Expression of the bifunctional suicide gene CDUPRT increases radiosensitization and bystander effect of 5-FC in prostate cancer cells Journal Article
| Authors: | Xing, L.; Sun, X.; Deng, X.; Kotedia, K.; Urano, M.; Koutcher, J. A.; Ling, C. C.; Li, G. C. |
| Article Title: | Expression of the bifunctional suicide gene CDUPRT increases radiosensitization and bystander effect of 5-FC in prostate cancer cells |
| Abstract: | Purpose: To test the hypothesis that, with 5-fluorocytosine (5-FC) treatment, the co-expression of cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) can lead to greater radiosensitization and bystander effect than CD-expression alone. Methods and materials: R3327-AT cell lines stably expressing CD or CDUPRT were generated. The 5-FC and 5-FU cytotoxicity, and the radiosensitivity with/without 5-FC treatment, of these cells were evaluated under both aerobic and hypoxic conditions. The bystander effect was assessed by apoptosis staining and clonogenic survival. The pharmacokinetics of 5-FU and 5-FC metabolism was monitored in mice bearing CD- or CDUPRT-expressing tumors using <sup>19</sup>F MR spectroscopy (MRS). Results: CDUPRT-expressing cells were more sensitive to 5-FC and 5-FU than CD-expressing cells. CDUPRT-expression further enhanced the radiosensitizing effect of 5-FC, relative to that achieved by CD-expression alone. A 25-fold lower dose of 5-FC resulted in the same magnitude of radiosensitization in CDUPRT-expressing cells, relative to that in CD-expressing cells. The 5-FC cytotoxicity in co-cultures of parental cells mixed with 10-20% CDUPRT cells was similar to that in 100% CDUPRT cells. <sup>19</sup>F MRS measurements showed that expression of CDUPRT leads to enhanced accumulation of fluorine nucleotide (FNuc), relative to that associated with CD-expression alone. Conclusion: Our study suggests that CDUPRT/5-FC strategy may be more effective than CD/5-FC, especially when used in combination with radiation. |
| Keywords: | controlled study; human cell; fluorouracil; nonhuman; mouse; animals; mice; apoptosis; gene expression; animal experiment; animal model; cancer cell culture; cell line, tumor; transfection; prostatic neoplasms; blotting, western; gene expression regulation, neoplastic; mice, nude; probability; western blotting; reference values; magnetic resonance spectroscopy; radiosensitivity; drug metabolism; drug cytotoxicity; disease models, animal; fluorine nuclear magnetic resonance; radiosensitization; coculture techniques; 5-fluorocytosine; bystander effect; cytosine deaminase; uracil phosphoribosyltransferase; flucytosine; pentosyltransferases; radiation tolerance |
| Journal Title: | Radiotherapy and Oncology |
| Volume: | 92 |
| Issue: | 3 |
| ISSN: | 0167-8140 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2009-09-01 |
| Start Page: | 345 |
| End Page: | 352 |
| Language: | English |
| DOI: | 10.1016/j.radonc.2009.04.003 |
| PUBMED: | 19433338 |
| PROVIDER: | scopus |
| PMCID: | PMC2830274 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 30 November 2010" - "CODEN: RAOND" - "Source: Scopus" |
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