Friday, August 19, 2022

While war is undoubtedly a terrible thing, and World War II stands out from almost every other war in terms of horror, it is also true that the energy invested in the development of new weapons, tools and strategies for dealing with the enemy can have long-term benefits that carry over into peacetime. Thus, the research and engineering efforts of WWII led to the subsequent availability of such inventions as radar, cryptography, early crude computers and nuclear power, among many others. Many of these items were developed under the strictest secrecy during wartime and only became available for public use after the war was over.

To explore the origins of chemotherapy, we must go back to World War I. In the midst of this horrific war, with millions of men fighting in the trenches, one of the weapons that was introduced and took a terrible toll was poison-gas warfare. This was developed by the Germans; the main such chemical utilized was so-called mustard gas (because of its odor). It would be sprayed across the battlefield and seep across—men who were unprotected by their gas masks would suffer terrible lung damage, eye irritation, skin eruptions and boils, and could end up with permanent damage, possibly even death. This weapon was particularly suited to the trench warfare of WWI.

With the advent of WWII, trench warfare did not develop in the same way as in the prior war. As a consequence, poison gas never became as important a part of the armamentarium as in WWI. Nevertheless, the U.S. and its allies did have top-secret programs to develop more sophisticated and improved versions of poison gas, as did the Nazis. This program worked in parallel to other super-secret weapons programs, such as the Manhattan Project, which ultimately resulted in the atomic bomb.

Sulfur mustard was the primary chemical used for weapons research, but it soon developed that nitrogen mustards, developed in the 1930s, were more efficacious and deadly. In research on animals and rodents, it was discovered that this compound had a profound impact on the proliferation of lymphoid cells, bone marrow cells and cells lining the gastrointestinal tract. The group of pharmacologists that explored the properties of these compounds had the idea to try them out on tumors in mice and discovered that they caused dramatic regression of the tumors.

Because of the war effort, these results were kept top-secret until after the war, but it formed the basis for the first chemotherapeutic drugs.

It should be appreciated that at this time in history, in the early 1940s, the idea of a drug whose administration would cause tumor regression would have seemed the idea of a quack. However, in 1942, a patient with a lymphosarcoma (what we now call a lymphoma) was given nitrogen mustard intravenously with dramatic regression of his tumor. The response did not last long and the tumor recurred, but subsequently several other patients were similarly treated with similar results. By 1948, 150 patients had been treated with non-Hodgkin lymphoma, Hodgkin lymphoma or leukemia, with the best results for Hodgkin lymphoma. The main scientists were from Yale and the work was still secret but became public at that time. Nitrogen mustard is still utilized to this day as a chemotherapeutic agent.

Following this success, similar compounds with antiproliferative effects were developed that were antiproliferative and were toxic to the bone marrow; this class of drugs that included nitrogen mustard was known as alkylating agents. They became the mainstay of chemotherapy for years. Another drug that was discovered was aminopterin; it blocked DNA replication and was related to folic acid—it was used initially by Sidney Farber in the treatment of childhood leukemia. Aminopterin is similar to methotrexate, a drug that later replaced it and is still widely used today. These drugs fall into the category of anti-metabolites. Methotrexate was the first drug successfully used for a solid tumor, choriocarcinoma, a rare type of uterine cancer; this goes back to the mid-1950s.

For those of you interested in the subject, there is a fascinating book, “Death Be Not Proud” by John Gunther, which used to be assigned reading in some high schools in decades past. It is a true memoir of a teenager with a brain tumor and his experiences. I mention it because he was treated with intravenous nitrogen mustard in 1946 and may have been one of the first people with a solid tumor ever treated with chemotherapy.

Thus, prior to WWII, localized therapies were the mainstay of cancer treatment. Surgery was predominant and radiation therapy was used on occasion or for palliative purposes. There was no true inkling that drug therapy could have an impact on cancer. It was the observations that emanated from the top-secret poison gas program that led to the discovery of the possibility of drug therapy and the extraordinary developments that followed.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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