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From the field of battle, an early strike at cancer

Yale Medicine Magazine, 2005 - Summer

At the start of World War II, the U.S. government asked Yale to study chemical warfare agents. Building on research that had languished for years, two young scientists found in a derivative of mustard gas the first effective chemotherapy for cancer.

Early in 1942 two young assistant professors in Yale’s new Department of Pharmacology, Louis S. Goodman, M.D., and Alfred Gilman, Ph.D., took on the study of nitrogen mustard. This agent was derived from a lethal gas used in the trenches of World War I, and the United States, which had just entered World War II, feared it might again be used in battle. By year’s end, the two young scientists had found in an agent of death a medicine with lifesaving possibilities. Their use of nitrogen mustard with a human patient ushered in a new era of cancer treatment. “This was the first patient in the world treated by chemotherapy,” said David S. Fischer, M.D., clinical professor of medicine, who gave a talk on the history of chemotherapy for the Beaumont Medical Club in March.

Scientists had been seeking a “magic bullet” for cancer since ancient times—the Romans practiced mastectomy, and Egyptians used topical preparations derived from medicinal herbs. By the 11th century the Arab physician Ibn Sina, known in the West as Avicenna, was using arsenical therapy systemically. The use of arsenicals in an effort to treat cancer continued for centuries, but without effect, said Fischer. “Until about 1900, the only real therapy for cancer was to cut it out,” he said. “Cancer, by definition, was a surgical disease.” Following Wilhelm Conrad Roentgen’s discovery of the X-ray in 1895, medicine added radiation, which could shrink tumors, to its arsenal of cancer therapies.

After World War I, however, medical researchers noticed an interesting effect of mustard gas—it destroyed lymphatic tissue and bone marrow. Perhaps, they reasoned, it could also kill cancer cells in the lymph nodes. But, Fischer said, this idea went nowhere. “They saw the relationship, but they didn’t do anything about it.”

Some experiments in this area continued and revealed that topical applications of nitrogen mustard, derived from the sulfa mustard used in battle, caused tumors in mice to regress. But that line of research also languished for a decade, until 1942, when the government’s Office of Scientific Research and Development contracted with institutions around the country, including Yale, to study chemical warfare agents. Goodman and Gilman, who had recently published the first edition of what would become a classic text, The Pharmacological Basis of Therapeutics, began to study the effects of nitrogen mustard on lymphoma.

“They did their studies mainly in mice,” Fischer said. “They found absolutely dramatic regression of the lymphoma.” Further studies in rabbits were equally encouraging. Goodman, Gilman and their team decided it was time for a clinical trial. Gustaf E. Lindskog, M.D., an assistant professor of surgery, recommended a patient, J.D., a 48-year-old silversmith in the terminal stages of lymphosarcoma. Radiation no longer had any effect on his tumors.

“As his condition seemed hopeless, he was offered experimental therapy with nitrogen mustard,” Fischer said. “In December of 1942, this 48-year-old patient was given 10 consecutive doses of nitrogen mustard, a 10th of a milligram to a milligram per kilogram of body weight, roughly 2.5 times what became the standard dose. Nobody had any idea of what dose to give him.” (The scientists had decided that there was a safe distance between a lethal dose and a therapeutic dose of nitrogen mustard.)

Within two days they noted a softening of the tumor masses. By the end of treatment the tumors disappeared. A month later, however, the patient relapsed, and subsequent courses of treatment were less effective. Nevertheless the scientists were encouraged. “This was proof,” said Fischer, “that cancer could be treated by chemicals.”

Further trials followed. Around the country, 67 patients, including seven at Yale, were treated with nitrogen mustard. The clinical trials remained a military secret, even from caregivers, until 1946—the first Yale patients’ charts said only, “0.1 mg. per kg. compound X given intravenously.”

By 1943 the team responsible for the first successful clinical trial of chemotherapy had disbanded. Goodman continued his research in Salt Lake City. Gilman entered the Army. Lindskog went on to become chair of surgery at Yale. But they had made a major contribution to cancer therapy by proving the worth of nitrogen mustard. Scientists began to look at other alkylating agents—which can attack cells at any point in their life cycle. And nitrogen mustard, which was incorporated into multidrug chemotherapy for Hodgkin’s disease, remains a potent agent against cancer today.