1947

Antifolates

Sidney Farber (1903–1973), Yellapragada Subba Rao (1895–1948)

Pediatric pathologist Sidney Farber had seen how folate supplements (a form of vitamin B) could restore normal blood production in some types of anemia, and in 1947 he decided to see if that was true for leukemia, too. Unfortunately, giving folic acid to leukemia sufferers actually made the disease accelerate, so Farber wisely jettisoned that hypothesis in favor of the opposite one: if extra folic acid made leukemia worse, perhaps blocking the folate pathway could help slow it down. Indeed, a diet specifically chosen to be deficient in folic acid did seem to help.

Indian biochemist Yellapragada Subba Rao was also working on the medicinal chemistry of folate analogs at Lederle Laboratories in New York, trying to develop a better folic acid supplement for anemia patients. Some of the compounds he produced were close enough to the natural substance to be enzyme inhibitors in the biochemical pathway, and he provided one of these, aminopterin, to Farber to test for his “antifolate” idea. This compound showed dramatic effects in children with leukemia. Ten out of the sixteen patients given the treatment showed temporary remissions, an unprecedented response. In fact, it was so unheard-of that Farber’s results were initially simply not believed. But other folate analogs showed efficacy, too, and other clinics were able to reproduce the study.

The most widely active and well-tolerated antifolate, methotrexate, also a product of Farber and Subba Rao’s collaboration, went on to be tried against numerous forms of cancer (successfully against some), and along with several other antifolates, it is still in the therapeutic arsenal. It’s a strong inhibitor of the enzyme dihydrofolate reductase, which is part of a pathway whose end products are the purine and pyrimidines that form the “rungs” in the ladder-like structure of DNA. Rapidly dividing cells—in this case, cancer cells—have to produce more DNA, since each new daughter cell gets a full copy, so starving a cancer cell of the materials it needs to produce all that DNA can be fatal to it. Chemotherapy would attack such targets for the rest of the century and beyond.

Fluorescent-tagged animal cells in a disease model of leukemia. The cell on the right is dividing, an all-too-common sight in cancer-cell cultures.