期刊
CANCER GENE THERAPY
卷 19, 期 10, 页码 675-683出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cgt.2012.54
关键词
lung cancer; nuclear translocation; suicide gene therapy
类别
资金
- University of Copenhagen
- Danish Cancer Society
- Novo Nordisk Foundation
- Aase and Ejnar Danielsens Foundation
- Katrine and Vigo Skovgaards Foundation
- Beckett Foundation
Lung cancer currently causes the majority of cancer-related deaths worldwide and new treatments are in high demand. Gene therapy could be a promising treatment but currently lacks sufficient efficiency for clinical use, primarily due to limited cellular and nuclear DNA delivery. In the present study, we investigated whether it was possible to exploit the endogenous nuclear-shuttling activity by the nuclear factor kappa B (NF kappa B) system, which is highly prominent in many cancers as well as lung cancer. We observed that insertion of a DNA nuclear-targeting sequence (DTS) recognized by NF kappa B could improve plasmid nuclear delivery and enhance the therapeutic effect of a validated transcriptionally cancer-targeted suicide gene therapy system. A clear correlation between the number of inserted NF kappa B-binding sites and the therapeutic effect of the suicide system was observed in both small cell lung cancer (SCLC) and non-SCLC cell lines. The effect was observed to be due to elevated nuclear translocation of the suicide gene-encoding plasmids. The results show that a significant improvement of gene therapeutic efficiency can be obtained by increasing the intracellular trafficking of therapeutic DNA. This is to our knowledge the first time a DTS strategy has been implemented for suicide gene therapy.
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