Thymidylate synthase: A critical target in cancer therapy?
Thymidylate synthase: A critical target in cancer therapy?
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DOI：
10.2741/1408
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发表时间：
2004-09-01
影响因子：
3.1
通讯作者：
Rustum, YM
中科院分区：
文献类型：
--
作者：
Rustum, YM
在过去的四十年里，潜在活性药物的合成和测试（例如，抗代谢物）已经集中于作为DNA和RNA合成的前体的现有代谢物的结构修饰。近年来，焦点已转移到靶向特异性试剂的合成。因此，目前药物开发的重点是抑制肿瘤组织中优先表达的特异性靶标，最终目标是提高这些新药物的治疗效果和选择性。临床前，在具有预期靶点特异性表达的肿瘤中进行了原理验证研究。胸苷酸合成酶（TS）仍然是5-氟尿嘧啶（5-FU）及其前药UFT/LV（Orzel）、卡培他滨（Xeloda）和S-1的关键靶点，主要是因为该酶对于DNA合成前体2 '-脱氧胸苷-5'-单磷酸的合成至关重要。虽然氟嘧啶抗代谢物具有其他作用位点，但抗叶酸剂ZD 1694（雷替曲塞，Tomudex（R））和AG 337（ThymitagTM）是更特异和有效的TS抑制剂。因此，希望这种酶的显著和持续抑制可以导致与对这些药剂的敏感性和抗性相关的分子标记物的下游调节。认识到靶酶抑制的程度和持续时间可能取决于靶酶胸苷酸合成酶的表达水平也是至关重要的。临床前和临床系统中的相关研究表明，酶水平（mRNA和蛋白质）与用氟嘧啶或Tomudex（R）治疗的结肠直肠癌患者的治疗反应之间存在密切关系。然而，反应者和非反应者之间存在显著重叠。这些数据是一致的假设，预测抗癌药物的反应是多因素的，和TS是一个target.Clinically，虽然结直肠癌患者的总体反应各种TS抑制剂是相似的，毒性档案是不同的。5-FU前药的可用性提供了更大的治疗选择性的可能性，这是基于胸苷磷酸化酶（5-FU的活化酶）在肿瘤组织中的表达水平高于正常组织对应物的证据。TS抑制剂的成功应用很可能不仅基于肿瘤与正常组织中TS水平的测量，而且基于这种抑制对与细胞增殖、凋亡和细胞周期调节相关的分子标志物的后果的描述。
For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials.Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2'-deoxythymidine- 5'-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 ( raltitrexed, Tomudex(R)) and AG337 (Thymitag(TM)) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase.Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level ( mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex(R). However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target.Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation.