Participation of DNA repair in the response to 5-fluorouracil

Abstract

The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer. Intracellular metabolites of 5-FU can exert cytotoxic effects via inhibition of thymidylate synthetase, or through incorporation into RNA and DNA, events that ultimately activate apoptosis. In this review, we cover the current data implicating DNA repair processes in cellular responsiveness to 5-FU treatment. Evidence points to roles for base excision repair (BER) and mismatch repair (MMR). However, mechanistic details remain unexplained, and other pathways have not been exhaustively interrogated. Homologous recombination is of particular interest, because it resolves unrepaired DNA intermediates not properly dealt with by BER or MMR. Furthermore, crosstalk among DNA repair pathways and S-phase checkpoint signaling has not been examined. Ongoing efforts aim to design approaches and reagents that (i) approximate repair capacity and (ii) mediate strategic regulation of DNA repair in order to improve the efficacy of current anticancer treatments.

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

“…One of the major problems associated with 5-FU therapy is the development of resistance to the drug. Resistance to 5-FU may occur by a number of mechanisms, including alterations in the enzymes implicated in the metabolism or in the mechanism of action of the drug, especially in the target enzyme (for review, see Peters et al, 2002), also, alterations in molecules such as p53 (Lowe et al, 1993;Bunz et al, 1999;Longley et al, 2002;Tominaga et al, 2010) and in proteins critical in the response to DNA damage, such as ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3 related (ATR) (for review, see Wyatt and Wilson III, 2009). For example, ATR has been shown to be an essential mediator in the antitumoral properties of 5-FU (Wilsker and Bunz 2007) through the control exerted on the mismatch repair system (Liu et al, 2008) or on CHK1, a regulatory component of the DNA damage checkpoint (Jardim et al, 2009).…”

Arabidopsis Uracil DNA Glycosylase (UNG) Is Required for Base Excision Repair of Uracil and Increases Plant Sensitivity to 5-Fluorouracil

“…We next explored the consequences exerted by elevated uracil levels on Arabidopsis plants lacking AtUNG activity. We decided to alter the dUTP/dTTP ratio by growing plants in the presence of 5-FU, an uracil analog widely used as a chemotherapeutic agent in the treatment of solid tumors (26). This anticancer agent inhibits thymidylate synthase and depletes thymidine nucleotides for DNA synthesis.…”

“…This anticancer agent inhibits thymidylate synthase and depletes thymidine nucleotides for DNA synthesis. As a result, it leads to a dUTP/dTTP imbalance that in turn favors misincorporation of dUMP into DNA (26). Wild-type and atung Ϫ/Ϫ plants were germinated in plates containing different concentrations of 5-FU (Fig.…”

Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks

“…1). Despite the fact that the major cause of 5-FU cytotoxicity is its effect on RNA metabolism (2), 5-FU or 5-fluoro-2 0 -deoxyuridine (FdUrd), a deoxynucleoside form of the 5-FU metabolite, also affects DNA metabolism by inducing several types of DNA damage, especially during DNA replication (3). Consistently, 5-FU-or FdUrd-induced cytotoxicity is correlated with DNA damage during DNA replication (4,5).…”

“…dTTP starvation due to TS inhibition by FdUMP may perturb replication fork progression or replication-coupled DNA repair processes (3) and enhance misincorporation of dUTP or FdUTP into DNA, which becomes a target of uracil DNA glycosylases (6,7). The repair intermediates are converted into DNA single-or doublestrand breaks, which may then cause cytotoxicity (3,7).…”