Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells

  • Authors:
    • Hung Tsung Hsiao
    • Ligang Xing
    • Xuelong Deng
    • Xiaorong Sun
    • C. Clifton Ling
    • Gloria C. Li
  • View Affiliations

  • Published online on: June 6, 2014     https://doi.org/10.3892/or.2014.3238
  • Pages: 723-729
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Abstract

The hypoxic microenvironment, an important feature of human solid tumors but absent in normal tissue, may provide an opportunity for cancer-specific gene therapy. The purpose of the present study was to investigate whether hypoxia-driven triple suicide gene TK/CD/UPRT expression enhances cytotoxicity to ganciclovir (GCV) and 5-fluorocytosine (5-FC), and sensitizes human colorectal cancer to radiation in vitro and in vivo. Stable transfectant of human colorectal HCT8 cells was established which expressed hypoxia-inducible vectors (HRE-TK/eGFP and HRE-CD/UPRT/mDsRed). Hypoxia-induced expression/function of TK, CD and UPRT was verified by western blot analysis, flow cytometry, fluorescent microscopy and cytotoxicity assay of GCV and 5-FC. Significant radiosensitization effects were detected after 5-FC and GCV treatments under hypoxic conditions. In the tumor xenografts, the distribution of TK/eGFP and CD/UPRT/mDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC and GCV in mice in combination with local irradiation resulted in tumor regression, as compared with prodrug or radiation treatments alone. Our data suggest that the hypoxia-inducible TK/GCV+CDUPRT/5-FC triple suicide gene therapy may have the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy.

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August 2014
Volume 32 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Copy and paste a formatted citation
APA
Hsiao, H.T., Xing, L., Deng, X., Sun, X., Ling, C.C., & Li, G.C. (2014). Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells. Oncology Reports, 32, 723-729. https://doi.org/10.3892/or.2014.3238
MLA
Hsiao, H. T., Xing, L., Deng, X., Sun, X., Ling, C. C., Li, G. C."Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells". Oncology Reports 32.2 (2014): 723-729.
Chicago
Hsiao, H. T., Xing, L., Deng, X., Sun, X., Ling, C. C., Li, G. C."Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells". Oncology Reports 32, no. 2 (2014): 723-729. https://doi.org/10.3892/or.2014.3238