On the night of December 2, 1943, German bombers attacked the southern Italian port of Bari. Serving as a vital hub for the Allied troops during World War II, the harbor was crowded with ships loaded with ammunition and supplies. As explosions lit up the sky, seventeen ships sank, including the United States Liberty ship, John Harvey. The ship’s cargo of bombs blew up, spilling oil into the water and dispersing smoke into the air.
Hundreds of sailors covered in oil escaped, but after a few hours, the sailors began exhibiting unusual symptoms. Burns and blisters appeared on their skins, and eye irritation and labored breathing set in. Within a day, their health rapidly deteriorated, and some sailors died. The doctors could not determine the cause of their deaths or recommend a treatment.
The United States Army dispatched Lieutenant Colonel Stewart Francis Alexander, a young medical doctor from New Jersey, to investigate the sailors’ mysterious deaths. “When he arrived at Bari, he appreciated a garlic-like smell of mustard gas, so he immediately suspected,” said Michael Nevins, a retired New Jersey cardiologist and internist who was Alexander’s friend and colleague. “The credit goes to his nose.”
The John Harvey had been carrying a secret load of 2,000 mustard gas bombs. Mustard gas gained its worldwide infamy as a chemical warfare agent during World War I. By the time World War I ended in 1918, mustard gas had intoxicated an estimated 1.2 million soldiers and contributed to 80% of the chemical casualties, making it the deadliest war gas of its time (1). The outbreak of World War II in 1939 intensified nations’ efforts to develop, manufacture, and stockpile chemical weapons. Not long after, mustard gas made its reappearance in Bari.
Alexander’s subsequent investigation marked an unexpected turn in the story of mustard gas. Scientists in various laboratories and medical institutions around the world started to recognize the potential for harnessing mustard gas’ toxic properties and transformed it into a weapon to combat a different enemy: cancer. Their efforts eventually converted this deadly chemical agent into chemotherapy.
From skin to blood
Working with mustard gas had never been safe. In 1860, when Frederick Guthrie from the University of Edinburgh first synthesized mustard gas by reacting ethylene and sulfur dichloride, he experienced irritation on his own skin (2). That same year, Albert Niemann at the University of Göttingen repeated the reaction and suffered skin reddening and blistering (3). Later, Viktor Meyer at the University of Göttingen achieved the first reliable synthesis of pure mustard gas by modifying the formula, resulting in a more toxic product (4). In 1913, Hans Thacher Clarke at the University of Berlin further developed Meyer’s formulation and introduced a more efficient method for synthesizing mustard gas (5). Due to accidental exposure, Clarke was hospitalized, but ultimately, his method was employed for large-scale mustard gas production during warfare.
Dangerous chemicals never intimidated Alexander. “Back in high school, he had a chemistry lab in the basement of the house,” said Nevins. In 1941, two years before the tragic incident in Bari, Alexander had just begun his medical practice in New Jersey when he received a summons from the United States Army. The United States Chemical Warfare Service (CWS), which was established during World War I for producing poison gas and defensive equipment, sought out medical experts across the country to bolster the army’s preparedness for potential chemical gas attacks.
The CWS brought Alexander into the Medical Research Laboratory at the Edgewood Arsenal facility in Maryland to conduct research on chemical warfare agents and develop prevention and treatment methods. At Edgewood, Alexander consulted specialists, evaluated the toxicity of different agents on animals, and learned to identify different toxins, including chlorine, phosgene, and mustard gas by their odors. Soon, he became a chemical weapons expert.
In early 1942, the CWS assigned Alexander to investigate a new chemical agent called nitrogen mustard, a volatile liquid with a chemical structure similar to mustard gas that had little to no odor. Using rabbits, Alexander set up experiments on various organs and systems, including the skin, eyes, respiratory tract, and blood. Like mustard gas, nitrogen mustard caused burns on the skin and different organs. However, the agent’s effects on the blood astonished Alexander.
