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

Hung Tsung Hsiao, Ligang Xing, Xuelong Deng, Xiaorong Sun, C. Clifton Ling, Gloria C. Li

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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 GCVand 5-FC. Significant radiosensitization effects were detected after 5-FC and GCVtreatments 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 GCVin 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.

Original languageEnglish
Pages (from-to)723-729
Number of pages7
JournalOncology Reports
Volume32
Issue number2
DOIs
Publication statusPublished - 2014 Aug

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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