title: 5-Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line.
abstract: 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.
authors.affiliation: Departamento de Biofísica/Centro de Biotecnologia Universidade Federal do Rio Grande do Sul, UFRGS Porto Alegre, RS, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Matuo
authors.forename: Fabrício Garmus
authors.initials: FG
authors.lastname: Sousa
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Escargueil
authors.forename: Ivana
authors.initials: I
authors.lastname: Grivicich
authors.forename: Daniel
authors.initials: D
authors.lastname: Garcia-Santos
authors.forename: José Artur Bogo
authors.initials: JA
authors.lastname: Chies
authors.forename: Jenifer
authors.initials: J
authors.lastname: Saffi
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
authors.forename: João Antonio Pêgas
authors.initials: JA
authors.lastname: Henriques
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D005468:Fluorodeoxyuridylate / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D005472:Fluorouracil / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D006657:Histones / Q000235:genetics; D006801:Humans; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones; D009153:Mutagens; D005468:Fluorodeoxyuridylate; D005472:Fluorouracil