Uracil in DNA: Consequences for carcinogenesis and chemotherapy

Berger, Sondra H.; Pittman, Douglas L.; Wyatt, Michael D.

doi:10.1016/j.bcp.2008.05.019

Cited by 69 publications

(73 citation statements)

References 69 publications

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“…In both cases, 5-FU acts faster than FdUMP. The formation of γH2AX-foci after 5-FU treatment did not seem to be a direct effect of the drug since it appeared concomitantly with the S-phase arrest and could reflect collapsed replication forks (Berger et al, 2008). DSB, detected after 12 h treatment with 5-FU, could also result from apoptosis induction, which is observed earlier for 5-FU (12 h) than for FdUMP (24 h).…”

Section: Discussionmentioning

confidence: 95%

5‐Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line

Matuo

Sousa

Escargueil

et al. 2008

J of Applied Toxicology

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5-Fluorouracil (5-FU) is an antineoplasic drug widely used to treat cancer. Its cytotoxic effect has been principally ascribed to the misincorporation of fluoronucleotides into DNA and RNA during their synthesis, and the inhibition of thymidylate synthase (TS) by FdUMP (one of the 5-FU active metabolites), which leads to nucleotide pool imbalance. In the present study, we compared the ability of 5-FU and FdUMP to induce apoptosis and to influence the cell cycle progression in human colon SW620 adenocarcinoma cells in regards to their genotoxic and clastogenic activities. Our study demonstrates that 5-FU induces SSB, DSB and apoptosis earlier than FdUMP. Interestingly, while both drugs are able to induce apoptosis, their effect on the cell cycle progression differed. Indeed, 5-FU induces an arrest in G1/S while FdUMP causes an arrest in G2/M. Independently of the temporal difference in strand breaks and apoptosis induction, as well as the differential cell cycle modulation, both drugs presented similar clastogenic effects. The different pattern of cell cycle arrest suggests that the two drugs induce different types of primary DNA lesions that could lead to the activation of different checkpoints and recruit different DNA repair pathways.

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Section: Discussionmentioning

confidence: 95%

5‐Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line

Matuo

Sousa

Escargueil

et al. 2008

J of Applied Toxicology

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“…because riboflavin is a cofactor for this enzyme but under low folate conditions MTHFR could compete with thymidylate synthase for their common substrate 5,10-methylenetetrahydrofolate making the latter unavailable for the conversion of dUMP to dTTP and thus increase uracilinduced incorporation into DNA which leads to elevated chromosome instability and possibly centromere dysfunction [Berger et al, 2008]. For these reasons it was considered important to also test the possibility that increased riboflavin in a low folate background might increase whole chromosome aneuploidy.…”

Section: Discussionmentioning

confidence: 99%

Folate deficiency in human peripheral blood lymphocytes induces chromosome 8 aneuploidy but this effect is not modified by riboflavin

Lü

Fenech

et al. 2009

Environ and Mol Mutagen

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Chromosome 8 aneuploidy is a common event in certain cancers but whether folate (F) deficiency induces chromosome 8 aneuploidy is not known. Furthermore the impact of riboflavin (R) deficiency, which may alter activity of a key enzyme in folate metabolism, on these events is unknown. Therefore, the aim of our research was to test the following hypotheses: (a) F deficiency induces chromosome 8 aneuploidy; (b) chromosome 8 aneuploidy is affected by F deficiency to a similar degree as chromosome 17 and (c) R deficiency aggravates the risk of aneuploidy caused by F deficiency. These hypotheses were tested in long-term cultures of lymphocytes from twenty female healthy volunteers (aged 30-48 years). Lymphocytes were cultured in each of the four possible combinations of low (L) and high (H) F (LF, 20 nmol/L, HF 200 nmol/L, respectively) and L and H R (LR 1 nmol/L, HR 500 nmol/L, respectively) media (LFLR, LFHR, HFLR, HFHR) for 9 days. Chromosomes 8 and 17 aneuploidy was measured in mononucleated (MONO) and cytokinesis-blocked binucleated (BN) cells using dual-color fluorescence in situ hybridization (FISH) with fluorescent centromeric probes specific for chromosomes 8 and 17. Culture in LF media (LFLR or LFHR) induced significant and similar increases in frequencies of aneuploidy of chromosomes 8 and 17 (P < 0.001) relative to culture in HF media (HFLR or HFHR). There was no significant effect of R concentration on aneuploidy frequency for either chromosome. We conclude that F deficiency is a possible cause of chromosome 8 aneuploidy.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Matsuoka

Iimori

Niimi

et al. 2015

Molecular Cancer Therapeutics

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Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2 0 -deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTDinduced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G 2 phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD-treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102.

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Uracil in DNA: Consequences for carcinogenesis and chemotherapy

Cited by 69 publications

References 69 publications

5‐Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line

5‐Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line

Folate deficiency in human peripheral blood lymphocytes induces chromosome 8 aneuploidy but this effect is not modified by riboflavin

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

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