NEW FOLATE ANALOGS OF THE 10-DEAZA-AMINOPTERIN SERIES - FURTHER EVIDENCE FOR MARKEDLY INCREASED ANTITUMOR EFFICACY COMPARED WITH METHOTREXATE IN ASCITIC AND SOLID MURINE TUMOR-MODELS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (1) , 26-30
Abstract
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, were examined in therapy experiments utilizing a group of murine tumor models. These new analogs were found to be markedly superior to methotrexate against 4 of 5 ascites tumors (L1210 leukemia, sarcoma 180, Ehrlich carcinoma and Tapper carcinosarcoma) and against 4 of 5 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 the most effective of the group. These analogs achieved log10 reduction in tumor burden several-fold greater 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-aminopeterin was < 5-fold more effective than methotrexate in retarding tumor growth. Evidence for partial regressions and marked effects against metastic 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.