A group of
folate analogs of the
10-deaza-aminopterin series, which were designed on the basis of the results of an intensive biochemical and pharmacokinetic program, have been examined in
therapy experiments utilizing a group of murine
tumor models. These new analogs were found to be markedly superior to
methotrexate against four of five
ascites tumors (
L1210 leukemia,
Sarcoma 180, Ehrlich
carcinoma and Tapper
carcinosarcoma) and against four of five solid
tumors (S180, Tapper
carcinosarcoma, E0771 mammary
adenocarcinoma,
Lewis lung carcinoma, and T241
sarcoma). Analogs alkylated (methyl or ethyl) at the 10 position of
10-deaza-aminopterin were found to be the most effective of the group. These analogs achieved log10 reduction in
tumor burden several-fold greater in magnitude than
methotrexate against L1210 and S180
ascites tumors and there were also long-term survivors.
10-Deaza-aminopterin itself gave a result intermediate between those obtained with the 10-alkyl derivatives and
methotrexate. Against the solid forms of the Tapper
tumor some partial regressions were obtained with
methotrexate and
10-deaza-aminopterin, but a far greater number, extending over a longer period were obtained with the 10-ethyl derivative of
10-deaza-aminopterin. Against the E0771
tumor,
10-deaza-aminopterin was 2-fold and the ethyl derivative of
10-deaza-aminopterin was greater than 5-fold more effective than
methotrexate in retarding
tumor growth. Evidence for partial regressions and marked effects against metastatic disease were also obtained in the case of the 10-alkyl derivative. Similar results were also obtained with the T241
sarcoma. For
Lewis lung carcinoma the relative potency was about the same but overall antitumor effects were more modest.