Novel polypyrimidine antitumor agent FdUMP[10] induces thymineless death with topoisomerase I-DNA complexes
Novel polypyrimidine antitumor agent FdUMP[10] induces thymineless death with topoisomerase I-DNA complexes
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DOI：
10.1158/0008-5472.can-04-1302
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Pommier, Y
中科院分区：
文献类型：
--
作者：
Liao, ZY;Sordet, O;Pommier, Y
FdUMP[10]是5-氟-2'-脱氧尿苷5'-单磷酸（FdUMP）的10mer，是5-氟尿嘧啶（FU）的胸苷酸合成酶抑制代谢物，在国家癌症研究所的比较分析中，与DNA拓扑异构酶1 （Top1）抑制剂喜树碱最密切相关，但与FU无关。FdUMP[10]比FdUMP或5-氟-2′-脱氧尿苷（FdU）具有更强的抗增殖活性，且活性明显高于FU。缺乏Top1的喜树碱耐药P388/CPT45细胞对FdUMP[10]以及FdUMP、FdU和胸苷酸合成酶抑制剂雷替曲西（Tomudex）具有交叉耐药。FdUMP[10]诱导DNA单链断裂和细胞Top1-DNA复合物。在FdUMP、FdU、雷替曲塞和FU的反应中也观察到这种复合物。FdUMP[10]诱导的Top1-DNA复合物不受caspase抑制剂z-VAD-fmk的抑制，并且独立于凋亡DNA片段的形成，表明它们不对应于凋亡的Top1-DNA复合物。在生化分析中，Top1直接被捕获在尿嘧啶和FdU错配位点。我们认为，由于胸腺嘧啶合成酶抑制和胸腺嘧啶耗尽，FdUMP[10]通过在尿嘧啶和FdU错误结合位点捕获Top1来破坏DNA。
FdUMP[10], a 10mer of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), the thymidylate synthase inhibitory metabolite of 5-fluorouracil (FU), is most closely correlated with the DNA topoisomerase 1 (Top1) inhibitor camptothecin in the National Cancer Institute COMPARE analysis, but not with FU. FdUMP[10] exhibits more potent antiproliferative activity than FdUMP or 5-fluoro-2'-deoxyuridine (FdU) and is markedly more active than FU. Camptothecin-resistant P388/CPT45 cells lacking Top1 are cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate synthase inhibitor raltitrexed (Tomudex). FdUMP[10] induces DNA single-strand breaks and cellular Top1-DNA complexes. Such complexes are also observed in response to FdUMP, FdU, raltitrexed, and FU. The FdUMP[10]-induced Top1-DNA complexes are not inhibited by the caspase inhibitor z-VAD-fmk and form independently of apoptotic DNA fragmentation, indicating that they do not correspond to apoptotic Top1-DNA complexes. In biochemical assay, Top1 is directly trapped at uracil and FdU misincorporation sites. We propose that FdUMP[10] damages DNA by trapping Top1 at uracil and FdU misincorporation sites resulting from thymidylate synthase inhibition and thymine depletion.