Heat-directed gene targeting of adenoviral vectors to tumor cells
| Autor: | Henry J. Klamut, Anthony Brade, Pei-Xiang Li, Fei-Fei Liu, Paul Szmitko, Duc Ngo |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Cancer Research
Genetic Vectors Cell Gene Expression Mice SCID Transfection Adenoviridae Viral vector HeLa Mice Genes Reporter Gene expression Tumor Cells Cultured medicine Animals Humans HSP70 Heat-Shock Proteins HSF1 Molecular Biology Gene biology Chemistry Gene targeting Promoter Genetic Therapy Hyperthermia Induced beta-Galactosidase biology.organism_classification Interleukin-12 medicine.anatomical_structure Gene Targeting Cancer research Molecular Medicine Female |
| Zdroj: | Cancer Gene Therapy. 7:1566-1574 |
| ISSN: | 1476-5500 0929-1903 |
| DOI: | 10.1038/sj.cgt.7700267 |
| Popis: | Targeting therapeutic gene expression to tumor cells represents a major challenge for cancer gene therapy. The strong transcriptional response exhibited by heat shock genes, along with the beneficial therapeutic effects of hyperthermia have led us to develop a heat-directed gene-targeting strategy for cancer treatment. Heat shock gene expression is mediated in large part by the interaction of heat shock factor 1 with specific binding sites (heat shock elements; HSE) found in the promoters of heat-inducible genes. Here we present a quantitative analysis of heat-inducible gene expression mediated by the wild-type hsp70b gene promoter, as well as a modified hsp70b promoter containing additional HSE sequences. β-Galactosidase (β-gal) expression was induced between 50- and 800-fold in a panel of human breast cancer cell lines infected with an adenoviral vector containing the wild-type hsp70b promoter (Ad.70b.βg) following treatment at 43°C for 30 minutes. Infection with an adenoviral vector containing the modified hsp70b promoter (Ad.HSE.70b.βg) resulted in a 200- to 950-fold increase in β-gal expression under the same conditions, and also provided a 1–2°C decrease in the threshold of activation. Significant increases in the heat responsiveness of the Ad.HSE.70b.βg construct were observed in five of six tumor cell lines tested, as well as under thermotolerant conditions. Finally, we demonstrate that localized heating of a HeLa cell xenograft can effectively target β-gal gene expression following intratumoral injection of Ad.70b.βg. Adenoviral vectors incorporating heat-inducible therapeutic genes may provide useful adjuncts for clinical hyperthermia. Cancer Gene Therapy (2000) 7, 1566–1574. |
| Databáze: | OpenAIRE |
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