The modern era of cancer chemotherapy research, rooted in laboratory observation and experimentation, is barely 30 years old. It had its origin shortly before World War II with the work of C. B. Huggins, University of Chicago, suggesting a rational basis for the antitumor effect of castration or estrogen (female sex hormone) therapy in patients with disseminated cancer of the prostate. In 1966, Dr. Huggins shared the Nobel Prize for Medicine and Physiology in recognition of his initiation of the drug treatment of cancer.
The next milestone was the discovery in the early 1940's of the anticancer effectiveness of a family of compounds known as nitrogen mustards, as a byproduct of the military investigation of chemical warfare agents. Nitrogen mustards are related chemically to mustard gas, a poison war gas known since the late 1800's; the basic molecule of the nitrogen mustards differs from that of mustard gas in containing an atom of nitrogen in place of sulfur. Nitrogen mustards were developed during World War II in a search for more effective vesicant (blister causing) war gases. Extensive laboratory studies showed that mustard gas and the nitrogen mustards also readily penetrate the skin to reach the circulation and destroy cells. This cytotoxic action is reflected first in the formed elements of the blood, particularly the leukocytes (white blood cells), and then in the lining of the gastrointestinal tract. Lymphatic tissue, bone marrow, and the intestinal tract are the sites that are most susceptible to the effects of nitrogen mustards.
Cancer drugs of the nitrogen mustard class are chemical cousins of mustard gas, a deadly war poison. Principal difference is an atom of nitrogen (N) in place of sulfur (S).
In 1942, Drs. A. Gilman, L. S. Goodman, and their colleagues prepared a report, under the mantle of military secrecy, on the effects of the intravenous administration of a nitrogen mustard known by the military code name of HX3 in seven patients with metastatic diseases treated at the New Haven Hospital in Connecticut. Although the drug caused considerable toxicity, a marked regression of enlarged nodes was observed in a patient with lymphosarcoma (solid tumor arising in the lymph system).
During 1943, clinical trials were initiated with HN2 [N-methylbis(2-chloroethyl)amine], which became the most widely used of the nitrogen mustards. By the time military restrictions were removed in 1946, a total of 160 patients had been treated by several groups of investigators, who concluded that the most favorable effects were obtained in patients with Hodgkin's disease, a type of neoplastic disease primarily affecting the lymph glands and other infection-fighting tissues.
A clinical experiment took place inadvertently on December 3,1943, when the Liberty ship, the John E. Harvey, carrying 100 tons of mustard gas was sunk during a bombing in Bari Harbor, Italy. An astute medical officer concluded that victims who had survived the initial shock of the blast and immersion in the water covered with burning oil died of the late results of mustard gas poisoning. The Medical Laboratories of the Chemical Warfare Service analyzed samples of tissue from the victims and confirmed the damage to the lymphatic system and the bone marrow. These observations suggested at once the significance of compounds of this type for the possible treatment of neoplastic disorders of the tissues that form white blood cells.