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From Warfare to Mainstay: Mustard Derivatives Play Evolving Role in Cancer Therapy

Andrew D. Smith
Published: Monday, Jan 09, 2012
Photos depicting beginnings of Mustard Derivatives

An American soldier demonstrates gas masks for man and horse, circa 1918. Chemotherapy pioneer Jonathan L. Hartwell, PhD, right, at the National Cancer Institute about 1950. Photos courtesy of the National Archives, Bureau of Medicine and Surgery, and the National Cancer Institute

Mustard gas first rained down on sleeping British soldiers in July 1917. They awoke to the name-inspiring smell and the horrifying sensation that they were burning alive.

Several hundred men endured minutes of unspeakable pain before suffocating. They were the lucky ones. Many survivors endured hours of agony and forever lost their eyesight, along with much of their skin and most of their lung function.

By the 1918 armistice, mustard gas had killed or maimed tens of thousands and proved itself so effective a chemical weapon that Saddam Hussein chose it 7 decades later to slaughter Kurds.

So how was this ingredient in deadly chemical warfare transformed into the first chemotherapy agent in cancer treatment? As the oncology community takes note of the 40th anniversary of the “War on Cancer,” the leap from mustard gas to nitrogen mustard marks an intriguing touchstone in the battle against the disease and a case study of an oncologic agent that is still evolving.

An Accidental Discovery

The discovery of nitrogen mustard’s potential in cancer therapy could easily have taken place in 1919. Edward Bell Krumbhaar, MD, PhD, who would go on to become a leading pathologist and cardiac physician in Philadelphia, Pennsylvania, was a medical officer with the American forces in France when he studied the effects of mustard gas on soldiers and noted its tendency to kill bone marrow and suppress white blood cell production.1

The breakthrough realization about the potential for using nitrogen mustard in cancer treatment, however, did not come until World War II, when the US government asked researchers at Yale School of Medicine in New Haven, Connecticut, to study potential antidotes to mustard gas as a weapon. They realized the agent’s promise as a treatment for lymphoid malignancies and began developing a mouse model for testing.2

The chemical first proved itself by sending scores of mice into miraculous, though temporary, remissions. Then in 1942, a 10-dose treatment of nitrogen mustard did the same for a 48-year-old man with lymphosarcoma.

The full story of that patient’s experience was not revealed until last year when 2 Yale School of Medicine physicians dug out his case history from a storage facility.2 They learned that “JD,” a Polish immigrant who worked in a ball bearing factory, agreed to try the experimental treatment after radiation and surgery had failed to beat back the cancer. His treatment with a compound identified only as “a lymphocidal” or “substance X” because of wartime secrecy, spanned 96 days before his death.

Tests in other servicemen progressed equally well. The remissions were all temporary, but they were the first ever created by chemicals. It was a massive breakthrough, first published after wartime secrecy laws expired in 1946.3

In the years that followed, researchers and physicians bombarded nearly every tumor type with nitrogen mustard derivatives. Mustard compounds found a place in many of the chemotherapy cocktails that became the standard of care for most types of metastasized cancers.

Andrew Pearson, MD

Andrew Pearson, MD

Derivatives Studied in New Regimens

The compound’s potent lethality has ensured its descendents a place in oncology treatment regimens today, even amid advances in targeted therapies.

“We keep coaxing wonderful new tricks out of some very old dogs,” said Andrew Pearson, MD, a professor of Paediatric Oncology at the Institute of Cancer Research in London, in an interview.

Pearson led the clinical trials that established a regimen of busulphan and melphalan, a mustard gas derivative that is a half-century old, as the standard of care for high-risk pediatric patients with neuroblastoma.

Until 1987, no treatment showed any effect, and the disease, if metastasized, carried a swift death sentence. The prospects of long-term survival remain poor, with <40% of highrisk patients surviving beyond 5 years.

Fresh hopes for this patient population have emerged in recent years, however, through investigation of new ways to use melphalan, according to research presented at American Society of Clinical Oncology annual meeting in Chicago, Illinois, in June.4


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