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Bending the Curve Trial by Trial
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Nitrogen mustards and oxazaphosphorinesIn useSyntheticNeeds review

Mechlorethamine

Also known as Nitrogen mustard, HN2, Mustargen, Valchlor

The nitrogen mustard first given to a patient with lymphosarcoma in 1942 and reported in 1946. The US injection (Mustargen) is listed as discontinued; a topical gel is approved for early mycosis fungoides-type cutaneous T-cell lymphoma.

From discovery to approval

  1. c. 1942 · Earliest report found

    Yale pharmacologists tested nitrogen mustard in animals, and a patient with lymphosarcoma received the first recorded dose on 27 August 1942, according to his chart as reported in 2011. The first medical reports followed in 1946. The year shown is that of this first recorded dose; the compound's synthesis is not dated here.[2][3][4][5][6][7][8]

  2. 1942 · First use in people

    A 2011 account of the patient's chart records the first dose on 27 August 1942 (0.1 mg/kg, ten daily intravenous injections) in a man with lymphosarcoma; the chart differed from earlier recollected accounts. The same account also mentions experimental use on military volunteers, without dates. Gilman's 1963 paper is titled 'The initial clinical trial of nitrogen mustard'.[2]

  3. 1949-03-15 · FDA regular · 7 years after first description

    Mustargen for injection, NDA 006695, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history, which lists the product as discontinued. The original label is not available there, so the indication at approval is not stated here; a 2004 label lists palliative treatment of Hodgkin disease (stages III and IV), lymphosarcoma, chronic myelocytic or lymphocytic leukaemia, polycythemia vera, mycosis fungoides and bronchogenic carcinoma, and of metastatic carcinoma with effusion. The type regular is an inference: no accelerated-approval wording was found.[8]

  4. 2013-08-23 · FDA regular · 71 years after first description

    Topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy (NDA 202317; the Drugs@FDA history classes it as a new formulation, standard review, orphan). The type regular is an inference: no accelerated-approval wording was found.[9]

How it works

US labels describe an alkylating agent that inhibits rapidly proliferating cells. The 2004 injection label says it reacts rapidly with water and cell components, so no active drug remains a few minutes after injection.[1]

Where it came from and why

Mustard gas exposure in the First World War was reported in 1919 to lower circulating white cells. In the Second World War, reports of severe toxicity led the US to fund antidote research at Yale, where Gilman and Goodman saw nitrogen mustard lower lymphocyte counts in rabbits and shrink lymphomas in mice.

The effect of mustard gas on blood cells was described in 1919, when Edward Krumbhaar treated exposed soldiers at a hospital in France and reported a fall in circulating white cells [2]. In the Second World War, reports of severe toxicity led the US Office of Scientific Research and Development to fund antidote research at Yale, with a team led by the pharmacologists Alfred Gilman and Louis Goodman [2]. They saw nitrogen mustard lower lymphocyte and granulocyte counts in rabbits, and tumour size fell and life was prolonged in mice with transplanted lymphomas [2].

A man with lymphosarcoma that no longer responded to radiotherapy or surgery was offered the drug. His chart, found in 2010, records the first dose on 27 August 1942, followed by ten daily intravenous injections [2]. A biopsy afterwards showed no tumour, but his blood counts then fell, the tumours returned by day 49, and he died on 1 December 1942 [2]. Because of wartime censorship, the chart never uses the words nitrogen mustard [2]. Earlier accounts of the patient rested on recollection and differed from the chart; Fenn and Udelsman published the chart findings in 2011 [3].

In 1946 the Yale work reached the medical literature, in a paper by Gilman and Philips in Science and a report by Goodman and colleagues in JAMA [4] [5]. Drugs@FDA lists the original Mustargen approval as 15 March 1949 [8].

Cancers

  • Hodgkin disease, lymphosarcoma and leukaemia

    Reported in 1946 for Hodgkin disease, lymphosarcoma, leukaemia and certain allied disorders (from the paper's title).[5]

  • Mycosis fungoides-type cutaneous T-cell lymphoma

    The 2013 gel label covers topical treatment of stage IA and IB disease in patients who have had prior skin-directed therapy; the 2004 injection label also lists mycosis fungoides among its palliative uses.[10]

  • Metastatic carcinoma with effusion

    The 2004 injection label lists intrapleural, intraperitoneal or intrapericardial use for palliative treatment of metastatic carcinoma causing effusion.[1]

Family and partners

Drugs derived from it: Bendamustine

Worth knowing

  • The first patient's chart, found in 2010, never uses the words nitrogen mustard because of wartime censorship; it refers to the substance as 'a lymphocidal' or 'substance X'.[2]
  • A 2011 account says the first dose was 0.1 mg/kg, based on toxicology studies in rabbits.[2]
  • The 2004 US injection label says the drug combines with water and reactive cell compounds so quickly that it is no longer present in active form a few minutes after administration.[1]
  • A topical mechlorethamine gel (Valchlor) was approved by the FDA on 23 August 2013 for stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma after prior skin-directed therapy.[9]
  • Drugs@FDA lists the Mustargen injection as discontinued.[8]

On this site

References

  1. U.S. Food and Drug Administration. Mustargen (mechlorethamine HCl for injection), prescribing information, NDA 006695 supplement 031 (action date 9 February 2004). Source
  2. Christakis P. The birth of chemotherapy at Yale. Bicentennial lecture series: Surgery Grand Round. Yale J Biol Med. 2011;84(2):169-72. PubMed
  3. Fenn JE, Udelsman R. First use of intravenous chemotherapy cancer treatment: rectifying the record. J Am Coll Surg. 2011;212(3):413-7. PubMedDOI
  4. GILMAN A, PHILIPS FS. The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides. Science. 1946;103(2675):409-15. PubMed
  5. Goodman LS, Wintrobe MM, et al. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc. 1946;132:126-32. PubMedDOI
  6. GILMAN A. The initial clinical trial of nitrogen mustard. Am J Surg. 1963;105:574-8. PubMedDOI
  7. Idle JR, Beyoğlu D. Ifosfamide - History, efficacy, toxicity and encephalopathy. Pharmacol Ther. 2023;243:108366. PubMedDOI
  8. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 006695 (Mustargen, mechlorethamine hydrochloride). Page read 2026-10-26. Source
  9. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 202317 (Valchlor, mechlorethamine gel). Page read 2026-10-26. Source
  10. U.S. Food and Drug Administration. Valchlor (mechlorethamine) gel, prescribing information, NDA 202317 original approval (revised 8/2013). Source