Cancer chemotherapy had a dark origin — it was born out of mustard gas, a deadly chemical weapon used during wartime. However, it took an unexpected turn when scientists discovered its potential for killing cancer cells, leading to a new dawn in cancer treatment.
View this interactive milestone article from Drug Discovery News to explore the stories behind chemotherapy's development from a noxious war gas to effective cancer therapy.
By Yuning Wang, PhD
During World War I, when mustard gas caused devastating effects on the human body, scientists noticed its unexpected potential for treating cancer and began making a series of breakthrough discoveries. These efforts transformed mustard gas from a deadly poison to an effective cancer drug, ushering in a new cancer treatment era.
1917 King of Battle gases
In July 1917, during World War I, the British infantry based in Ypres, Belgium, reported explosions of German gas shells that released mustard-colored gas with a garlic-like odor into the air. After several hours, the soldiers experienced irritation and pain in their eyes, throats, and lungs. Later, severe burns and blisters appeared on their exposed skin. They had been poisoned with mustard gas.
Mustard gas is a liquid that evaporates readily into poisonous gas. It penetrates the skin and induces pus-filled blisters. Mustard gas in high concentrations can attack corneas and cause serious damage to the respiratory system, often resulting in prolonged illness and even death after days or weeks.
British scientist Frederick Guthrie from the University of Edinburgh chemically synthesized mustard gas in 1860 from ethylene and sulfur dichloride and noticed its irritating effects on his own skin (1). In 1886, Viktor Meyer, a German scientist at the University of Göttingen established a method for synthesizing mustard gas in high yield, recognized as Meyer’s method (2). In 1913, English biochemist Hans Thacher Clarke at the University of Berlin improved Meyer’s formulation and developed the Meyer-Clarke method, leading to the largescale production of mustard gas (3).
Relying on the Meyer-Clarke method, the German army unleashed this lethal chemical weapon in World War I. Following its first use in the Ypres attack, mustard gas continued to create terror across the battlefield, eventually causing more casualties than all other chemical agents combined.
1919 Vanished blood cells
When the United States entered World War I, pathologist Edward Bell Krumbhaar served in the American expeditionary forces in France along with his wife, Helen Dixon Krumbhaar. The couple examined mustard gas victims from the 1917 Ypres battle and observed strange phenomena in the soldiers’ blood.
Instead of seeing continued surges of white blood cells associated with inflammation typically seen following gas poisonings, the Krumbhaars noticed rapid declines and even disappearances of circulating leukocytes, which led to death in some cases (3). The Krumbhaars conducted 55 autopsies of mustard gas victims and observed significant bone marrow damage and depletion of white blood and hematopoietic cells. Edward Krumbhaar reasoned that mustard gas was toxic to the bone marrow and inhibited blood regeneration, leaving patients vulnerable to secondary infections (5).
How mustard gas destroyed blood cells was unclear. Forty years later, two British chemists, Philip Lawley and Peter Brookes at the Royal Cancer Hospital elucidated the underlying mechanism: mustard gas alkylates DNA, which disrupts cell replication and causes cellular damage (6). In a 2021 review article, Bert W. O’Malley, a molecular and cellular biologist at Baylor College of Medicine, illustrated the DNA alkylating properties of mustard gas (3). “If a poison stops cells from dividing, then the cells that divide the fastest will be inhibited the most,” O’Malley explained.
The Krumbhaars noted the striking effects of mustard gas exposure in two publications in 1919 (4,5). After the war ended, Edward Krumbhaar returned to America to work at the Philadelphia General Hospital and later became a pathologist at the University of Pennsylvania. His observation of mustard gas poisoning did not receive much attention until a decade later.
1931 Signs of hope
During the interwar years, several scientists caught a glimpse into the potential benefits of the war gas. James Ewing, a pathologist from Cornell Medical College who had a long-standing interest in cancer, worked at the United States Army Medical Museum during World War I and witnessed the tragedy of mustard gas attacks. Intrigued by the peculiar nature of mustard gas burns, he wondered if the agent could help treat neoplastic growth.
