Louis Goodman (1906–2000), Alfred Gilman (1908–1984)
FROM WAR GAS TO CANCER CHEMOTHERAPY. The backstory for cancer chemotherapy began on July 12, 1917, when Allied troops near Ypres in Flanders were bombarded with German mustard gas–charged shells. Early attention focused on the blistering effects on the skin, eyes, and respiratory tract. Two years later, the ability of mustard gas (sulfur mustard) to decrease the number of white blood cells and to break down lymph tissue was recognized.
The story continued during World War II. In 1942, Yale pharmacologists Louis Goodman and Alfred Gilman conducted wartime secret studies with a series of nitrogen mustard derivatives for potential use as war gases. In 1943, Bari, a major Italian seaport for supplying Allied troops, was subject to a German air raid. Seventeen ships, including the Liberty ship USS John Harvey and its secret cargo of nitrogen mustard, were lost along with some 1,000 servicemen. Survivors exposed to nitrogen mustard experienced a dramatic decrease in white blood cells. At the war’s conclusion in 1946, the results of Goodman and Gilman’s studies were published. The nitrogen mustards caused shrinkage of tumors of lymphoid cells, pointing to their potential use for treating lymphoma, Hodgkin’s disease in particular. Cancer treatment options were no longer limited to radiation and surgery.
From these studies came the first cancer chemotherapeutic drugs, which prevent the cancer cell from dividing and growing. The first of these nitrogen mustard alkylating agents was HN2 or nitrogen mustard (Mustargen), given intravenously. Over the next decade, others included chlorambucil (Leukeran), busulfan (Myleran), and cyclophosphamide (Cytoxan)—all orally active drugs that are most effective against slow-growing tumors.
Although effective against many cancers and potentially lifesaving, alkylating agents are far from innocuous. They are also toxic to noncancerous cells that grow rapidly. These effects include depression of bone marrow, in which blood cells are produced (the most serious side effect that limits the dose of drug); hair follicle injury causing hair loss; and severe nausea and vomiting.
Goodman and Gilman’s greatest legacy is their authorship and then editorship of The Pharmacological Basis of Therapeutics, a classic text first published in 1941, and its eleventh edition, in 2006.
SEE ALSO Amethopterin and Methotrexate (1947), Mercaptopurine (1953).
After being exposed to mustard gas during World War I, Allied troops (and their military dogs and horses) stationed on the Western front were issued gas masks. A gas mask covers and protects the mouth, nose, and face and is equipped with a filter canister that absorbs the toxic gas.