Hypoxia targeted bifunctional suicide gene expression enhances radiotherapy in vitro and in vivo Journal Article
| Authors: | Sun, X.; Xing, L.; Deng, X.; Hsiao, H. T.; Minami, A.; Koutcher, J. A.; Clifton Ling, C.; Li, G. C. |
| Article Title: | Hypoxia targeted bifunctional suicide gene expression enhances radiotherapy in vitro and in vivo |
| Abstract: | Purpose: To investigate whether hypoxia targeted bifunctional suicide gene expression-cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) with 5-FC treatments can enhance radiotherapy. Materials and methods: Stable transfectants of R3327-AT cells were established which express a triple-fusion-gene: CD, UPRT and monomoric DsRed (mDsRed) controlled by a hypoxia inducible promoter. Hypoxia-induced expression/function of CDUPRTmDsRed was verified by western blot, flow cytometry, fluorescent microscopy, and cytotoxicity assay of 5-FU and 5-FC. Tumor-bearing mice were treated with 5-FC and local radiation. Tumor volume was monitored and compared with those treated with 5-FC or radiation alone. In addition, the CDUPRTmDsRed distribution in hypoxic regions of tumor sections was visualized with fluorescent microscopy. Results: Hypoxic induction of CDUPRTmDsRed protein correlated with increased sensitivity to 5-FC and 5-FU. Significant radiosensitization effects were detected after 5-FC treatments under hypoxic conditions. In the tumor xenografts, the distribution of CDUPRTmDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC to mice in combination with local irradiation resulted in significant tumor regression, as in comparison with 5-FC or radiation treatments alone. Conclusions: Our data suggest that the hypoxia-inducible CDUPRT/5-FC gene therapy strategy has the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy. © 2011 Elsevier Ireland Ltd. All rights reserved. |
| Keywords: | hypoxia; radiosensitization; cytosine deaminase; uracil phosphoribosyltransferase; 5-flurocytosine |
| Journal Title: | Radiotherapy and Oncology |
| Volume: | 105 |
| Issue: | 1 |
| ISSN: | 0167-8140 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2012-10-01 |
| Start Page: | 57 |
| End Page: | 63 |
| Language: | English |
| DOI: | 10.1016/j.radonc.2012.07.011 |
| PROVIDER: | scopus |
| PUBMED: | 22938726 |
| PMCID: | PMC3747309 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 December 2012" - "CODEN: RAOND" - "Source: Scopus" |
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