Enhanced suicide gene therapy by chimeric tumor-specific promoter based on HSF1 transcriptional regulation.
Two tandem cassettes, one containing the telomerase reverse transcriptase gene (hTERT) promoter upstream of a constitutively activated form of heat shock transcription factor 1 (cHSF1) and followed by the other containing the heat shock protein 70B (hsp70B) promoter ( HSE) upstream of the cytosine deaminase (CD) gene, could greatly enhance the efficiency of CD gene therapy while retaining tumor specificity in vitro and in vivo. This hTERT-cHSF1/ HSE promoter could restrict gene expression in tumor cells and was about 1.5-3-fold more potent than the cytomegalovirus (CMV) promoter. hTERT-cHSF1/HSE-CD transfection led to tumor cells more sensitive to 5-fluorocytosine compared with hTERT-CD and its toxicity was comparable to that of CMV-CD. Besides enhancement of promoter activity, cHSF1 overexpression itself could enhance the bystander effect of CD gene therapy that could be reversed by anti-Fas antibody. This system also led to activation of stress-related genes such as hsp70 in tumor cells, which in the presence of cell killing by the cytotoxic gene is a highly immunostimulatory event. Furthermore, a more potent anti-tumor effect of hTERT-cHSF1/HSE-CD was observed in nude mice inoculated with Bcap37 cells. No obvious activity of the hTERT-cHSF1/ HSE promoter was observed in normal tissues after intravenous administration. These results indicate that the hTERT-cHSF1/ HSE promoter is highly tumor-specific and strong with potential application in targeted gene therapy, and therefore may be useful for construction of vectors for systemic therapy.[1]References
- Enhanced suicide gene therapy by chimeric tumor-specific promoter based on HSF1 transcriptional regulation. Wang, J., Yao, M., Zhang, Z., Gu, J., Zhang, Y., Li, B., Sun, L., Liu, X. FEBS Lett. (2003) [Pubmed]
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