Adams E R, Leffert J J, Craig D J, Spector T, Pizzorno G
Yale University School of Medicine, Department of Internal Medicine, New Haven, Connecticut 06520, USA.
Cancer Res. 1999 Jan 1;59(1):122-7.
Biochemical modulation of 5-fluorouracil (5-FU) has been used over the past 20 years to improve the therapeutic efficacy of this antineoplastic agent. Recently, modulation of the catabolic pathway of this fluoropyrimidine has been the focus of extensive preclinical and clinical investigation. Dihydropyrimidine dehydrogenase catalyzes the rate-limiting step in the catabolism of 5-FU and rapidly degrades 60-90% of the drug. An irreversible inactivating inhibitor of this enzyme, 5-ethynyluracil (EU), markedly improves the antitumor effect of 5-FU in animal models. Early clinical studies have shown a substantial alteration of the systemic disposition of 5-FU with an increase in 5-FU terminal half-life and have also indicated that EU allows safe oral administration of 5-FU by improving the oral bioavailability of the fluoropyrimidine, which is otherwise too erratic and unpredictable for a drug with such a limited therapeutic window. We evaluated the effect of EU on the metabolism of 5-FU in mice bearing colon 38 tumors using 19F nuclear magnetic resonance spectroscopy. Ex vivo measurements of tissue extracts from liver, kidney, and tumor indicated a >95% elimination of alpha-fluoro-beta-ureidopropionic acid and a-fluoro-beta-alanine signals in the tissues of mice that received 2 mg/kg of EU before administration of 5-FU. The spectra also showed an increased formation of fluoronucleotides in both normal and tumor tissues, a prolonged presence of 5-FU, and the accumulation of 5-fluorouridine that otherwise is undetectable, particularly in normal tissues. The in vivo NMR experiments on colon 38 tumors confirmed these findings, showing a complete elimination of the a-fluoro-beta-ureidopropionic acid and a-fluoro-beta-alanine signals in tumors treated with EU and a dramatic formation and accumulation of 5-fluorouridine mono-, di-, and triphosphates and 5-fluorouridine. Thus, by inactivating dihydropyrimidine dehydrogenase, EU prolonged the half-life for 5-FU, almost completely eliminated its catabolism for 4-6 h, which led to an increased accumulation of 5-fluorouridine mono-, di-, and triphosphates in both normal and tumor tissues.
在过去20年中，5-氟尿嘧啶（5-FU）的生化调节已被用于提高这种抗肿瘤药物的治疗效果。最近，这种氟嘧啶分解代谢途径的调节一直是广泛的临床前和临床研究的重点。二氢嘧啶脱氢酶催化5-FU分解代谢的限速步骤，并迅速降解60-90%的药物。这种酶的一种不可逆失活抑制剂5-乙炔基尿嘧啶（EU）在动物模型中显著提高了5-FU的抗肿瘤效果。早期临床研究表明，5-FU的全身处置有实质性改变，5-FU的终末半衰期延长，还表明EU通过提高氟嘧啶的口服生物利用度使5-FU能够安全口服给药，否则对于治疗窗如此有限的药物，其口服生物利用度过于不稳定且不可预测。我们使用19F核磁共振波谱评估了EU对荷结肠38肿瘤小鼠体内5-FU代谢的影响。对肝脏、肾脏和肿瘤组织提取物的体外测量表明，在给予5-FU前接受2mg/kg EU的小鼠组织中，α-氟-β-脲基丙酸和α-氟-β-丙氨酸信号消除率>95%。光谱还显示，正常组织和肿瘤组织中氟核苷酸的形成均增加，5-FU的存在时间延长，以及5-氟尿苷的积累，否则在正常组织中无法检测到5-氟尿苷。对结肠38肿瘤的体内核磁共振实验证实了这些发现，显示在用EU治疗的肿瘤中，α-氟-β-脲基丙酸和α-氟-β-丙氨酸信号完全消除，5-氟尿苷单磷酸、二磷酸和三磷酸以及5-氟尿苷大量形成并积累。因此，通过使二氢嘧啶脱氢酶失活，EU延长了5-FU的半衰期，几乎完全消除了其4-6小时的分解代谢，这导致正常组织和肿瘤组织中5-氟尿苷单磷酸、二磷酸和三磷酸的积累增加。
