Mustard gas, a potent chemical warfare agent, was first used in 1917 during World War I. Exactly 100 years later, the European Union approved the usage of a mustard gas derivative as a cancer treatment. What was it that took this chemical from the battlefields to hospitals?

Yperite – a chemical weapon

World War I is considered the first war of the modern age in which chemical warfare was used. A chemical that stands out among the ones used is mustard gas or yperite, a compound known formally as dichlorodiethyl sulfide. It was named after the city of Ypres where it was first used. It belongs to a larger group of mustard gases known as sulfur mustards. Sulfur mustards make use of several mechanisms. They damage DNA by alkylating and cross-linking purine bases. Because they contain cysteine groups, proteins are also subject to cross-linking when exposed to yperite, which leads to conformational changes and dysfunction in enzymes. Yperite also induces an acute inflammatory process leading to oxidative stress and finally resulting in apoptosis (cell death).

On a macroscopic level, these changes appear in the form of skin blisters, which is why this gas is also known as a vesicant (from the Latin word vesicula meaning blister). In addition to that, long-term effect such as chronic obstructive pulmonary disease, lung fibrosis, chronic conjunctivitis, abnormal skin pigmentation and various forms of cancer have also been observed. Around 100 000 people are considered to have died from exposure to sulfur mustards.

What is chlormethine?

Other than sulfur mustards which are internationally forbidden chemical warfare, there are also nitrogen mustards, whose structure contains nitrogen instead of sulfur. They are not considered chemical warfare and are instead being researched as chemotherapeutic agents. Amongst nitrogen mustards, an important chemical compound is chlormethine, otherwise known as mechlorethamine. Chlormethine is a synthetic DNA-alkylating agent. It emerged as a potential treatment when a condition known as lymphocytopenia, a decreased number of lymphocytes, was noticed in soldiers who survived mustard gas attacks.

A cure for cancer

When chlormethine became a research target in the 1940s, its efficiency in suppressing malignant T-cell growth was quickly noted. The mechanism through which chlormethine works is similar to the mechanism displayed by the aforementioned yperite. It alkylates DNA, inducing conformational changes in the molecule and causing breakage which leads to apoptosis in malignant cells. Another important avenue through which chlormethine destroys malignant cells is the direct suppression of DNA repair mechanisms.

Although in the past chlormethine was explored as a potential cure for multiple malignant diseases, e.g. Hodgkins’ lymphoma, today it’s most often used as a cure for mycosis fungoides, a form of T-cell lymphoma. It’s administered locally in the form of a gel or ointment and is generally considered safe for use. Minor side effects are possible, the most common one being contact dermatitis.

The future of chlormethine

Research conducted in the last couple of years since chlormethine has been introduced worldwide as a treatment points to its safety and efficacy. That is why it’s considered a first-line treatment for mycosis fungoides. Due to its ease of application and its positive effects on this malignant disease, chlormethine will most likely continue to be an important treatment in the world of oncology.

 

Literature

1. Guenova E et al. Mechanism of action of chlormethine gel in mycosis fungoides. J Eur Acad Dermatol Venereol, 2023, 37(9), 1739-1748.

2. iperit. Hrvatska enciklopedija, mrežno izdanje. Leksikografski zavod Miroslav Krleža, 2013 – 2024., https://www.enciklopedija.hr/. Pristupljeno 1.1.2024.

3. Koumourtzis M et al. Chlormethine Gel is Efficient and Safe in Mycosis Fungoides Skin Lesions. Acta Derma Venereol, 2022, 102, 1095.

4. mekloretamin. Medicinski leksikon – 1992. (mrežno izdanje). Leksikografski zavod Miroslav Krleža, 2023., https://ml.lzmk.hr/. Pristupljeno 2. 1. 2024.

5. Romano Jr JA, Lukey BJ, Salem H. Chemical Warfare Agents: Chemistry, Pharmacology, Toxicology, and Therapeutics. Boca Raton, CRC Press, 2008, str. 248 – 276

6. Wehkamp U et al. Chlormethine Gel for Patients with Mycosis Fungoides Cutaneous T Cell Lymphoma: A Review of Efficacy and Safety in Clinical Trial and Real-World Settings. Adv Ther, 2022, 39(9), 3979-4002.

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