Methotrexate: historical aspects

In the early 1940s, folic acid was isolated and found to cure some patients with megaloblastic anemia that did not respond to vitamin B12. As acute leukemia in children had some morphological features that resembled megaloblastic anemia, patients with acute leukemia were treated with folic acid or folate conjugates (polyglutamated forms of folic acid). These proved ineffective and, in fact, were thought to accelerate the disease. The subsequent demonstration by Heinle and Welch [] that a diet-induced deficiency of folic acid caused a decrease in the leukemia cell count, stimulated efforts, primarily by the Lederle group, to synthesize analogs of folic acid. One of these, aminopterin or 4-aminopterolylglutamic acid, proved to be a powerful antagonist that was shown by Farber et al. [], in a landmark paper, to produce remissions in children with acute lymphocytic leukemia (ALL). With this discovery, and the demonstration by Huggins and Hodges that estrogens caused regressions in prostate cancer [], and that nitrogen mustard caused regressions in patients with lymphoma [[], the modern era of chemotherapy was born in the 1940’s.