Rustum Y M, Harstrick A, Cao S, Vanhoefer U, Yin M B, Wilke H, Seeber S
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
J Clin Oncol. 1997 Jan;15(1):389-400. doi: 10.1200/JCO.1997.15.1.389.
Although fluoropyrimidines, in particular, fluorouracil (5-FU) and fluorodeoxyuridine (FdUrd), are active alone and in combination with other agents in a variety of human malignancies, therapeutic selectivity, resistance, and efficacy have been a major limitation in cancer therapy. Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation. With the recognition that TS is an important therapeutic target, direct and specific inhibitors have been developed and are under intensive preclinical and clinical evaluation, primarily in patients with colorectal cancer, with demonstrable activity. The direct TS inhibitors have been shown to be potent, with a high level of specificity under therapeutic conditions for TS. This includes ZD1694, AG337, and LY231514. To date, although the therapeutic activity of both direct and indirect inhibitors of TS is similar, differences in the magnitude and profile of toxicity have been observed. A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694.
Recognition that greater than 95% of the injected dose of 5-FU is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD) to therapeutically inactive products, but with toxicity to normal tissues, led to the development of inhibitors of this enzyme with the aim to modify the therapeutic index of 5-FU. Several inhibitors in combination with 5-FU are under preclinical and clinical evaluation, including uracil and 5-chloro-2,4-dihydroxy pyridine, as modulators of 5-FU derived from its prodrug tegafur and 5-ethynyluracil as a modulator of 5-FU.
In this review, an update of the present status of direct and indirect inhibitors of TS is discussed, as well as the future prospect for new drugs alone and in combination.
尽管氟嘧啶，特别是氟尿嘧啶（5-FU）和氟脱氧尿苷（FdUrd），在多种人类恶性肿瘤中单独使用或与其他药物联合使用时具有活性，但治疗选择性、耐药性和疗效一直是癌症治疗的主要限制因素。晚期和辅助性结直肠癌的临床前和临床结果证实，以胸苷酸合成酶（TS）为主要靶点的氟嘧啶的治疗效果，通过亚叶酸（LV）调节可显著提高。随着认识到TS是一个重要的治疗靶点，已经开发出直接和特异性抑制剂，并正在进行深入的临床前和临床评估，主要针对结直肠癌患者，且已显示出明显的活性。直接TS抑制剂已被证明具有强效，在治疗条件下对TS具有高度特异性。这包括ZD1694、AG337和LY231514。迄今为止，尽管TS的直接和间接抑制剂的治疗活性相似，但已观察到毒性程度和特征存在差异。一项将TS直接抑制剂（ZD1694）与间接抑制剂（5-FU/LV）进行的III期比较评估已经完成，结果显示活性相似，但ZD1694的毒性降低。
认识到超过95%的注射剂量的5-FU会被二氢嘧啶脱氢酶（DPD）迅速灭活为无治疗活性的产物，但对正常组织有毒性，这导致了该酶抑制剂的开发，目的是改变5-FU的治疗指数。几种与5-FU联合使用的抑制剂正在进行临床前和临床评估，包括尿嘧啶和5-氯-2,4-二羟基吡啶，作为5-FU前药替加氟的调节剂，以及5-乙炔基尿嘧啶作为5-FU的调节剂。
在本综述中，讨论了TS直接和间接抑制剂的现状更新，以及新药单独使用和联合使用的未来前景。
