Howell S B, Ensminger W D, Krishan A, Frei E
Cancer Res. 1978 Feb;38(2):325-30.
Thymidine rescue was administered following 63 courses of high-dose methotrexate in 20 patients. In the first part of this study, the methotrexate was given as a 24-hr infusion and the dose was escalated from 0.14 to 8.54 g/sq m; in the second part, methotrexate was infused to maintain a serum concentration of 15 micrometer for 30, 36, or 40 hr. Thymidine rescue was started immediately after the end of the methotrexate infusions, and consisted of 8 g/sq m/day for 3 days or until serum methotrexate was below a toxic level. Mucositis and myelosuppression were the major toxicities. Neither was dose related. Serum methotrexate levels were proportional to the logarithm of the methotrexate dose. There was a mean 6-fold increase in thymidine concentration during rescue. However, thymidine levels prior to and during rescue were not related to the incidence of subsequent toxicity. Recovery of DNA synthesis in bone marrow cells was evident by nucleoside precursor incorporation at 24 hr after the start of rescue. Two of 16 evaluable patients achieved partial responses. This study indicates that thymidine is an effective rescue agent for high-dose methotrexate in humans.
20名患者接受了63个疗程的大剂量甲氨蝶呤治疗后进行了胸苷解救。在本研究的第一部分，甲氨蝶呤采用24小时输注给药，剂量从0.14克/平方米逐步递增至8.54克/平方米；在第二部分，输注甲氨蝶呤以维持血清浓度为15微摩尔30、36或40小时。胸苷解救在甲氨蝶呤输注结束后立即开始，包括8克/平方米/天，持续3天或直至血清甲氨蝶呤低于中毒水平。粘膜炎和骨髓抑制是主要毒性反应。两者均与剂量无关。血清甲氨蝶呤水平与甲氨蝶呤剂量的对数成正比。解救期间胸苷浓度平均增加了6倍。然而，解救前和解救期间的胸苷水平与随后的毒性发生率无关。在解救开始24小时后，通过核苷前体掺入可明显看出骨髓细胞中DNA合成的恢复。16名可评估患者中有2名获得部分缓解。本研究表明，胸苷是人类大剂量甲氨蝶呤治疗的有效解救剂。
