuable agent for testing in kidney cancer patients. Gene Therapy (2009) 16, 1009-1020; doi: 10.1038/gt.2009.56; published online 14 May 2009
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