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 |
| DOI/URL: | |
| Notes: | Export Date: 1 August 2014 -- CODEN: OCRPE -- Source: Scopus |
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