Aiba K
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, Md 20892.
Gan To Kagaku Ryoho. 1988 Mar;15(3):392-408.
The biochemical modulation of 5-fluorouracil (FU) by using it in combination with leucovorin (LV) is reviewed. One of the mechanisms of action of FU is inhibition of thymidylate synthase (TS), a critical enzyme in the de novo synthesis of thymidylate required for DNA repair and synthesis. In the presence of 5, 10-methylene tetrahydrofolate, 5-fluoro-deoxyuridine monophosphate (FdUMP), which is an active nucleotide of FU, forms a ternary complex with TS, resulting in enzyme inhibition. The rationale for the use of LV with FU is to increase of formation and stability of catalytically inactive ternary complexes. In clinical trials, the dose schedules of 500 mg/m2 iv bolus or 500 mg/m2 continuously iv infusion is frequently used in order to obtain an ideal plasma concentration of active LV metabolites. Preliminary clinical trials using the combination of FU and LV appear to be capable of increasing of the clinical activity of FU for colorectal and breast cancers. Several randomized studies have supported the increase in response rates seen in the uncontrolled trials but additional studies are required to demonstrate a positive impact on the survival of treated patients.
本文综述了5-氟尿嘧啶（FU）与亚叶酸（LV）联合使用时的生化调节作用。FU的作用机制之一是抑制胸苷酸合成酶（TS），TS是DNA修复和合成所需胸苷酸从头合成过程中的关键酶。在5,10-亚甲基四氢叶酸存在的情况下，FU的活性核苷酸5-氟脱氧尿苷单磷酸（FdUMP）与TS形成三元复合物，导致酶抑制。LV与FU联合使用的理论依据是增加无催化活性的三元复合物的形成和稳定性。在临床试验中，经常使用500mg/m²静脉推注或500mg/m²持续静脉输注的剂量方案，以获得理想的活性LV代谢物血浆浓度。使用FU和LV联合的初步临床试验似乎能够提高FU对结直肠癌和乳腺癌的临床活性。几项随机研究支持了在非对照试验中观察到的缓解率增加，但还需要更多研究来证明对治疗患者生存的积极影响。
