Sirotnak F M, Otter G M, Schmid F A
Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Cancer Res. 1993 Feb 1;53(3):587-91.
10-Ethyl-10-deazaaminopterin (EDX, edatrexate) exhibits therapeutic activity against methotrexate (MTX)-resistant tumors in animals and patients. In an effort to improve its efficacy among more chemoresistant tumors, studies were initiated in murine models of advanced metastatic disease comparing EDX and MTX at their maximum tolerated dose alone and in a high-dose regimen incorporating low-dose, delayed Ca leucovorin (LCV) rescue. Both twice-weekly x 3 and weekly x 3 schedules of administration were used with LCV given 16, 20, and 24 h after EDX. The LCV dose required to protect mice was 1/40 and 1/20 of the EDX or MTX dose, respectively, on either schedule. Therapy was initiated 5 or 6 days following i.v. implant of 5 x 10(5) cells of the E0771 mammary adenocarcinoma, T241 fibrosarcoma, Lewis lung carcinoma, B16 melanoma, or C38 colon carcinoma. MTX was essentially ineffective (increase in life span = < 30%) when given alone and either ineffective or only modestly effective (increase in life span = 20-80%) in increasing survival when given in the high-dose regimen to tumor-bearing mice. EDX alone was more effective than MTX when it was given in either regimen of therapy. Also, EDX given in the high-dose regimen (either twice-weekly or weekly x 3) was markedly more effective than EDX alone. Increased survival with this regimen was 2-3-fold greater than EDX alone against all 5 tumors, and long-term survivors were obtained with E0771 (20%), T241 (30-40%), Lewis lung (10-15%), B16 (20%), and C38 (40%) tumors. The administration of 6 doses rather than 3 doses on the twice-weekly schedule against T241 and Lewis lung tumors required a modest increase in the LCV dose but substantially improved efficacy, with as much as 70% long-term survivors (T241 tumor). We conclude that the use of a high-dose regimen with delayed LCV rescue markedly improved the therapeutic effectiveness of EDX against advanced metastatic disease in tumor-bearing mice. These studies should provide a framework for further clinical work with EDX, using this modality of therapy.
10-乙基-10-脱氮氨基蝶呤（EDX，依达曲沙）对动物和患者体内耐甲氨蝶呤（MTX）的肿瘤具有治疗活性。为提高其在更多耐药肿瘤中的疗效，在晚期转移性疾病的小鼠模型中开展了研究，比较EDX和MTX单独使用时的最大耐受剂量，以及在一种包含低剂量、延迟给予的钙亚叶酸（LCV）解救的高剂量方案中的疗效。两种给药方案均采用每周两次，共3次，以及每周1次，共3次的给药计划，LCV在EDX给药后16、20和24小时给予。在任一给药计划中，保护小鼠所需的LCV剂量分别为EDX或MTX剂量的1/40和1/20。在静脉注射植入5×10⁵个E0771乳腺腺癌、T241纤维肉瘤、Lewis肺癌、B16黑色素瘤或C38结肠癌细胞5或6天后开始治疗。单独给予MTX基本无效（寿命延长＜30%），在高剂量方案中给予荷瘤小鼠时，要么无效，要么仅适度有效（寿命延长20 - 80%）。在两种治疗方案中，单独给予EDX均比MTX更有效。此外，在高剂量方案（每周两次或每周1次，共3次）中给予EDX明显比单独给予EDX更有效。该方案使所有5种肿瘤的生存期延长比单独使用EDX时增加了2至3倍，并且在E0771（20%）、T241（30 - 40%）、Lewis肺癌（10 - 15%）、B16（20%）和C38（40%）肿瘤中获得了长期存活者。在针对T241和Lewis肺癌肿瘤的每周两次给药计划中给予6剂而非3剂，需要适度增加LCV剂量，但疗效显著提高，T241肿瘤的长期存活者高达70%。我们得出结论，使用高剂量方案并延迟给予LCV解救可显著提高EDX对荷瘤小鼠晚期转移性疾病的治疗效果。这些研究应为使用这种治疗方式的EDX进一步临床工作提供框架。
