Failure of high-dose leucovorin to improve therapy with the maximally tolerated dose of 5-fluorouracil: a murine study with clinical relevance?
Failure of high-dose leucovorin to improve therapy with the maximally tolerated dose of 5-fluorouracil: a murine study with clinical relevance?
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高剂量亚叶酸未能改善最大耐受剂量 5-氟尿嘧啶的治疗：具有临床相关性的小鼠研究？
DOI：
10.1093/jnci/80.7.496
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Colofiore,JR
中科院分区：
文献类型：
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作者：
Martin,DS;Stolfi,RL;Colofiore,JR
几乎所有已完成和正在进行的甲酰四氢叶酸/5-氟尿嘧啶（LV/5-FU）联合治疗III期试验都使用了5-FU单药对照组，其中5-FU的给药方案与LV/5-FU组不同，或者其中5-FU未达到最大耐受剂量（MTD）。由于已知剂量强度和给药方案均会影响药物活性，因此在晚期首次传代自发性乳腺肿瘤的临床前CD 8 F1小鼠模型中，采用与5-FU单药治疗组和LV/5-FU联合治疗组相同的剂量（MTD）和给药方案，对LV/5-FU联合治疗进行了评价。总体而言，LV未改善MTD 5-FU治疗。此外，尽管LV可增加低于MTD的5-FU剂量的活性，但治疗结果与MTD的5-FU单药相当。在用5-FU的其他调节剂（例如，尿苷、PALA、甲氨蝶呤），在其MTD下用各种调节的5-FU组合治疗对LV没有改善。总之，尽管在这些体内临床前研究中LV可以增强5-FU的细胞毒性，但它并不能增强5-FU的选择性，这一结论与目前的许多临床报告不一致。不管是不是。这些鼠的发现不具有临床意义，只能通过对照组采用5-FU单药的MTD、LV/5-FU组采用5-FU的MTD（或接近耐受的MTD）以及两组采用相同给药方案设计的临床试验来确定。
Almost all of the completed and ongoing phase III trials of the leucovorin/5-fluorouracil (LV/5-FU) combination have used either a single-agent 5-FU control arm in which the 5-FU was administered in a different schedule from the LV/5-FU arm or one in which the 5-FU was not at the maximally tolerated dose (MTD). Because both dose intensity and scheduling are known to affect drug activity, the LV/5-FU combination was evaluated in the preclinical CD8F1murine model of advanced first-passage spontaneous breast tumors using the same dose (at MTD) and schedule for 5-FU alone and in the LV/5-FU combination arm. Overall, therapy with 5-FU at MTD was not improved by LV. Further, although the activity of 5-FU doses lower than the MTD could be increased by LV, the therapeutic result was comparable to that of single-agent 5-FU at MTD. In an evaluation with other modulators of 5-FU (e.g., uridine, PALA, methotrexate), therapy with various modulated 5-FU combinations at their MTD was not improved with LV. In conclusion, although LV can enhance the cytotoxicity of 5-FU in these in vivo preclinical studies, it does not confer enhanced selectivity to 5-FU, a conclusion at odds with many present clinical reports. Whether or. not these murine findings have clinical relevance can be determined only by clinical trials designed with the MTD of 5-FU alone in the control arm, the MTD of 5-FU (or as close as tolerated) in the LV/5-FU arm, and identical schedules in both arms.