Martin D S, Stolfi R L, Sawyer R C, Spiegelman S, Young C W
Cancer Res. 1983 Oct;43(10):4653-61.
Although clinical trials of high-dose methotrexate (MTX) sequenced before 5-fluorouracil (FUra) with leucovorin (LV) rescue apparently have resulted in increased numbers of tumor responses, this increased antitumor activity often has been accompanied with toxicity. The present report describes an attempt to improve therapeutic results with this drug combination by appropriate metabolic modulation in the preclinical BALB/c X DBA/8 F1 murine breast tumor model. A LV rescue schedule consisting of 300 mg/kg administered at 4.5 and 19.5 hr after high-dose MTX (300 mg/kg/week for 3 weeks) prevented MTX toxicity. When FUra was administered 2.5 hr after MTX (with LV rescue), the dose of FUra had to be decreased, and we could not obtain convincing evidence for a differential cytotoxic effect on tumor versus normal host tissue. However, when a delayed uridine rescue schedule was added to protect the host from the toxic activity of FUra, the FUra dose could be increased even in the presence of high-dose MTX, and the therapeutic result was enhanced significantly without an increase in host toxicity. Finally, it was possible to add N-phosphonacetyl-L-aspartate to this drug combination (in the appropriate sequence: N-phosphonacetyl-L-aspartate before high-dose MTX-before high-dose FUra, followed by double rescue with LV and uridine) without producing increased toxicity to yield a significant increase in partial tumor regression rate. The biochemical rationale for the selection and sequence of administration of these agents is discussed.
尽管在5-氟尿嘧啶（FUra）之前序贯使用高剂量甲氨蝶呤（MTX）并联合亚叶酸（LV）解救的临床试验显然已使肿瘤反应数量增加，但这种增强的抗肿瘤活性常常伴随着毒性。本报告描述了在临床前BALB/c×DBA/8 F1小鼠乳腺肿瘤模型中，通过适当的代谢调节来改善这种药物组合治疗效果的尝试。一种LV解救方案，即在高剂量MTX（300 mg/kg/周，共3周）给药后4.5小时和19.5小时给予300 mg/kg，可预防MTX毒性。当在MTX给药后2.5小时给予FUra（同时进行LV解救）时，FUra的剂量必须降低，而且我们未能获得关于对肿瘤组织与正常宿主组织有不同细胞毒性作用的确凿证据。然而，当添加延迟尿苷解救方案以保护宿主免受FUra的毒性作用时，即使在存在高剂量MTX的情况下，FUra剂量仍可增加，并且治疗效果显著增强，而宿主毒性并未增加。最后，在这种药物组合中加入N-磷酰乙酰-L-天冬氨酸（按照适当顺序：在高剂量MTX之前 - 在高剂量FUra之前，随后用LV和尿苷进行双重解救）不会产生额外毒性，可使部分肿瘤退缩率显著提高。文中讨论了这些药物选择及给药顺序的生化原理。
