Mustard Gas to Chemotherapy

By James Patton

Mustard gas, the most effective chemical weapon ever developed,  wasn’t made from mustard—it just smelled sort of like it.  It wasn’t a gas, either, like chlorine. When dispersed it was an aerosol—tiny droplets suspended in the air. Masks were pretty ineffective against it because it was a vesicant (blister agent), not an asphyxiant. Although the initial fatality rate was very low, those exposed to mustard gas were usually hors de combat for quite a while, reducing the size of troop formations and stressing medical care capabilities. 

WWI Mustard Gas Patient

Mustard gas was pervasive. It could contaminate clothing, equipment or even the ground itself. It was persistent, remaining toxic for a long time, and it wasn’t dispersed by wind or converted by exposure to water. It was insidious. If delivered in cold weather it didn’t become toxic until it was warmed up. It is stocked today in chemical weapons arsenals around the world, including ones in Colorado and Kentucky, although all U.S. stocks are being safely destroyed under a program to be completed no later than 2023. 

The most common mustard gas was Bis(2-chloroethyl)sulfide, commonly known as sulfur mustard. Chemists on both sides of the war tinkered with the molecules to produce a more ideal formulation. One of the most effective of these derivatives was nitrogen mustard Bis(2-chloroethyl) methylamine. 

As early as 1919 it was known that mustard gas suppressed the production of blood cells. Autopsies performed at the University of Pennsylvania on 75 WWI soldiers who had died by mustard gas showed decreased white blood cell counts. However, at the time this line of inquiry wasn’t pursued. 

 

After the start of WWII, the newly created Office of Scientific Research and Development (OSRD) funded research at Yale University to find an antidote to mustard gas. Two pharmacologists at Yale, Louis Goodman MD (1906–2000) and Alfred Gilman Ph. (1908–1994), noticed that many soldiers affected by mustard gas had a surprisingly low number of immune cells in their blood—cells that, if mutated, could develop into leukemia and/or lymphoma.

Louis Goodman, MD

Goodman and Gilman hypothesized that if mustard gas could destroy normal white blood cells, it seemed likely that it could also destroy cancerous ones. After successful animal trials, Goodman and Gilman looked for a human volunteer with a white blood cell cancer to test mustard gas as a cancer therapy. They found a male with advanced lymphoma, who was officially known as “J.D.” He had a massive tumor on his jaw which interfered with sleeping and swallowing; he couldn’t even fold his arms because of the tumors in the lymph nodes of his armpits. His prognosis was hopeless.

In August 1942, J.D. agreed to let them try a new experimental drug, which Goodman and Gilman called “synthetic lymphocidal chemical,” but it was actually nitrogen mustard (HN-2). Because it was wartime, the experiment was classified and the drug was officially referred to as “substance X”.

J.D. received a number of infusions and with each he became a little better. He regained the ability to sleep and to swallow—he was more comfortable and he had less pain.

This was a major breakthrough in the history of medicine. It was the beginning of what we call chemotherapy, although the results of this study were not published until 1946, after they were declassified. Goodman and Gilman later published a seminal work, The Pharmacological Basis of Therapeutics, now in its 14th edition. (Alfred Gilman’s son shared the Nobel Prize for Medicine in 1994 for his work on G-proteins.)

Meanwhile, Sir Alexander Haddow, PhD and MD (1907–1976) at the Chester Beatty Research Institute, University of London, had been searching for compounds that could slow or stop the growth of cancerous tumors, and in 1946 he came across the work of Goodman and Gilman with nitrogen mustard. 

In 1948, Haddow published his groundbreaking research in the journal Nature, showing exactly which bits of the nitrogen mustard molecule were needed to kill cancer cells. Perhaps more important, he also found out how to make the chemical less toxic but with more potent cancer-killing activity.

The Molecular Structure of Chlorambucil
Still in Use Today

Haddow first showed that nitrogen Mustards could stop the growth of tumors in rats. Then, in experiments akin to building with Legos, he altered bits of the molecule, replacing them with different "bricks." Replacing certain bits, in particular either of two chlorine atoms, rendered the molecule useless against tumor growth in rats.

This was an important finding, showing that the molecule needed both chlorine atoms to work. And replacing certain other parts of the molecule altered its activity too. Through this molecular puzzle Haddow worked out which pieces were needed to make a treatment that would benefit cancer patients everywhere.

He continued his research, showing how these chemicals actually worked. It was by somehow linking together with molecules inside the cancer cell, which triggered the cell to self-destruct, shut down and break apart. Other researchers later showed that these linked molecules were DNA. 

And so mustard gas went from the front lines of WWI into the front lines of cancer treatment. For the pioneer J.D, this came too late. Although it gave him a few months with less pain and greater comfort, he died six months after first treated with substance “X.”

Sir Alexander Haddow, PhD and MD

Haddow’s subsequent work launched the start of a new era of cancer treatment—chemotherapy. All of the drugs that he later produced worked in the same basic way. The first chemotherapy drug was actually HN-2 itself, but as a pharmaceutical it was called Mustine (later known as Chlormethine) and is no longer commonly used in its original IV formulation because of excessive toxicity. Also the supply is tightly controlled because of its weapon capability. Other nitrogen mustards that were developed include Cyclophosphamide, Uramustine, Melphalan, and Bendamustine (which has recently re-emerged as a viable chemotherapy). 

Nitrogen mustard-derived chemotherapy is still used to treat some cancers today. The chemical structure that Haddow published in 1948 is only a few atoms away from the structure of the drug Chlorambucil, which is still used to treat a type of leukemia called Chronic Lymphocytic Leukemia and another blood cancer called Non-Hodgkin’s Lymphoma (NHL). The NHL survival rate has nearly trebled since the early 1970s and now over 60 per cent of those with NHL survive for at least ten years, thanks largely to Chlorambucil. Research continues on these drugs to reduce side effects.

Haddow’s work also led to the development of more chemotherapy drugs that aren’t nitrogen mustard derivatives but have radically changed the prognosis for other cancers. Two examples of these are Cisplatin and Carboplatin. Cisplatin even has the two critical chlorine atoms, the same as mustard gas, and it’s largely responsible for the fact that 96 per cent of men with testicular cancer now survive the disease long-term.

Sources: Cancer Research UK and the BBC