Heidelberger C
Cancer Treat Rep. 1981;65 Suppl 3:3-9.
The specific rationale for the development of the fluorinated pyrimidines and the predictions of their mode of action have been described. The mode of action of 5-FU involves incorporation into RNA and metabolic activation to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which inhibits the essential enzyme for DNA synthesis, thymidylate synthetase. I believe that the latter effect is responsible for the major chemotherapeutic activity. Our studies on the mechanism of the inhibition of that enzyme have led to the demonstration that a ternary covalent complex of enzyme, inhibitor, and cofactor is formed that results in essentially irreversible inhibition. The nature of this ternary complex has enabled us to devise ultrasensitive competitive ligand binding assays for thymidylate synthetase, FdUMP, and dUMP, the substrate of the enzyme. These determinants will be studied in needle biopsy specimens obtained from cancer patients undergoing chemotherapy with 5-FU in a prospective clinical investigation.
已描述了氟嘧啶类药物研发的具体理论依据及其作用方式的预测。5-氟尿嘧啶（5-FU）的作用方式包括掺入RNA并代谢活化为5-氟-2'-脱氧尿苷-5'-单磷酸（FdUMP），后者可抑制DNA合成的关键酶胸苷酸合成酶。我认为后一种作用是主要化疗活性的原因。我们对该酶抑制机制的研究已证明，会形成酶、抑制剂和辅因子的三元共价复合物，从而导致基本上不可逆的抑制。这种三元复合物的性质使我们能够设计出针对胸苷酸合成酶、FdUMP和该酶底物dUMP的超灵敏竞争性配体结合测定法。在一项前瞻性临床研究中，将对接受5-FU化疗的癌症患者的针吸活检标本中的这些决定因素进行研究。