Ewing’s views prompted Frank Adair and Halsey Bagg, researchers from the Memorial Hospital, to test the effects of mustard gas on cancer. In 1931, based on their observation that mustard gas burns were unlike heat or acid burns, Adair and Bagg performed studies on skin cancer in mice using diluted mustard gas solutions. The tumors disappeared after a few weeks (7).
Encouraged by the results, Adair and Bagg applied the agent to thirteen people with various skin cancers. With repeated surface application, the mustard gas solution reduced or completely destroyed the lesions on patients’ skins. Months after the treatment, most patients remained healthy (7).
In their paper in 1931, Adair and Bagg expressed optimism about the utility of mustard gas for fighting cancer but also cautioned about its extreme toxicity. “Since a cancer cell divides more and faster, it’s more sensitive than normal tissues. Clinicians hope to use poisons to cause cancer regression,” said O’Malley. “But if they go too far, they can kill the patient.” There were no follow-up studies for another decade.
1942 The first chemotherapy patient
The outbreak of World War II sparked fears of repeat mustard gas attacks, leading the United States Office of Scientific Research and Development to commission experts at Yale School of Medicine to develop antidotes to potential chemical warfare agents. Two Yale pharmacologists, Alfred Gilman and Louis Goodman, took on the study of nitrogen mustard, a mustard gas-related blister agent referred to as “substance X” in a top secret research program.
Gilman and Goodman first tested the toxicity of nitrogen mustard on rabbits and observed the rapid disappearance of circulating lymphocytes and granulocytes. Their findings led them to wonder if the agent could effectively treat patients with lymphoid tumors. They approached Gustaf Lindskog, a surgeon at Yale School of Medicine. Soon, the trio found a lymphoma patient known only in recorded files as “JD.”
For decades, JD’s files were lost until Robert Udelsman, a surgeon now at the Miami Cancer Institute and his colleague, John Fenn, a surgeon at Yale School of Medicine unearthed the medical records of the first patient treated intravenously with nitrogen mustard. In the recovered files (8), physicians noted that JD’s “outlook is utterly hopeless on the present regime.”
On August 27, 1942, JD received the first dose of intravenous chemotherapy at New Haven Hospital, followed by a second injection two days later. By the end of September, his tumors disappeared, and he had no detectable cancer cells in his lymph nodes. “They actually showed the lymphocyte and tumors shrinking,” said Udelsman. “It proved that, yes, chemotherapeutic agents can work in humans.”
Unfortunately, JD’s tumors returned and become resistant to nitrogen mustard. He eventually died in December. “It’s an interesting and sad story in many ways, but still, the birth of chemotherapy,” said Udelsman. This study by Gilman and Goodman was published in 1946 after the United States military lifted the secrecy associated with the war gas program (9).
1949 The first FDA approved drug
The remarkable cancer regression in JD encouraged Gilman and Goodman to treat additional patients. In collaboration with several other institutions around the country, they pursued other clinical studies.
In 1946, Gilman, Goodman, and their colleagues published the reports of their clinical investigations. They conducted clinical trials on 67 patients with Hodgkin’s disease, lymphosarcoma, and various types of leukemia using two forms of nitrogen mustard, bis(2-chloroethyl)methylamine and tris(betachloroethyl)amine hydrochloride. Most patients’ conditions improved, with clinical remissions lasting from weeks to months (9).
Eventually, Gilman and Goodman left Yale (10). Gilman entered the United States Army and Goodman moved to Salt Lake City, Utah and founded a department of pharmacology at the University of Utah College of Medicine. Their work inspired other research groups to conduct clinical investigations of nitrogen mustard.
In March 1949, bis(2-chloroethyl)methylamine, later named mechlorethamine or chlormethine, became the first chemical agent to receive United States Food and Drug Administration (FDA) approval for the treatment of hematologic malignancies (11).