For a typical burn injury, the immune system usually ramps up white blood cell production to fight off infections. In Alexander’s nitrogen mustard experiments, the opposite happened. Within several days after exposure to nitrogen mustard, the rabbits’ white blood cell numbers drastically dropped until they completely disappeared. The rabbits’ lymph nodes melted away, and their bone marrow became depleted of blood cells (6).
After obtaining the same results from other laboratory animals such as rats and mice, Alexander believed that nitrogen mustard disrupted the body's blood production by attacking white blood cells. He began to wonder if nitrogen mustard would have the same effects on humans. If it did, it might be developed to treat leukemia, a condition marked by uncontrolled growth of white blood cells. Alexander documented his findings and hypothesis in a report published internally within the CWS in June 1942, but his report went unappreciated (6).
A year later, in the aftermath of the Bari attack, Alexander examined the sailors and confirmed his suspicions of mustard gas exposure. As he went through the doctors’ medical case sheets and pathology reports, one recurring observation stood out: the white blood cell counts of severely injured patients took a sharp downward turn on the third or fourth day after the incident. These results agreed with Alexander’s animal studies at Edgewood, supporting Alexander’s interest in turning a poison into a drug to treat leukemia and lymphoma.
In December 1943, after conducting extensive blood and bone marrow tests, Alexander submitted a report on his investigation of the Bari disaster (6). His report was immediately classified by the government to avoid triggering a chemical war. But the United States military medical advisers, including Cornelius Rhoads, chief of the CWS’s Medical Division, carefully appraised Alexander’s work, finally taking note of nitrogen mustard’s therapeutic potential. “Rhoads was very excited about the possibilities of how this could be turned into something useful in peacetime,” said Nevins.
The substance X project
While Alexander served in the CWS investigating chemical weapons at Edgewood, another research program on war gas was secretly occurring 200 miles away. In 1942 at Yale School of Medicine, the school’s Dean, Milton Winternitz, signed a government contract with the Office of Research and Development.
Winternitz had previously studied war gas poisonings during World War I and recognized the urgent need to investigate new chemical warfare agents and develop antidotes. He assigned two young pharmacologists, Alfred Gilman and Louis Goodman, to study the toxicity of the new chemical agent nitrogen mustard, which was coded as substance X.
Gilman and Goodman began their testing by exposing rabbits to substance X. Like Alexander, they observed the rapid disappearance of lymphocytes and granulocytes in the rabbits. “The systemic effects of the nitrogen mustards were far more fascinating than the blisters they produced on the skin,” Gilman recalled in an article published in The American Journal of Surgery in 1963 (7). They wondered if this agent could destroy fast growing cancer cells before it attacked the host.
The pair consulted Thomas Dougherty, an anatomist at Yale School of Medicine, who provided them with a mouse transplanted with advanced lymphosarcoma. When Gilman and Goodman treated this mouse with nitrogen mustard, its tumor softened and shrunk after just two administrations of the chemical. With more doses, the tumor disappeared. Much to everyone’s surprise, the mouse survived a remarkably long time (7).
Gilman and Goodman eagerly wanted to move forward with a human trial and presented their animal experimentation data to Gustaf Lindskog, the chair of surgery at Yale School of Medicine. Intrigued by the encouraging results, Lindskog agreed to supervise the trial. The team soon found a potential candidate, a 47-year-old patient with cancer at Yale New Haven Hospital.
The patient had terminal lymphosarcoma and had undergone all possible treatment options without any success. Since all hope for recovery seemed lost, Lindskog approached the patient, known to history as JD, with a bold experiment that might save his life.
“They had a detailed conversation with him about what they were undertaking, and that this was an experimental option, and that nobody knew what was going to happen,” said Dieter Lindskog, grandson of Gustaf Lindskog and orthopedic surgeon at Yale School of Medicine.
JD decided to take the risk. “They had no idea, clue, or anything resembling guidance on dosing,” said Lindskog. Their best hint was their toxicity studies on rabbits, which suggested a dosage of 0.1 mg per kilogram of nitrogen mustard. A few days later, JD became the first recipient of intravenous chemotherapy for cancer.
