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Published On January 14, 2016

CLINICAL RESEARCH

The Grim and Marvelous Story of Chemotherapy

Research on chemical treatments for cancer began in the ashes of a world war.

War, for all its horrors, has often served as a crucible for medical discovery. Emergency medicine, anesthesia and plastic surgery all owe debts to the suffering of soldiers. But one of modern medicine’s greatest medical gifts didn’t come from a doctor’s ingenious idea on the battlefield. It came from one of the cruelest weapons ever invented. 

Part of the story starts on Dec. 2, 1943, when a squadron of German bombers attacked the Italian port of Bari. The harbor was a major supply point for the Allied invasion of Italy, and the Axis bombers laid waste to the city and 16 of the ships docked in its port. As hundreds of victims poured into hospitals and treatment centers, doctors noticed that many of them showed strange symptoms—blindness, chemical burns and large blisters. Rescuers and townspeople reported similar injuries.

A message was sent to Allied headquarters, which dispatched Lieutenant Colonel Stewart F. Alexander, a chemical warfare expert, to figure out what was going on. By plotting the locations of the casualties, Alexander eventually determined what seemed to be the epicenter of the mysterious ailments: a U.S. cargo ship, the John Harvey, which had exploded. Its entire crew was killed. Alexander’s final clue to the source of the strange symptoms was a garlicky smell that some victims remembered. The John Harvey had been carrying secret and illegal cargo: 100 tons of mustard gas bombs.

A clear liquid at room temperature, mustard gas easily vaporizes, stays on the landscape for weeks, and absorbs quickly into the skin. When it does make contact, it can cause painful blisters, burning eyes and, in about 1% of cases, death. Because of the casualties it caused in World War I, mustard gas, along with other chemical weapons, was banned by international treaty in 1925, and the parties in World War II had pledged never to use those weapons. 

After the discovery that its own illegal cargo was to blame, the United States said nothing about the mustard gas bombs—not even to medical personnel treating the wounded. But during Alexander’s investigation, he took careful notes about a medically fascinating side effect of sulfur mustard. Victims of the chemical explosion had shrunken lymph nodes and astonishingly low white blood cell counts. Some had as few as 100 cells per cubic millimeter, compared with a normal range of 4,300 to 10,800.  Alexander was prohibited from making his findings public.

But back in the United States, other scientists were on a similar research track. In the aftermath of the attack on Pearl Harbor, the government had jumped back into studying chemical warfare agents and their antidotes. The Office of Scientific Research and Development commissioned a study at Yale on the chemistry of nitrogen mustard, a recently developed variation of mustard gas. Two pharmacologists, Louis Goodman and Alfred Gilman, began to look into earlier clues that this substance attacked lymphocytes, a kind of white blood cell that lives primarily in the lymph nodes.

They tested the substance—because of wartime secrecy, they called it “substance X” in their notes—on a mouse with lymphoma, or cancer of the lymph nodes. After two treatments the tumor began to soften and shrink. Eventually the tumor grew back, but the mouse lived an impressive 84 days from the time the tumor appeared.

Goodman and Gilman then found a human subject, a 47-year-old patient with a lymphatic tumor in his neck. The tumor had resisted radiation treatment and was judged fatal. In August 1942, the doctors administered the first of 10 injections of the “synthetic lymphocidal chemical.” Within four days the patient reported feeling better, and over the following months his tumors shrank significantly.

The pharmacologists could not reveal their results until after the war. But when it was over, Goodman and Gilman’s research and details from the attack in Bari combined to draw widespread interest to chemotherapy for cancer. In further trials, nitrogen mustard worked on several human malignancies, including acute childhood leukemia, which at the time was almost 100% lethal. Varieties of that toxic substance, including chlorambucil and melphalan, are still widely used today.