However, the toxic effects of nitrogen mustard, which often caused systematic toxicity to the patients, were still demoralizing (12). “In patients with terminal cancers, it is always a balance between the toxicity and efficacy of any given drug,” said Udelsman. Finding better and safer agents and treatment methods became the next mission for researchers.
1950s Changing chemotherapy
Upon the development of nitrogen mustard in the 1940s, researchers continued searching for more therapeutic alkylating agents by testing thousands of molecules. “There are many different pathways needed to inhibit or kill a cell. So, people just shotgun for drugs that would do one or the other,” said O’Malley. “There’s nothing magic about it.”
During the 1950s, several new chemotherapy drugs emerged, including chlorambucil, a nitrogen mustard analog that treats chronic lymphocytic leukemia and lymphoma, and busulfan, an alkylating agent that fights leukemia (3,13). The success of nitrogen mustard also stimulated research on other potential antitumor compounds, such as folic acid, which gave rise to methotrexate, the first effective drug for solid tumors (14).
In the 1960s, researchers began to address the issue of drug resistance in cancer chemotherapy by introducing combination chemotherapy using drugs that work via different mechanisms. Patients achieved longer remission from cancer with dramatically increased survival rates.
Today, there are more than 100 different chemotherapy drugs, making chemotherapy a mainstay of cancer treatment. Meanwhile, novel cancer treatment approaches such as targeted therapies are rapidly evolving. “It’s useful for people to look at the history of things to see the mistakes made and how something develops to provide new pathways for the future,” said O’Malley. “It’s a constant battle.”
References
1. Guthrie, F. XIII.—On some derivatives from the olefines. Q. J. Chem. Soc. 12, 109–126 (1860).
2. Meyer, V. Ueber Thiodiglykolverbindungen. Berichte der deutschen chemischen Gesellschaft 19, 3259–3266 (1886).
3. Gilad, Y., Gellerman, G., Lonard, D. M. & O’Malley, B. W. Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations. Cancers 13, 669 (2021).
4. KRUMBHAAR, E. B. RÔLE OF THE BLOOD AND THE BONE MARROW IN CERTAIN FORMS OF GAS POISONING: I. PERIPHERAL BLOOD CHANGES AND THEIR SIGNIFICANCE. Journal of the American Medical Association 72, 39–41 (1919).
5. Krumbhaar, E. B. & Krumbhaar, H. D. The Blood and Bone Marrow in Yelloe Cross Gas (Mustard Gas) Poisoning. J Med Res 40, 497-508.3 (1919).
6. Brookes, P. & Lawley, P. D. The reaction of mustard gas with nucleic acids in vitro and in vivo. Biochemical Journal 77, 478–484 (1960).
7. Adair, F. E. & Bagg, H. J. EXPERIMENTAL AND CLINICAL STUDIES ON THE TREATMENT OF CANCER BY DICHLORETHYLSULPHIDE (MUSTARD GAS. Ann Surg 93, 190–199 (1931).
8. Fenn, J. E. & Udelsman, R. First Use of Intravenous Chemotherapy Cancer Treatment: Rectifying the Record. Journal of the American College of Surgeons 212, 413 (2011).
9. Goodman, L. S. & Wintrobe, M. M. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc 132, 126–132 (1946).
10. Gilman, A. The initial clinical trial of nitrogen mustard. The American Journal of Surgery 105, 574–578 (1963).
11. Puyo, S., Montaudon, D. & Pourquier, P. From old alkylating agents to new minor groove binders. Critical Reviews in Oncology/Hematology 89, 43–61 (2014).
12. Gilman, A. & Philips, F. S. The Biological Actions and Therapeutic Applications of the B-Chloroethyl Amines and Sulfides. Science (1946). doi:10.1126/ science.103.2675.409
13. DeVita, V. T., Jr. & Chu, E. A History of Cancer Chemotherapy. Cancer Research 68, 8643–8653 (2008).
14. Wright, J. C., Prigot, A., Wright, B. P., Weintraub, S. & Wright, L. T. An Evaluation of Folic Acid Antagonists in Adults with Neoplastic Diseases. J Natl Med Assoc 43, 211–240 (1951).