Markedly improved efficacy of edatrexate compared to methotrexate in a high-dose regimen with leucovorin rescue against metastatic murine solid tumors.
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.
Sirotnak
F M
FM
Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Otter
G M
GM
Schmid
F A
FA
D000230:Adenocarcinoma / Q000188:drug therapy*; D000630:Aminopterin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy; D002955:Leucovorin / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D016879:Salvage Therapy
C040210:edatrexate; D000630:Aminopterin; D002955:Leucovorin; D008727:Methotrexate