Chemotherapy is Poison. No, Literally.

In 2018, an estimated 1.7 million Americans were diagnosed with cancer, and most of these patients, at some point, will likely receive chemotherapy as part of their treatment plan. This anti-cancer therapy is not one drug, but a category of drugs: All of them work by entering cells and stopping them from dividing into new cells, with the hope that they will stop tumors from growing until they fall apart and go away. Chemotherapy drugs cause considerable damage to any cells that are actively dividing in the body, leading to severe side effects including nausea, hair loss, and immunosuppression.

For that reason, we often call these drugs poisons. But there’s more truth to this designation than you might think: the oldest class of chemotherapy drugs actually derived from mustard gas, a poison the Germans used as a chemical weapon during World War I.

The First Appearance of Mustard Gas

In 1917, as British troops were advancing into Belgium in the middle of the First World War, the occupying German forces staged an attack in the town of Ypres, starting the Third Battle of Ypres. During the battle, as bullets flew and explosions shook the ground, British troops in the trenches suddenly saw a strange mist approach their feet and noticed a funny smell in the air. A day later, their throats, lungs, and eyes began to burn and large blisters developed on their skin.

They had been attacked with mustard gas, one of several chemical weapons the Germans introduced during the war. The chemical attack in Ypres took 10,000 lives.

Doctors examined the bodies of soldiers attacked with mustard gas, trying to understand why it was so toxic. They found that the chemical agent affected the soldiers’ immune systems, defeating their bodies’ natural defenses against infection.

Around the same time, cancer researchers back in the United States were working out ways to test thousands of chemicals’ cancer-fighting properties in the search for more effective drugs to treat the disease. Throughout the 1930s, scientists examined over 3,000 chemicals to see if they could be used as anti-cancer drugs. This work led to advancements in how we test these compounds more efficiently, but the research didn’t lead to any new drugs. It wasn’t until World War II that they started to make real progress – by accident!

Mustard Gas Returns

The Geneva protocol of 1925 banned the use of chemical weapons, including mustard gas, in war. But during World War II, the Americans were nervous that the Germans would break the rules and, in a repeat of World War I, ambush their troops with these banned substance. So, to be safe, American ships secretly carried caches of chemical weapons to use as a defense tactic as they approached the battle lines.

But in 1943, this plan backfired when an American ship storing a secret cargo of mustard gas was attacked by German planes. The attack caused the cargo to spill, exposing the sailors on the ship to the poisonous gas. Again examining the soldier’s bodies to understand the effects of mustard gas, doctors noticed a similar result as they did during World War I: the gas affected the soldiers’ immune systems. Combined with laboratory research on mustard gas, doctors and researchers realized that mustard gas depleted the sailors’ bone marrow and lymph nodes, the areas where white blood cells are made.

When this information made it back to United States, it gave the cancer research community here — the one that had spent the last 20 years trying to find new cancer treatments — a fresh idea.

A New Approach to Cancer Therapy

In patients with lymphoma, tumor tissue starves healthy lymph node tissue and takes its place. Researchers hypothesized that mustard gas might be able to slow down the uncontrollable growth of this tumor tissue.

Based on this hypothesis, Alfred Gilman and Louis Goodman at Yale received funding from the U.S. Office of Scientific Research and Development (OSRD) to begin studying whether a derivative of mustard gas, called nitrogen mustard, would be effective in treating the cancer. In their pre-clinical research, the gas worked! Lymphoma tumors shrank when they were exposed to mustard gas.

Riding high on their success, Gilman and Goodman presented their data to a colleague of theirs, thoracic surgeon Gustaf Lindskog, who was looking for new treatments for his patients with non-Hodgkin’s lymphoma. They started with one patient, who we only know him by his initials: “JD.” Patient JD was a 47-year-old factory worker who writhed in pain from his cancer, which was not responding to radiation therapy. With JD’s consent, the team administered ten daily doses of the unproven treatment. Paired with blood transfusions, JD showed signs of improvement after only a few weeks. By 1943, Lindskog tried using nitrogen mustard to treat several patients with non-Hodgkin’s lymphoma and he saw similar results: the nitrogen mustard led to a marked improvement in the patients’ conditions.

These results immediately set off a rush to covertly manufacture more nitrogen mustard (covert because the US Government’s possession of it was still a secret) and study its effects on cancer under the watchful eye of the OSRD. But all of the data that scientists generated as part of this classified defense program, along with the official account of and subsequent research on the mustard gas spill on the American warship, were sealed until 1946.

After the war, however, the government’s knowledge of nitrogen mustard’s potential as a cancer therapy became known to the broader scientific community. Research on this continued and directly led to the first family of chemotherapy drugs, which are still used to treat non-Hodgkin’s lymphoma today.

How Does Nitrogen Mustard Treat Cancer?

When a cell divides, it needs to replicate its own DNA so the new cell gets a copy without the old one having to sacrifice its own. But replicating DNA is not so easy. The genetic information in DNA is locked up in letters of the genetic code, which are linked together in base pairs, like teeth in a zipper. Normally, this information is hidden from the machinery whose job is to replicate it.

For this machinery to do its job, the DNA has to unzip, breaking up these pairs and separating the DNA strand into two. At this point, instead of being tied to its partner, each “tooth” in the DNA is exposed, making room for replication machinery to latch on. Once these machines latch on, they can run down the code on both strands of the DNA, filling in the missing half of each and creating two new DNA strands in the process.

This video from Ameoba Sisters illustrates this process:

Nitrogen mustard, like mustard gas, glues genetic base pairs together so they can’t unzip. A stuck zipper means DNA cannot replicate, which means cells cannot divide. This stops tumors from growing.

In this way, nitrogen mustard, like all chemotherapies, are poisons: they are chemicals that kill cells.

Starting a chemotherapy regimen can be dreadful for many patients because of the terrible side effects they produce: nausea, weight loss, and hair loss, to name a few. These side effects happen because the body is being attacked by a chemical weapon of sorts, with the ultimate aim of killing tumors. But instead of just killing tumor cells, these chemicals damage other cells as well. In fact, they kill any rapidly-dividing cells, including the ones that cause hair to grow.

Fortunately, old chemotherapy drugs are now being replaced with more targeted cancer therapies. These drugs don’t just attack any rapidly-dividing cell, but rather, they seek out signals that make tumor cells different than healthy cells and specifically target them for attack. There are many types of therapies today that target different processes in growing tumor cells, but overall, their purpose is to effectively treat a cancer patient without poisoning the rest of their body. As cancer therapies continue to advance, therapies will become even more targeted, giving patients a better chance at living a long and healthy life, free of terrible side effects.

Chemotherapy is not the only class of drugs discovered by accident during World War II. Learn about the strange history of antidepressants here.