New concepts for the development and use of antifolates
New concepts for the development and use of antifolates
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DOI：
10.1002/stem.140041
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发表时间：
1996-01-01
期刊：
影响因子：
5.2
通讯作者：
Allegra, CJ
中科院分区：
文献类型：
--
作者：
Chu, E;Grem, JL;Allegra, CJ
大约三分之一的结直肠癌患者处于晚期，因此无法治愈，对于这些患者来说，开发新的化疗策略至关重要。5-氟尿嘧啶(5-FU)的生化调节导致5-FU的活性增加了近两倍，最近的临床前研究表明，干扰素也可以调节5-FU的活性，并可能导致患者的应答率提高，5-FU耐药的关键机制之一似乎是该酶抑制剂治疗后急性诱导胸苷合成酶(TS)水平，这一机制基于一种新的自动调节反馈途径，其中TS蛋白调节其自身的翻译效率。该酶的调节功能依赖于其被生理配体或包括氟嘧啶和抗叶酸在内的抑制剂占据的状态。目前正在努力利用这种蛋白质/信使RNA相互作用的知识进行治疗，鉴于TS的重要性，我们实验室已经开发出能够定量检测新鲜或石蜡包埋组织中该酶水平的抗体；初步研究表明，TS水平可预测直肠癌患者的预后并可用于预测氟嘧啶类药物的疗效；利用5-FU与亚叶酸钙和干扰素的双重调节的新策略正在进展期和辅助性疾病环境中进行研究。随着新的、更有效的抑制剂的开发，关于TS的新的机制概念的出现将有望导致未来的治疗收益。
Approximately one-third of all cases of colorectal carcinoma present in an advanced and, therefore, incurable stage, For these patients, the development of new chemotherapeutic strategies is of central importance. Biochemical modulation of 5-fluorouracil (5-FU) has resulted in approximately a two-fold increase in activity of 5-FU, Recent preclinical investigations suggest that interferon can also modulate the activity of 5-FU and may result in enhanced response rates in patients, One of the critical mechanisms of resistance to 5-FU appears to be the acute induction in thymidylate synthase (TS) levels following therapy with inhibitors of this enzyme, This mechanism is based on a novel autoregulatory feedback pathway wherein the TS protein regulates its own translational efficiency. Regulatory function of the enzyme is dependent on its state of occupancy by either the physiologic ligands or inhibitors, including fluoropyrimidines and antifolates. Ongoing efforts are directed towards utilizing knowledge of this protein/messenger RNA interaction for therapeutic benefit, Given the importance of TS, our laboratory has developed antibodies capable of quantitating the levels of this enzyme in fresh or paraffin-embedded tissues, preliminary investigations suggest that the level of TS has prognostic importance in patients with rectal carcinoma and may be used to predict responsiveness to fluoropyrimidine agents, Novel strategies utilizing dual modulation of 5-FU with leucovorin and interferon are under investigation in both the advanced and adjuvant disease settings. Emerging mechanistic concepts regarding TS, along with the development of new, more potent inhibitors will hopefully result in future therapeutic gains.