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

• Published in: Journal of applied toxicology 2009-05, Vol.29 (4), p.308-316
• Main Authors: Matuo, Renata, Sousa, Fabrício Garmus, Escargueil, Alexandre E., Grivicich, Ivana, Garcia-Santos, Daniel, Chies, José Artur Bogo, Saffi, Jenifer, Larsen, Annette K., Henriques, João Antonio Pêgas
• Format: Article
• Language: English
• Subjects: 5-fluorouracil; Activation; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - toxicity; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; cell cycle arrest; Cell Line, Tumor; Cell Survival - drug effects; Colon; Comet Assay; cytotoxicity; Deoxyribonucleic acid; DNA Damage; DNA, Neoplasm - drug effects; Drugs; FdUMP; Fluorodeoxyuridylate - chemistry; Fluorodeoxyuridylate - pharmacokinetics; Fluorodeoxyuridylate - toxicity; Fluorouracil - chemistry; Fluorouracil - pharmacokinetics; Fluorouracil - toxicity; Gastroenterology. Liver. Pancreas. Abdomen; genotoxicity; Histones - genetics; Human; Humans; Medical sciences; Metabolites; Micronucleus Tests; Mutagens - toxicity; Progressions; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Toxicology; Tumors
• ISSN: 0260-437X; 1099-1263; 1099-1263
• DOI: 10.1002/jat.1411

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. Our study demonstrates that 5‐FU induces SSB, DSB, and apoptosis earlier than FdUMP in SW620 cells. 5‐FU induces an arrest in G1/S while FdUMP 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 type of primary DNA lesions that recruit different DNA repair pathways.