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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism
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Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism

机译：胸苷酸合酶的诱导作为5-氟尿嘧啶耐药机制

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摘要

Thymidylate synthase (TS) is a key enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate (dTMP) from 2'-deoxyuridine-5'-monophosphate (dUMP), for which 5,10-methylene-tetrahydrofolate (CH_2-THF) is the methyl donor. TS is an important target for chemotherapy; it is inhibited by folate and nucleotide analogs, such as by 5-fluoro-dUMP (FdUMP), the active metabolite of 5-fluorouracil (5FU0. FdUMP forms a relatively stable ternary complex with TS and CH_2 THF, which is further stabilized by leucovorin (LV). 5FU treatment can induce TS expression, which might bypass dTMP depletion. An improved efficacy of 5FU might be achieved by increasing and prolonging TS inhibition, a prevention of dissociation of the ternary complex, and prevention of TS induction. In a panel of 17 colon cancer cells, including several variants with acquired resistance to 5FU, sensitivity was related to TS levels, but exclusion of the resistant variants abolished this relation. For antifolates, polyglutamylation was more important than the intrinsic TS level. Cells with low p53 levels were more sensitive to 5FU and the antifolate raltitrexed (RTX) than cells with high, mutated p53. Free TS protein down-regulates its own translation, but its transcription is regulated by E2F, a cell cycle checkpoint regulator. Together, this results in low TS levels in stationary phase cells. Although cells with a low TS might theoretically be more sensitive to 5FU, the low proliferation rate prevents induction of DNA damage and 5FU toxicity. TS levels were not related to polymorphisms of the TS promoter. Treatment with 5FU or RTX rapidly induced TS levels two- to five-fold. In animal models, 5FU treatment resulted in TS inhibition followed by a two-to three-fold TS induction. Both LV and a high dose of 5FU not only enhanced TS inhibition, but also prevented TS induction and increased the antitumor effect. In patients, TS levels as determined by enzyme activity assays, immunohistochemistry and mRNA expression, were related to a response to 5FU. 5FU treatment initially decreased TS levels, but this was followed by an induction, as seen with an increased ratio of TS protein over TS-mRNA. The clear retrospective relation between TS levels and response now forms the basis for a prospective study, in which TS levels are measured before treatment in order to determine the treatment protocol.
机译：胸苷酸合酶（TS）是从2'-脱氧尿苷-5'-单磷酸盐（dUMP）从头合成2'-脱氧胸苷5'-单磷酸盐（dTMP）的关键酶，其中5,10-亚甲基-四氢叶酸（CH_2-THF）是甲基供体。 TS是化疗的重要靶点;它会受到叶酸和核苷酸类似物的抑制，例如被5-氟尿嘧啶（5FU0）的活性代谢物5-fluoro-dUMP（FdUMP）抑制。FdUMP与TS和CH_2 THF形成相对稳定的三元复合物，并通过亚叶酸钙单糖进一步稳定（LV）。5FU治疗可以诱导TS表达，可能绕过dTMP耗竭;可以通过增加和延长TS抑制作用，防止三元复合物解离和防止TS诱导来提高5FU的疗效。在17种结肠癌细胞中，包括几个对5FU具有耐药性的变体，敏感性与TS水平相关，但排除耐药变体则消除了这种关系;对于抗叶酸药物，多谷氨酰化作用比内在TS水平更为重要。对pFU的敏感度高于对p53高突变细胞的5FU和抗叶酸raltitrexed（RTX）的表达。游离TS蛋白下调其自身翻译，但其转录受E2F调节，一个细胞周期检查点调节器。在一起，这导致固定相电池中的TS水平较低。尽管理论上低TS的细胞可能对5FU更为敏感，但低增殖率会阻止DNA损伤和5FU毒性。 TS水平与TS启动子的多态性无关。用5FU或RTX进行治疗可迅速诱导TS水平升高2至5倍。在动物模型中，5FU处理导致TS抑制，然后诱导2至3倍的TS诱导。 LV和高剂量的5FU不仅增强了TS抑制作用，而且还阻止了TS诱导并增强了抗肿瘤作用。在患者中，通过酶活性测定，免疫组织化学和mRNA表达确定的TS水平与对5FU的应答有关。 5FU处理最初降低了TS水平，但随后进行了诱导，如TS蛋白与TS-mRNA的比率增加所看到的。 TS水平与反应之间明确的回顾关系现在构成前瞻性研究的基础，在该研究中，应在治疗前测量TS水平，以确定治疗方案。

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