Allegra C J, Chabner B A, Sholar P W, Bagley C, Drake J C, Lippman M E
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD 20892.
NCI Monogr. 1987(5):199-202.
The active metabolite of FUra, 5-fluorodeoxyuridine monophosphate (5-FdUMP), requires the presence of reduced folates to form a covalent ternary complex with the target enzyme thymidylate synthase (TS). In vitro and in vivo studies have demonstrated a potentiation of the cytotoxic effects of FUra when combined with the reduced folate, leucovorin. We have applied this concept to the treatment of metastatic breast cancer in a phase II trial, as recent clinical studies on patients with colorectal carcinoma have suggested an enhanced efficacy for the combination of FUra plus leucovorin. Patients entered on the present study are undergoing treatment with a 5-day daily regimen of leucovorin (500 mg/m2, iv) followed by FUra (375 mg/m2, iv). Toxicity and response data are currently being collected on patients who have failed "standard" combination regimens that included FUra. In patients with accessible tumor, serial biopsies are being obtained during treatment with the combination of FUra and leucovorin and during therapy with FUra alone to assess the degree of 5-FdUMP binding to the target enzyme, TS, in the presence and absence of exogenously administered leucovorin. Preliminary results from the biochemical studies suggest an enhanced saturation of TS by the fluorinated pyrimidine when administered with leucovorin.
氟尿嘧啶（FUra）的活性代谢产物5-氟脱氧尿苷一磷酸（5-FdUMP）需要还原型叶酸的存在才能与靶酶胸苷酸合成酶（TS）形成共价三元复合物。体外和体内研究均表明，FUra与还原型叶酸亚叶酸钙联合使用时，其细胞毒性作用会增强。我们已将这一理念应用于一项II期试验中转移性乳腺癌的治疗，因为最近针对结直肠癌患者的临床研究表明，FUra加亚叶酸钙联合使用疗效更佳。参与本研究的患者正在接受为期5天的治疗方案，即先静脉注射亚叶酸钙（500 mg/m²），随后静脉注射FUra（375 mg/m²）。目前正在收集那些对包含FUra的“标准”联合治疗方案无效的患者的毒性和反应数据。对于有可触及肿瘤的患者，在接受FUra和亚叶酸钙联合治疗期间以及单独接受FUra治疗期间，会进行系列活检，以评估在有和没有外源性给予亚叶酸钙的情况下，5-FdUMP与靶酶TS的结合程度。生化研究的初步结果表明，与亚叶酸钙联合使用时，氟化嘧啶对TS的饱和作用增强。
