Chlormethine ( INN, BAN), also known as mechlorethamine ( USAN, USP), mustine, HN2, and (in

post-Soviet states The post-Soviet states, also referred to as the former Soviet Union or the former Soviet republics, are the independent sovereign states that emerged/re-emerged from the dissolution of the Soviet Union in 1991. Prior to their independence, they ...

) embikhin (эмбихин), is a

nitrogen mustard Nitrogen mustards (NMs) are cytotoxic organic compounds with the bis(2-chloroethyl)amino ((ClC2H4)2NR) functional group. Although originally produced as chemical warfare agents, they were the first chemotherapeutic agents for treatment of canc ...

sold under the brand name Mustargen among others. It is the prototype of

alkylating agent Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...

s, a group of

anticancer An anticarcinogen (also known as a carcinopreventive agent) is a substance that counteracts the effects of a carcinogen or inhibits the development of cancer. Anticarcinogens are different from anticarcinoma agents (also known as anticancer or ant ...

chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base

guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...

. As the chemical is a blister agent, its use is strongly restricted within the

Chemical Weapons Convention The Chemical Weapons Convention (CWC), officially the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction, is an arms control treaty administered by the Organisation for ...

where it is classified as a Schedule 1 substance. Mechlorethamine belongs to the group of

alkylating agents Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...

Uses

It has been derivatized into the

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

analogue estramustine phosphate, used to treat

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

. It can also be used in chemical warfare where it has the code-name HN2. This chemical is a form of nitrogen

mustard gas Mustard gas or sulfur mustard are names commonly used for the organosulfur compound, organosulfur chemical compound bis(2-chloroethyl) sulfide, which has the chemical structure S(CH2CH2Cl)2, as well as other Chemical species, species. In the wi ...

and a powerful

vesicant A blister agent (or vesicant) is a chemical compound that causes severe skin, eye and mucosal pain and irritation in the form of severe chemical burns resulting in fluid filled blisters. Named for their ability to cause vesication, blister a ...

. Historically, some uses of mechlorethamine have included lymphoid malignancies such as

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumula ...

polycythemia vera In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. Approximately 98% of PV patients have a JAK2 gene mutation in their blood-forming cells (compared with 0.1-0 ...

, and

lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...

. Mechlorethamine is often administered intravenously, but when compounded into a topical formulation it can also be used to treat skin diseases. There have been studies demonstrating that topical administration of mechlorethamine has efficacy in mycosis fungoides-type cutaneous T cell lymphoma. Another use of chlormethine is in the synthesis of pethidine (meperidine).

Side effects and toxicity

Mechlorethamine is a highly toxic medication, especially for women who are pregnant, breastfeeding, or of childbearing age. At high enough levels, exposure can be fatal. The adverse effects of mechlorethamine depend on the formulation. When used in chemical warfare, it can cause immunosuppression and damage to mucous membranes of the eyes, skin, and respiratory tract. Mucous membranes and damp or damaged skin are more affected by exposure to HN-2. Though symptoms of exposure are generally delayed, the DNA damage it causes occurs very quickly. More serious exposures cause symptoms to develop sooner. Eye symptoms develop first, in the first 1–2 hours (severe exposure) or 3–12 hours (mild to moderate exposure) followed by airway (2-6/12–24 hours) and skin symptoms (6–48 hours). Hot, humid weather shortens the latent (symptom-free) period. Symptoms of toxic exposure to HN-2 vary based on the route of exposure. Eye exposure causes lacrimation (tear production), burning, irritation, itching, a feeling of grittiness or dryness,

blepharospasm Blepharospasm is a neurological disorder characterized by intermittent, involuntary spasms and contractions of the orbicularis oculi muscle, orbicularis oculi (eyelid) muscles around both eyes. These result in abnormal twitching or blinking, an ...

(spasms of the eyelid), and

miosis Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...

(pinpoint pupils). More severe cases cause

edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

(swelling from fluid accumulation) in the eyelids,

photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom, photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence o ...

