Enhanced suicide gene therapy by chimeric tumor‐specific promoter based on HSF1 transcriptional regulation

FEBS Letters

Liu, Xinyuan¹  Zhang, Zilai¹  Yao, Mingzhong²  Sun, Lanying¹  Zhang, Yanhong¹  Li, Binhua¹  Gu, Jinfa¹  Wang, Jinhui¹ 

[1] Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, PR China;Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089, USA

关键词: Telomerase reverse transcriptase;    Heat shock factor;    Cytosine deaminase;    Tumor-specific promoter;    Heat shock protein 70;    Fas;    HSF1;    heat shock transcription factor 1;    hTERT;    telomerase reverse transcriptase;    CD;    cytosine deaminase;    hsp;    heat shock protein;    5-FC;    5-fluorocytosine;    DMEM;    Dulbecco's modified Eagle's medium;    CMV;    cytomegalovirus;    SV40;    simian virus 40;    RT-PCR;    reverse transcriptase polymerase chain reaction;    Ad;    adenovirus;   

DOI  :  10.1016/S0014-5793(03)00606-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown