Some Observations on the Effect of Folic Acid Antagonists on Acute Leukemia and Other Forms of Incurable

By SIDNEY FARBER, M.D. T HE PRODUCTION of temporary remissions in the course of acute leukemia in children by the administration of the compound, 4-aminopteroylglutamic acid ( aminopterin)’ ‘ ‘-a biologic antagonist to folic acid*_has raised a number of theoretic and practical questions. Confirmation of this finding has been reported from several sources3; temporary remissions equally impressive have been obtained in adults with acute leukemia by Dameshek.4 It is the purpose of this paper to summarize briefly the status of our observationst on the action of folic acid antagonists on acute leukemia and other incurable forms of cancer for the interest of those now working with these agents, to state the nature of some of the problems which have arisen, and to indicate some directions of further research. The demonstration by Lewisohn and his colleagues5 of the occurrence of complete regression in about one-third of single spontaneous breast cancers in three different strains of mice treated with fermentation L. casei factor, later shown to be pteroyltriglutamic acid (Hutchings et al. 6) and the subsequent synthesis of this compound by SubbaRow and his co-workers7 led to our study of the effect of pteroyltriglutamic acid on incurable cancer in man. Among the patients so treated were i i children with acute leukemia. The occurrence of what we called an ‘ ‘acceleration phenomenon’ ‘ in the viscera and bone marrow of these patients and an experience with folic acid deficiency experimentally produced in the rat suggested that it would be worth while to ascertain if this acceleration phenomenon might be employed to advantage in the treatment of acute leukemia in children, either by the use of radiation or nitrogen mustard therapy after pretreatment with folic acid or conjugates of folic acid, or by the immediate use of folic acid inhibitors or