“The patient’s tumor had a marvelous response,” said Lindskog. Within 48 hours, the tumor began to soften, and the patient felt better. By the tenth day, when the series of injections ended, his tumor was no longer palpable, and all cancer symptoms had disappeared.
By day 49, the patient’s tumor made a vigorous return and became resistant to nitrogen mustard. Despite receiving two additional courses of treatment, his condition failed to improve. He eventually passed away on day 96 (8). Due to the confidentiality surrounding chemical warfare agents, the medical records of this trial were censored and were later lost to time, leaving many details undisclosed.
Modern chemotherapy
In June 1943, the nitrogen mustard research group at Yale University dispersed, but the clinical trials testing nitrogen mustard’s therapeutic potential continued. Goodman collaborated with researchers in several institutions around the country to treat additional patients.
Gilman, Goodman, and their collaborators released details about their studies in 1946 after World War II had ended and the secrecy associated with the war gas program had been lifted. In this landmark report, they documented 67 nitrogen mustard clinical trials, including JD’s case, for treating Hodgkin’s disease, lymphosarcoma, and various types of leukemia. The report demonstrated significant tumor regression in most patients, with clinical remissions lasting from weeks to months (8).
Rhoads, who previously appreciated Alexander’s Bari report, was further encouraged by Gilman and Goodman’s clinical trials. He started vigorously seeking funding for developing chemotherapy after the war. In 1948, Rhoads became the director of the Memorial Sloan-Kettering Cancer Center, which spearheaded the development of several important chemotherapy drugs, including mustard derivatives and other antitumor compounds.
In 1949, the United States Food and Drug Administration approved mechlorethamine, a nitrogen mustard compound, as the first chemotherapy drug for hematologic malignancies (9). Around that time, scientists started to understand how the agent works in the body. Two chemists, Philip Lawley and Peter Brookes at the Royal Cancer Hospital, unraveled the molecular mechanisms behind the agent's cancer-killing properties.
Mustard gas and nitrogen mustard both belong to a class of chemicals known as alkylating agents. In the cell, these agents undergo a series of reactions to form a highly reactive intermediate, which covalently modifies DNA in a reaction referred to as DNA alkylation. DNA alkylation disrupts cell replication and causes cellular damage, which makes alkylating agents particularly effective at destroying rapidly dividing cells such as white blood cells and cancer cells (10,11).
This information stimulated researchers to synthesize and test more alkylating compounds to fight cancer. Several new chemotherapy drugs emerged during the 1950s, such as chlorambucil and busulfan, alkylating agents that treat leukemia by stopping white blood cells from growing and spreading (9). Over the following decades, scientists introduced more than 100 different chemotherapy drugs into clinical practice to treat numerous cancer types, including leukemia, lymphoma, myeloma, sarcoma, and breast, lung, and ovarian cancers.
Chemotherapy created an entire new specialty, practice, and field of medicine. At this point, there will absolutely be leaps, breakthroughs, and huge paradigm changes.
- Dieter Lindskog, Yale School of Medicine
Chemotherapy has led to remarkable remission rates and prolonged survival for numerous patients. Its success in killing fast-dividing cancer cells laid the foundation for the development of more effective therapeutic approaches, such as targeted therapies and immunotherapies. “Chemotherapy created an entire new specialty, practice, and field of medicine,” said Lindskog. “At this point, there will absolutely be leaps, breakthroughs, and huge paradigm changes.”
Setting the record straight
As researchers continue to make leaps and bounds in chemotherapy development, others are still uncovering hidden details about its early days. Although JD's case was published in Gilman's report in 1946, the details of the case were minimal, and JD’s medical records disappeared.
In 2010, John Fenn, a surgeon and Lindskog’s colleague at Yale School of Medicine, learned about the saga of the first chemotherapy trial Gilman, Goodman, and Lindskog conducted during World War II. Fascinated by it, Fenn teamed up with his colleague, Robert Udelsmam, a former clinical professor of surgery at Yale School of Medicine and current surgeon at the Miami Cancer Institute, to unearth JD’s medical records.
