10-Ethyl-10-deaza-aminopterin: structural design and biochemical, pharmacologic, and antitumor properties

The new folate analog 10-ethyl-10-deaza-aminopterin (10EdAM) was equivalent to methotrexate (MTX) as an inhibitor of dihydrofolate reductase, but was more effectively transported and polyglutamylated in most tumor cells. Also, the transport and polyglutamylation of 10EdAM in tumor cells vis-a-vis normal proliferative tissue is substantially increased compared to MTX, favoring much greater accumulation of 10EdAM as cytotoxic polyglutamates in some of these tumor cells. 10EdAM was superior to MTX against 4 of 6 murine ascites tumors (L1210, S180, Ehrlich and Tapper) and far superior against 4 of 6 solid murine tumors (S180, Tapper, E0771 mammary AC, T241 fibrosarcoma). 10EdAM produced 10% to 30% complete regressions against S180, E0771 and T241 tumors. Both agents showed similar activity against P288 and 1498c leukemias and the Lewis lung tumor, but were inactive against B16 melanoma. Marked superiority of 10EdAM compared to MTX was also shown against the following human tumor xenografts: MX-1 (mammary carcinoma), LX-1 (small cell lung carcinoma) and CX-1 (colon carcinoma). 10EdAM produced 30% to 40% complete regressions against the MX-1 tumor.