This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by An, Q. Articles by Barnes, D. E. Search for Related Content PubMed PubMed Citation Articles by An, Q. Articles by Barnes, D. E.

5-Fluorouracil Incorporated into DNA Is Excised by the Smug1 DNA Glycosylase to Reduce Drug Cytotoxicity

Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, United Kingdom

Requests for reprints: Tomas Lindahl, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, EN6 3LD, United Kingdom. Phone: 44-17-0762-5993/5995; Fax: 44-20-7269-3803; E-mail: tomas.lindahl{at}cancer.org.uk.

5-Fluorouracil (FU) has been widely used for more than four decades in the treatment of a range of common cancers. The fluorine-substituted uracila analogue is converted to several active metabolites but the mechanism of cytotoxicity has remained unclear. In a widely cited but unsubstantiated model, FU is thought to kill cells via the inhibition of thymidylate synthase and increased use of dUTP in place of TTP during DNA replication, with subsequent excision of high levels of uracil causing the fragmentation of newly synthesized DNA. Using gene-targeted cell lines defective in one or both of the two mammalian uracil-DNA glycosylase repair enzymes, we were able to test this model of FU cytotoxicity. Here, we show that incorporation of FU itself into DNA has been previously underestimated and is a predominant cause of cytotoxicity. FU readily becomes incorporated into the DNA of drug-treated cells, and accumulation of FU in the genome, rather than uracil excision, is correlated with FU cytotoxicity in mammalian cells. Furthermore, the Smug1, but not the Ung, uracil-DNA glycosylase excises FU from DNA and protects against cell killing. The data provides a clearer understanding of the action of FU, suggesting predictive biomarkers of drug response and a mechanism for acquired resistance in tumors. [Cancer Res 2007;67(3):940–5]

This article has been cited by other articles:

				N. Krynetskaia, H. Xie, S. Vucetic, Z. Obradovic, and E. Krynetskiy High Mobility Group Protein B1 Is an Activator of Apoptotic Response to Antimetabolite Drugs Mol. Pharmacol., January 1, 2008; 73(1): 260 - 269. [Abstract] [Full Text] [PDF]

				M. T. Morgan, M. T. Bennett, and A. C. Drohat Excision of 5-Halogenated Uracils by Human Thymine DNA Glycosylase: ROBUST ACTIVITY FOR DNA CONTEXTS OTHER THAN CpG J. Biol. Chem., September 21, 2007; 282(38): 27578 - 27586. [Abstract] [Full Text] [PDF]