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Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina

Requests for reprints: Michael D. Wyatt, College of Pharmacy, University of South Carolina, CLS 109, 700 Sumter Street, Columbia, SC 29208. Phone: 803-777-0856; Fax: 803-777-8356. E-mail: wyatt{at}cop.sc.edu

Thymidylate synthase (TS) is an important target of several classes of chemotherapeutic agents. Although the precise mechanism of cytotoxicity in thymidylate deprivation remains obscure, uracil misincorporation and DNA strand breaks are recognized as important events during thymidylate deprivation. Base excision repair (BER) plays a primary role in removing damaged or modified bases from the genome, including uracil. Because of uracil misincorporation, BER is hypothesized to play a role in the cellular response to thymidylate deprivation. In this study, we used murine embryo fibroblasts wild-type or homozygous null for DNA polymerase ß (ß-pol), which plays a central role in BER. We found that, compared with wild-type, ß-pol null cells were resistant to the toxic effects of raltitrexed (Tomudex, ZD1694), a folate inhibitor of TS. There was little difference in TS levels or in TS-ligand complex formation between the cell lines. Furthermore, cells deficient in XRCC1, a scaffold protein for the final steps of BER, were also modestly resistant to raltitrexed compared with XRCC1-proficient cells. Cell cycle analysis revealed that the responses of the wild-type and ß-pol null cells were similar during drug exposure. However, following drug removal, the ß-pol null cells appeared to resume cell cycle progression more rapidly than the wild-type cells. The results suggest that BER plays a role in modulating the toxic effects of TS inhibitors, and that this role occurs during recovery from TS inhibition.

Key Words: Base excision repair • raltitrexed • thymidylate deprivation • DNA polymerase ß

Grant support: NIH grant P20 RR-017698 from the COBRE Program of the National Center for Research Resources.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 8/03; revised 3/23/04; accepted 4/ 6/04.