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
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DOI：
10.1002/jat.1411
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发表时间：
2009-05-01
影响因子：
3.3
通讯作者：
Pegas Henriques, Joao Antonio
中科院分区：
文献类型：
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作者：
Matuo, Renata;Sousa, Fabricio Garmus;Pegas Henriques, Joao Antonio
5-氟尿嘧啶（5-FU）是一种广泛用于治疗癌症的抗肿瘤药物。其细胞毒性作用主要归因于5-FU活性代谢产物HUMP在DNA和RNA合成过程中错误掺入DNA和RNA，以及抑制胸苷酸合成酶（TS），导致核苷酸库失衡。在本研究中，我们比较了5-FU和FdUMP诱导人结肠SW 620腺癌细胞凋亡和影响细胞周期进程的能力，以及它们的遗传毒性和致染色体断裂活性。我们的研究表明，5-FU诱导SSB，DSB和细胞凋亡早于FdUMP。有趣的是，虽然两种药物都能够诱导细胞凋亡，但它们对细胞周期进程的影响不同。事实上，5-FU诱导G1/S期阻滞，而HUMP导致G2/M期阻滞。独立的时间差异链断裂和凋亡诱导，以及差异细胞周期的调制，这两种药物提出了类似的致染色体断裂的影响。细胞周期阻滞的不同模式表明，这两种药物诱导不同类型的原发性DNA损伤，可能导致不同检查点的激活并招募不同的DNA修复途径。版权所有（C）2008约翰威利父子有限公司
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 HUMP (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 HUMP 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 (C) 2008 John Wiley & Sons, Ltd.