“We contacted a senior colleague in pathology,” Udelsmam recalled. “The pathology department had an independent database for the archive of every patient ever seen at Yale based on their diagnosis, the patient's name, their medical record, and the year.”
Lacking key information such as name, date of birth, and medical record number, Fenn and Udelsmam had only the patient's initials, which matched with numerous pathology reports from the early 1940s. After months of searching, they identified a promising pathology chart of a patient with lymphosarcoma and a medical record number, but that did not lead them to JD’s medical records. Suspecting errors in the record number, they began rearranging the number sequences and inserting additional numbers. After several failed searches, they eventually tracked down JD’s complete medical records. “It was exciting at the time,” said Udelsman. “I remember when John put the chart down on my hands. I had the original chart right in front of me. I couldn't believe we found it!”
If this is really the first form of intravenous chemotherapy with an antineoplastic agent in the world, it’s giant! It should be in every textbook.
- Robert Udelsmam, Miami Cancer Institute
The uncovered records shed new light on JD's personal background and clinical course. As a Polish immigrant, JD moved to the United States at age 18 and lost his family during the war. “He didn't speak English and worked in a ball bearing factory. He had no spouse, no children,” said Udelsman. “It sounded like a very lonely, isolated life.”
The lost files also added context to JD's previous treatments, offering insights into why he might have chosen to participate in the experimental trial. He was diagnosed with lymphosarcoma in 1940 and underwent multiple radiation treatments at Yale New Haven Hospital in 1941. Unfortunately, his tumor became progressively unresponsive, causing respiratory distress, dysphagia, and weight loss. Physicians noted in JD’s medical records that his outlook was “utterly hopeless” (12).
“They were watching his tumor grow on a daily basis,” noted Udelsman. “In difficult situations, doctors are more inclined to use potentially toxic agents and toxic doses of an agent to try to have a therapeutic benefit.”
Although the treatment did not ultimately save JD’s life, Udelsman was not surprised. “It is common in chemotherapy that patients develop clones of lymphocytes that are refractory to treatment. A few cells remain that are surviving, and they become more and more refractory to the drug,” he explained. “Nowadays, we use combination chemotherapeutic treatments for this very reason.”
In 2011, Fenn and Udelsmam published their investigation of JD’s case in the Journal of the American College of Surgeons, finally setting JD’s record straight six decades after the case and bringing light to the complicated history of chemotherapy treatment (12). “If this is really the first form of intravenous chemotherapy with an antineoplastic agent in the world, it’s giant!” said Udelsman. “It should be in every textbook.”
References
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- Guthrie, F. XIII.—On some derivatives from the olefines. Q J Chem Soc 12, 109–126 (1860).
- Niemann, A. Ueber die Einwirkung des braunen Chlorschwefels auf Elaylgas. Justus Liebigs Annalen der Chemie 113, 288–292 (1860).
- Meyer, V. Ueber Thiodiglykolverbindungen. Berichte der deutschen chemischen Gesellschaft 19, 3259–3266 (1886).
- Duchovic, R. J. & Vilensky, J. A. Mustard Gas: Its Pre-World War I History. J Chem Educ 84, 944 (2007).
- The Great Secret | Jennet Conant | W. W. Norton & Company.
- Gilman, A. The initial clinical trial of nitrogen mustard. The American Journal of Surgery 105, 574–578 (1963).
- 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).
- Puyo, S., Montaudon, D. & Pourquier, P. From old alkylating agents to new minor groove binders. Critical Reviews in Oncology/Hematology 89, 43–61 (2014).
- Lawley, P. D. & Brookes, P. Interstrand cross-linking of DNA by difunctional alkylating agents. Journal of Molecular Biology 25, 143–160 (1967).
- Brookes, P. & Lawley, P. D. The reaction of mustard gas with nucleic acids in vitro and in vivo. Biochemical Journal 77, 478–484 (1960).
- 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).
