Sasaki T, Ota K, Wakui A, Akazawa S, Ogawa M, Ariyoshi Y, Yura J, Inagaki J, Hoshino A, Abe T
Dept. of Chemotherapy, Tokyo Metropolitan Komagome Hospital.
Gan To Kagaku Ryoho. 1993 Mar;20(4):485-91.
Leucovorin, given usually by i.v. injection or orally changes to 5, 10-methylene tetrahydrofolate in tumor as well as normal cells. And in normal FdUMP, an active metabolite of 5-FU, binds tightly to thymidylate synthase in the presence of cofactor, 5, 10-methylene tetrahydrofolate. This interaction leads to potentiate the cytotoxic effect of 5-FU by prolonged inhibition of thymidylate synthase. Phase I study using l-leucovorin (l-LV), an active form of leucovorin, combined with 5-FU, was conducted. In the weekly schedule, 5-FU was fixed to 600mg/m2, and l-LV dose was escalated from 125 mg/m2 to 250mg/m2, if toxicity was acceptable. On the other hand, in the five consecutive-day schedule, 5-FU was fixed to 370mg/m2 and l-LV was escalated from 25mg/m2 to 50mg/m2, 100mg/m2 and 200 mg/m2. l-LV 10mg/m2 was tested as reference. On weekly schedule of l-LV 250mg/m2, grade III diarrhea was seen in 2 cases and grade IV leucopenia was seen in one. In five consecutive-day schedule, at each dose of l-LV, stomatitis, nausea plus vomiting, anorexia, anemia and leucopenia were seen. However, the increase of toxicities were not seen by dose escalation of l-LV. Then, we have been conducted a randomized early phase II study using 250 mg/m2 of l-LV weekly (arm A) and 100mg/m2 (arm B) or 10mg/m2 (arm C) of l-LV for 5 consecutive days in gastric and colorectal cancer by multicenter cooperative study. Plasma concentrations of l-LV were maintained > 10(-5) mol/L for over 5 hrs. after 2 hrs. infusion of 250 mg/m2 of l-LV and for over one hr. after a rapid injection of 100mg/m2 of l-LV.
亚叶酸通常通过静脉注射或口服给药，在肿瘤细胞和正常细胞中转变为5,10-亚甲基四氢叶酸。在正常细胞中，5-氟尿嘧啶（5-FU）的活性代谢产物氟尿嘧啶脱氧核苷酸（FdUMP）在辅因子5,10-亚甲基四氢叶酸存在的情况下与胸苷酸合成酶紧密结合。这种相互作用通过延长对胸苷酸合成酶的抑制来增强5-FU的细胞毒性作用。开展了一项使用亚叶酸的活性形式L-亚叶酸（l-LV）联合5-FU的I期研究。在每周给药方案中，5-FU固定为600mg/m²，若毒性可接受，l-LV剂量从125mg/m²递增至250mg/m²。另一方面，在连续五天给药方案中，5-FU固定为370mg/m²，l-LV从25mg/m²递增至50mg/m²、100mg/m²和200mg/m²。以10mg/m²的l-LV作为对照进行测试。在l-LV 250mg/m²每周给药方案中，2例出现III级腹泻，1例出现IV级白细胞减少。在连续五天给药方案中，在每个l-LV剂量组均观察到口腔炎、恶心伴呕吐、厌食、贫血和白细胞减少。然而，未观察到l-LV剂量递增导致毒性增加。随后，我们通过多中心合作研究开展了一项随机早期II期研究，在胃癌和结直肠癌患者中比较每周使用250mg/m²的l-LV（A组）与连续五天使用100mg/m²（B组）或10mg/m²（C组）的l-LV的疗效。静脉输注250mg/m²的l-LV 2小时后，l-LV的血浆浓度维持>10⁻⁵mol/L超过5小时；快速注射100mg/m²的l-LV后，l-LV的血浆浓度维持>10⁻⁵mol/L超过1小时。
