THE USE OF FOLIC ACID ANTAGONISTS IN THE TREATMENT OF ACUTE AND SUBACUTE LEUKEMIA

Abstract

Abstract In summary, the folic acid antagonists have, in varying degrees, the capacity to induce remissions in about one third of the cases of acute and subacute leukemia, in adults as well as in children, and in both leukemic and leukopenic forms. Clinical, hematologic and (to lesser extent) marrow remissions, are obtained most commonly in the lymphoblastic types, least often in the monocytic types. It is possible that folic acid is required by the primitive white cell as a growth factor. The folic acid antagonists, which resemble folic acid so strikingly in chemical structure, may result in cell death by modifying various enzyme systems within the primitive cells. Both clinical and hematologic observations indicate that the proliferative process is by no means cured with aminopterin treatment. Acute leukemia may be likened to "wildfire" which, although damped by aminopterin, continues to "smolder." This smoldering may suddenly light up again into an active leukemic picture, unless continued maintenance therapy is given. Despite maintenance therapy, there finally comes a point in the leukemic process at which both the leukemia and increasing toxicity to drug make further progress impossible, and the patient dies. Other growth factors or enzymes are probably of at least as great an importance as PGA in the metabolism of the primitive white cells and when these are discovered and their antagonists synthesized, the therapeutic results in acute leukemia may be of more consistent and durable nature. It should be realized further that chemotherapeutic methods against leukemia and the leukocytic proliferations in general (and, in fact, against all proliferative disease) are at least in their very infancy. The results thus far obtained in acute leukemia, although to large extent disappointing, indicate that well-defined remissions can be secured in about a third of the cases. For a disease such as acute leukemia, in which remissions previously were highly unusual and of sporadic nature, this indicates a well-defined therapeutic advance and a need for continued investigation along the same general lines. Differences in results obtained by various groups of workers are difficult to explain. Several points may nevertheless be considered: some of the workers have given inadequate dosage of drug or have failed to use maintenance therapy; some have given folic acid in conjunction with anti-folic acid therapy; in some cases, a crude folic acid antagonist was used; and it is possible that some cases were not observed as minutely as seems necessary. An important factor, which can be determined only by the study of a large group of cases, is the natural variability of acute leukemia from case to case. We have the impression that our best results are obtained in the relatively subacute cases. The fulminating cases, with rapid onset of bleeding and a quick downhill course, are only slightly affected.