Chemotherapy for cancer began in the 1940s, growing out of a gruesome wartime discovery and a bold experiment on dying children. The first FDA-approved cancer chemotherapy drug, mechlorethamine (a nitrogen mustard compound), received approval in 1949. But the path from poison gas to cancer treatment stretches back further, and the breakthroughs that made chemotherapy genuinely effective came later. Here’s how it unfolded.
The Term Predates Cancer Treatment by Decades
The word “chemotherapy” was coined by German scientist Paul Ehrlich in the early 1900s, but he wasn’t talking about cancer. Ehrlich was searching for what he called “magic bullets,” chemicals that could kill infectious organisms like malaria parasites and bacteria without harming the patient. His vision was a drug with high affinity for the pathogen and low toxicity to the host. Starting in 1891, he experimented with methylene blue as an antimalarial agent, and his work eventually led to treatments for syphilis and other infections. The concept of using chemicals to selectively destroy harmful cells was in place. It just hadn’t been aimed at cancer yet.
A World War II Disaster Changed Everything
On the evening of December 2, 1943, German bombers attacked the harbor at Bari, on the eastern coast of southern Italy, sinking several Allied ships. One of them, the SS John Harvey, was secretly carrying a stockpile of mustard gas. When the ship exploded, the chemical contaminated the harbor and the sailors in it.
An American military doctor named Stewart Alexander was sent to investigate the unusual pattern of deaths. Most casualties in the first four days died from blast injuries and burns, as expected. But then a second wave of deaths began. Survivors who had seemed stable suddenly had their white blood cell counts plummet, and their lymph nodes shrank dramatically. Alexander recognized the pattern from classified research he’d done at Edgewood Arsenal in 1942, where rabbits exposed to nitrogen mustard showed the same collapse of white blood cells and lymphoid tissue.
Alexander’s report reached researchers at Yale University in early 1944. If nitrogen mustard could destroy white blood cells so effectively, they reasoned, it might work against cancers of those same cells. This spurred new efforts to develop nitrogen mustard as an anticancer drug, and early trials on patients with lymphoma showed tumor shrinkage. The responses were temporary, but the principle was proven: a chemical could push back a cancer.
The First Remissions in Children
The next leap came from Sidney Farber, a pathologist at Boston Children’s Hospital. Farber had been studying folic acid and noticed it seemed to accelerate leukemia in children. He wondered whether blocking folic acid might do the opposite. Working with chemist Yellapragada SubbaRow, he obtained a new compound called aminopterin that interfered with how cells use folic acid.
On December 16, 1947, Farber’s team began giving aminopterin to a critically ill 8-year-old boy with acute leukemia and a fever of 106°F. Four months later, the boy was in complete remission and reported to be in “excellent physical condition.” Farber then treated 16 critically ill children. Ten experienced unprecedented remissions, with normal bone marrow function restored. Two did not respond, and four died within months. The remissions were temporary, but Farber had demonstrated something no one had before: it was possible to suppress the growth of malignant cells and restore normal function, even briefly, using a drug.
These results, published in 1948, are widely considered the birth of modern cancer chemotherapy. They also launched the field of pediatric oncology.
FDA Approval and Government Investment
Merck gained the first FDA approval for a cancer chemotherapy drug in 1949 with mechlorethamine, the nitrogen mustard compound that had emerged from the wartime research. The following decade saw a surge in chemotherapy research and drug development.
In 1955, Congress established the Cancer Chemotherapy National Service Center with $5 million in funding. Its mission was to systematically screen chemical compounds for anticancer activity. By the late 1950s, the center had tested around 11,000 compounds. Between 1955 and 1967, over 114,000 synthetic and natural products were acquired and tested, each tracked with detailed records. This industrial-scale screening effort identified many of the drugs that would become standard treatments over the following decades.
Combination Chemotherapy and the First Cures
Early chemotherapy had a frustrating limitation. Single drugs could shrink tumors or induce remission, but cancers almost always came back. The cancer cells that survived were resistant to whatever drug had been used. Researchers at the National Cancer Institute, including Emil Frei and Emil Freireich, theorized that using multiple drugs simultaneously, each attacking cancer cells through a different mechanism, could prevent resistance.
In the mid-1960s, they developed a regimen called VAMP for childhood leukemia, combining drugs that worked through different pathways. Some suppressed bone marrow activity while others caused nerve-related side effects, meaning doctors could push each drug to its effective dose without compounding the same toxicity. The results, reported in 1965, produced what Freireich later called “the first cures that we’d seen with chemotherapy in an advanced cancer of any sort.”
Shortly after, a combination regimen called MOPP was developed for advanced Hodgkin lymphoma. It used four drugs given in repeating cycles. The overall response rate was 93 percent, with complete responses (no detectable disease) in 67 to 83 percent of patients depending on the regimen variation. MOPP became the standard treatment for Hodgkin lymphoma for nearly 20 years and proved that combination chemotherapy, given on a careful schedule, could cure cancers that were previously fatal. Its success became the template for combination regimens in many other cancer types.
From Poison to Precision
Traditional chemotherapy drugs are blunt instruments. They kill rapidly dividing cells, which includes cancer cells but also hair follicles, the gut lining, and bone marrow. That’s why the classic side effects of chemo, like hair loss, nausea, and vulnerability to infection, are so predictable.
By the late 1990s, a new generation of drugs began targeting the specific molecular abnormalities that drive individual cancers. Trastuzumab, approved between 1998 and 2001, was a lab-engineered antibody designed to block a protein called HER2 that fuels roughly 20 percent of breast cancers. Imatinib, approved in the same period, blocked the abnormal protein produced by a specific genetic mutation in chronic myeloid leukemia. Patients who had faced a median survival of a few years were suddenly living normal lifespans on a daily pill.
These targeted therapies didn’t replace traditional chemotherapy entirely. Many treatment plans still combine older drugs with newer targeted ones. But the shift represented a fundamental change in philosophy: from Ehrlich’s original dream of a “magic bullet” for infections, cancer treatment had finally developed its own version, chemicals designed to hit cancer cells while largely sparing healthy ones.