Antagonists in Man*

The folate antagonists, in particular amethoptenin (methotrexate), continue to be useful drugs for the treatment of certain neoplastic diseases in man. The effectiveness of amethoptenin in preventing DNA synthesis and cellular replication appears to be a consequence of inhibition of the enzyme dihydrofolate reductase. This premise is sup ported by in vivo studies which show that in patients treated with amethoptenin, the conversion of folate to reduced forms is blocked, as well as in vitro studies which dem onstrate that amethoptenin inhibits this enzyme activity at remarkably low concentna tions. The administration of amethopterin to subjects with leukemia as well as to subjects without hematologic disease results in increased dihydrofolate reductase activity in leukocytes and erythrocytes. This “induction―of dihydrofolate reductase activity parallels the amethoptenin concentration in blood cells. The binding of the folate antagonist to the reductase enzyme is tightest at pH 5.9. Because of the in vitro