Disconfirming Evidence, The Process

The mechanism of action of Methotrexate in Rheumatoid Arthritis is currently unknown. Methotrexate Drug Packaging Insert (2010)

So reads the insert or paperwork that accompanies every prescription of Methotrexate. Methotrexate is an anti-metabolite of folic acid: it blocks the activity of folic acid, a metabolite used for cell division (i.e., it's important for rapidly dividing cancer cells, such as those seen in leukemia).

In 1937 Richard Lewisohn, a surgeon at Mount Sinai Hospital in NYC observed that primary tumors were rarely seen in the spleen and guessed that injections of spleen extract might reduce tumors. Following this hunch he eventually achieved a regression of tumors in 30% of mice. This was the first successful anticancer results for a non-toxic substance. A series of investigations led Lewisohn and others to believe that the active ingredient of the extract was folic acid.

In 1947 Sidney Farber, a pathologist from the Harvard Medical School initiated human trials in leukemia patients with mimics of folic acid (conjugates). His results showed that these folic acid conjugates unexpectedly accelerated the disease. If folic acid accelerated the disease, Dr. Farber reasoned that blockers of folic acid might reduce the disease. Pteroylaspartic acid was a known blocker of folic acid that had been used in rats and mice to elicit folic acid deficiency, which leads to anemia and reduced white blood cell counts. Farber administered this to a four-year-old girl dying of acute leukemia. Although the girl did not survive, she showed a dramatic reduction in leukemic cells. Further investigations with other folic acid blockers (antifoliates) led to the first sustained remissions ever obtained in leukemia patients. Methotrexate later became the standard antifoliate treatment – it was shown to be effective in a variety of cancers and tumors.

In 1962 following development of other antileukemia drugs, notably cortisone, Donald Pinkel a former associate of Sidney Farber, at St. Jude’s Children’s Research Hospital in Memphis, Tennessee, developed an aggressive program aimed at an outright cure of leukemia in children. He administered several cytoxic drugs, a drug cocktail approach, to fight drug resistance in the cancer cells. He also recognized the persistence of small numbers of leukemic cells present in the brain after remission because of the poor penetration of the cytotoxic drugs into the central nervous system. He eliminated these few remaining cancer cells by irradiating the craniums of children when they first entered remission. By the early 1970s more than half his patients were still alive after five years. Today, 70 and 80 percent of children with the commonest type of acute leukemia are cured. Prior to the introduction of the antifoliate drugs no child ever survived beyond three months after diagnosis.

When you get prescribed the antifoliate Methotrexate for Rheumatoid Arthritis you are often also prescribed folic acid supplements – ostensibly to avoid the risk of anemia and infection from reduced white blood cell counts. After all it's the anti-folic acid action of Methotrexate that provides relief for Rheumatoid Arthritis – or is it?

This article was extracted and reworded from History of Drug Discovery.