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5‐Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line
Author(s) -
Matuo Renata,
Sousa Fabrício Garmus,
Escargueil Alexandre E.,
Grivicich Ivana,
GarciaSantos Daniel,
Chies José Artur Bogo,
Saffi Jenifer,
Larsen Annette K.,
Henriques João Antonio Pêgas
Publication year - 2009
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1411
Subject(s) - thymidylate synthase , apoptosis , dna damage , cell cycle , cell cycle checkpoint , biology , cancer research , programmed cell death , dna , cell culture , cell growth , microbiology and biotechnology , biochemistry , fluorouracil , cancer , genetics
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. Copyright © 2008 John Wiley & Sons, Ltd.