A general discussion is presented of the present status of folic acid antagonist therapy in acute leukemia in children and in other forms of incurable cancer. Conclusions reached in our initial report have been supported by a far greater experience. Temporary remissions in acute leukemia as marked as those caused by aminopterin have been produced by the use of two compounds closely related chemically to aminopterin—amethopterin and amino-an-fol, both of which, however, are also toxic compounds. Despite the increasing number of patients in whom temporary remissions have been produced, with survival in some far beyond the usual course of the disease, no evidence has been presented which would justify the use of the word "cure" of acute leukemia. A carcinolytic action on related and on certain unrelated forms of incurable cancer has been observed. Further research for less toxic related compounds with even greater effectiveness is not only justified by these studies but is imperative. The value of this direction of research in cancer has been established.
Two of the most pressing problems demanding solution are concerned with the nature, the prevention, and the treatment of toxic changes, including hemorrhage, produced by these folic acid antagonists and the causes, prevention and mechanism of hemorrhage in acute leukemia. The use of the folic acid antagonists in the treatment of incurable cancer including leukemia must remain in the realm of research until answers to these questions are found.