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

Authors: Hsiao, H. T.; Xing, L.; Deng, X.; Sun, X.; Ling, C. C.; Li, G. C.
Article Title: Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells
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.
Keywords: controlled study; human cell; nonhuman; colorectal cancer; mouse; animal tissue; cell viability; cell survival; gene expression; radiation; animal experiment; animal model; in vivo study; in vitro study; tumor regression; hypoxia; colon cancer; radiosensitivity; thymidine kinase; cell hypoxia; drug cytotoxicity; cancer control; drug dose increase; ganciclovir; hsv1 tk gene; cytosine deaminase; uracil phosphoribosyltransferase; flucytosine; suicide gene therapy; cd gene; human; female; priority journal; article; herpes simplex virus-1 thymidine kinase; colorectal cancer cell line; uprt gene
Journal Title: Oncology Reports
Volume: 32
Issue: 2
ISSN: 1021-335X
Publisher: Spandidos Publications  
Date Published: 2014-08-01
Start Page: 723
End Page: 729
Language: English
DOI: 10.3892/or.2014.3238
PROVIDER: scopus
PMCID: PMC4091884
PUBMED: 24912473
Notes: Export Date: 1 August 2014 -- CODEN: OCRPE -- Source: Scopus
Altmetric Score
MSK Authors
  1. Gloria C Li
    122 Li
  2. Ligang Xing
    15 Xing
  3. Xiaorong Sun
    19 Sun
  4. Xuelong Deng
    14 Deng
  5. Hung- Tsung Hsiao
    5 Hsiao
  6. C Clifton Ling
    313 Ling