Machover D, Grison X, Goldschmidt E, Zittoun J, Lotz J P, Metzger G, Richaud J, Hannoun L, Marquet J, Guillot T
J Natl Cancer Inst. 1992 Mar 4;84(5):321-7. doi: 10.1093/jnci/84.5.321.
Potentiation of the antitumor activity of fluorouracil (5-FU) by folinic acid has been demonstrated in patients with colorectal adenocarcinoma. Modulation is due to the interaction of thymidylate synthase, fluorodeoxyuridine monophosphate, and methylene tetrahydrofolate, which leads to the formation of a stable ternary complex with concomitant enzyme inactivation. Folinic acid consists of a mixture of equal parts of two stereoisomers differing in chirality at the C-6 carbon of the pteridine ring. Only the levorotatory (6S)-stereoisomer of folinic acid is transformed into active folate cofactors. However, the (6R)-stereoisomer of folinic acid is not inert; it was shown to interfere with the (6S) form at the cellular level.
The possibility of a deleterious effect of the unnatural stereoisomer on the modulation of 5-FU led us to carry out a phase I-II study of 5-FU combined with the (6S)-stereoisomer of folinic acid given in high doses for treatment of patients with advanced colorectal carcinoma. We also determined the plasma pharmacokinetics of folates after intravenous (IV) injection of (6S)-folinic acid at the dose used in this study.
Treatment consisted of 5-FU (350-550 mg/m2 per day by IV infusion for 2 hours) and (6S)-folinic acid (100 mg/m2 per day by IV bolus injection) given for 5 consecutive days; the treatment was repeated every 21 days. Twenty-five patients with advanced colorectal carcinoma, who had had no prior chemotherapy, were evaluated for antitumor activity. The quantity of folates in plasma was measured using a microbiological assay.
The median follow-up time was 9 months (range, 3.5-15.2 months). The response rate was 52% (complete response, 12%; partial response, 40%). The median time to disease progression for responding patients was 9.2 months (range, 5.9-15+ months). The estimated probability of survival at 12 months was 73%. Palliative improvement in quality of life was achieved in most patients who had symptoms due to the tumor before the start of treatment. The dose-limiting toxic effects were grade 3 diarrhea, dermatitis, and oral mucositis. Grade 4 toxicity did not occur. Myeloid toxicity was minor. After IV injection, (6S)-folinic acid was rapidly cleared from plasma (mean half-lives: alpha = 7.2 minutes and beta = 126 minutes). The mean concentration of the unchanged compound 2 hours after injection was 5.8 mumol/L.
The (6S)-form of folinic acid potentiates the antitumor effect of 5-FU given concomitantly.
Our results justify a more complete exploration of the pure active stereoisomer as a modulator of the fluoropyrimidines.
在结肠腺癌患者中已证实甲酰四氢叶酸可增强氟尿嘧啶（5-FU）的抗肿瘤活性。这种调节作用归因于胸苷酸合成酶、氟脱氧尿苷单磷酸和亚甲基四氢叶酸之间的相互作用，其导致形成稳定的三元复合物并伴随酶失活。甲酰四氢叶酸由蝶啶环C-6碳处手性不同的两种立体异构体等份混合组成。只有左旋（6S）-立体异构体的甲酰四氢叶酸可转化为活性叶酸辅因子。然而，甲酰四氢叶酸的（6R）-立体异构体并非无活性；已表明它在细胞水平上会干扰（6S）形式。
非天然立体异构体对5-FU调节作用产生有害影响的可能性促使我们开展一项I-II期研究，即高剂量给予（6S）-立体异构体的甲酰四氢叶酸联合5-FU治疗晚期结肠癌患者。我们还测定了在本研究中使用的剂量静脉注射（6S）-甲酰四氢叶酸后叶酸的血浆药代动力学。
治疗方案为5-FU（每天350 - 550mg/m²，静脉输注2小时）和（6S）-甲酰四氢叶酸（每天100mg/m²，静脉推注），连续给药5天；每21天重复一次治疗。对25例既往未接受过化疗的晚期结肠癌患者进行抗肿瘤活性评估。采用微生物测定法测量血浆中叶酸的量。
中位随访时间为9个月（范围3.5 - 15.2个月）。缓解率为52%（完全缓解12%；部分缓解40%）。缓解患者的疾病进展中位时间为9.2个月（范围5.9 - 15 +个月）。12个月时的估计生存率为73%。大多数在治疗开始前因肿瘤出现症状的患者在生活质量方面得到了姑息性改善。剂量限制性毒性反应为3级腹泻、皮炎和口腔黏膜炎。未发生4级毒性反应。骨髓毒性较轻。静脉注射后，（6S）-甲酰四氢叶酸迅速从血浆中清除（平均半衰期：α = 7.2分钟，β = 126分钟）。注射后2小时未改变化合物的平均浓度为5.8μmol/L。
（6S）-形式的甲酰四氢叶酸可增强同时给予的5-FU的抗肿瘤作用。
我们的结果证明更全面地探索纯活性立体异构体作为氟嘧啶调节剂是合理的。
