Thymidylate合酶:癌症治疗的一个关键目标?

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Thymidylate合酶:癌症治疗的一个关键目标?

Biosci前面。2004年9月1;9:2467 - 73。

PubMed ID

15353299 (在PubMed

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文摘

在过去的四十年,合成和测试潜在的活性药物(如抗代谢物)都集中在结构修改现有的代谢物作为DNA和RNA合成的前体。近年来,已经把重点转移到有针对性的综合代理。因此,目前药物开发的重点是针对抑制特定的目标优先(s)表示,如果不是全部,在肿瘤组织中,最终目标是提高治疗效果和选择性的这些新代理。功能型,原理研究进行了肿瘤与预定目标的具体表达式。希望翻译临床前研究结果实施临床试验的设计。Thymidylate合成酶(TS)仍然是一个关键的目标5 -氟尿嘧啶(研究者用)和其高活性化合物,UFT / LV (Orzel),卡培他滨(Xeloda)和s - 1,主要是因为这种酶合成2-deoxythymidine-5-monophosphate至关重要,DNA合成的前体。虽然fluoropyrimidine抗代谢物有其他网站的行动,抗ZD1694 (raltitrexed Tomudex)和AG337 (Thymitag)是更具体的和强有力的TS抑制剂。因此,希望明显和持续抑制这种酶可能导致下游调控相关的分子标记与这些药物敏感性和耐药性。也认识到的关键目标酶的抑制的程度和持续时间可能取决于目标酶的表达水平,thymidylate合成酶。相关研究在临床前和临床系统演示了酶水平之间的亲密关系(mRNA和蛋白)和对治疗的反应的患者结直肠癌fluoropyrimidine或Tomudex。 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.

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药物靶点

药物	目标	类	生物	药理作用	行动
氟尿嘧啶	Thymidylate合酶	蛋白质	人类	是的	其他/未知	细节