(extreme sensitivity to light), severe pain,

corneal ulcer Corneal ulcer, often resulting from keratitis is an inflammatory or, more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans part ...

ation, and blindness. Inhalation of chlormethine damages the upper and lower airways sequentially, with more severe exposures causing faster damage that afflicts lower parts of the respiratory tract. Early symptoms include

rhinorrhea Rhinorrhea (American English), also spelled rhinorrhoea or rhinorrhœa (British English), or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is an extremely common condition. It is a common symptom of allergie ...

(runny nose),

epistaxis A nosebleed, also known as epistaxis, is an instance of bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significan ...

(nosebleed), toneless voice, sneezing, barking cough, and

dyspnea Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that ...

(in smokers and asthmatics). Later symptoms include pain in the nose/sinuses and inflammation of the airway. In severe cases, there may be epithelial necrosis throughout the respiratory tract, causing pseudomembrane formation, which can obstruct the airway.

Pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

may develop and prove fatal. Skin exposure mainly causes

erythema Erythema (, ) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology inc ...

(redness) and vesication (blistering) at first, but absorption through the skin causes systemic toxicity. In cases where more than 25% of the skin is affected, fatal exposure is likely to have occurred. Though ingestion is uncommon, if mechlorethamine is swallowed it causes severe chemical burns to the gastrointestinal tract and concomitant nausea, vomiting, diarrhea, abdominal pain, and hemorrhage. Long-term effects of acute or chronic chlormethine exposure are caused by damage to the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

White blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

counts drop, increasing the risk of infection, and

red blood cell Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

and

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

counts may also drop due to

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

damage. Chronic eye infections may result from exposure, but blindness is temporary. Long-term effects on the respiratory system include

anosmia Anosmia, also known as smell blindness, is the lack of ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells. Anosmia can be categorized int ...

(inability to smell),

ageusia Ageusia (from negative prefix ''a-'' and Ancient Greek ''γεῦσις'' geûsis 'taste') is the loss of taste functions of the tongue, particularly the inability to detect sweetness, sourness, bitterness, saltiness, and umami (meaning 'savory t ...

(inability to taste), inflammation, chronic infections, fibrosis, and cancer. Skin that has been damaged by HN2 can change pigmentation or become scarred, and may eventually develop cancer.

History

The effect of vesicant (blister) agents in the form of

(sulfur mustard, Bis(2-chloroethyl) sulfide) on bone marrow and white blood cells had been known since the First World War. In 1935 several lines of chemical and biological research yielded results that would be explored after the start of the Second World War. The vesicant action of a family of chemicals related to the sulfur mustards, but with nitrogen substituting for sulfur was discovered—the "nitrogen mustards" were born. The particular nitrogen mustard chlormethine (mechlorethamine) was first synthesized. And the action of sulfur mustard on tumors in laboratory animals was investigated for the first time. After the US entry into the Second World War the nitrogen mustards were candidate chemical warfare agents and research on them was initiated by the Office of Scientific Research and Development ( OSRD). The OSRD let contracts to study them to two universities—Yale University and the University of Chicago. Inspired perhaps by the preliminary research in 1935, independently both groups thought to test whether a medically useful differential toxicity between animals and animal tumors existed. The Yale pharmacologists Louis Goodman and Alfred Gilman were the first to conduct a clinical trial, on 27 August 1942, using the agent HN3 (tris(2-chloroethyl)amine) on a patient known as J.D. The next year the Chicago group, led by Leon O. Jacobson, conducted trials with HN2 (chlormethine) which was the only agent in this group to see eventual clinical use. Wartime secrecy prevented any of this ground-breaking work on chemotherapy from being published, but papers were released once wartime secrecy ended, in 1946.

Chemistry

Chlormethine is combustible and becomes explosive under extreme conditions. It can react with metals to form gaseous hydrogen.

References

{{Portal bar , Medicine Amines Nitrogen mustard vesicants Chloroethyl compounds Orphan drugs