Skip to content
Bending the Curve Trial by Trial
?

Nitrogen mustards and oxazaphosphorinesIn useRational design

Cyclophosphamide

Also known as Cytoxan

A prodrug of a nitrogen mustard, designed in the 1950s to be inactive until activated in the body. Its 2013 US label lists lymphomas, myeloma, leukaemias, neuroblastoma, ovarian and breast cancer, and a childhood kidney condition.

From discovery to approval

  1. 1958 · First described

    In 1958 Arnold and Bourseaux published the synthesis and breakdown of cytostatically active cyclic phosphamide esters of bis(2-chloroethyl)amine, and with Brock a note on new cancer chemotherapeutics from this group. Brock later described the work as applying a transport-form and active-form principle to the nitrogen mustard group.[2][3][4][5][6][7][8]

  2. 1959-11-16 · FDA regular · 1 years after first description

    Cytoxan, NDA 012141 (tablets; the injection, NDA 012142, shows the same original action date), original approval, classed as a new molecular entity with priority review in the Drugs@FDA history. The original label is not available there, so the indication at approval is not stated here; the 2013 label lists malignant lymphomas, multiple myeloma, leukaemias, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma and breast carcinoma, and minimal change nephrotic syndrome in children. The type regular is an inference: no accelerated-approval wording was found.[8]

How it works

The 2013 US label says the mechanism is thought to involve cross-linking of tumour cell DNA. The drug is biotransformed mainly in the liver to active alkylating metabolites, which interfere with the growth of susceptible rapidly proliferating malignant cells.[1]

Where it came from and why

Brock described the aim as turning the reactive mustard group into an inactive transport form that tumour tissue would activate enzymatically, widening the therapeutic range of alkylating agents. A 2009 review says it was made to target cancer cells through their phosphamidases, an idea later found irrelevant to its activity.

In 1958 Arnold and Bourseaux published the synthesis and breakdown of cyclic phosphamide esters of bis(2-chloroethyl)amine with cytostatic activity [2], and with Brock a note describing the group as new cancer chemotherapeutics [3]. Brock later wrote that the oxazaphosphorines were based on applying the transport form and active form principle to the highly reactive nitrogen mustard group, converting it into an inactive transport form that is activated enzymatically in the target organ [4].

A 2009 review says cyclophosphamide was first synthesised to target cancer cells selectively, through activation by phosphamidases in those cells, but that this hypothesised tumour specificity proved irrelevant to its activity [6]. A 2023 history names Haddow, Gilman and Goodman, Gomori and Brock among those whose contributions led step by step to the oxazaphosphorines, with cyclophosphamide arriving in 1958 and its isomer ifosfamide soon after [7].

Drugs@FDA lists the original US approval of Cytoxan as 16 November 1959 [8].

Cancers

  • Malignant lymphomas

    The 2013 US label lists Hodgkin disease, lymphocytic, mixed-cell and histiocytic lymphomas and Burkitt lymphoma.[1]

  • Multiple myeloma and leukaemias

    The 2013 US label lists multiple myeloma, chronic lymphocytic and granulocytic leukaemia, acute myelogenous, monocytic and lymphoblastic leukaemia, and says it is usually ineffective in the acute blastic crisis of chronic granulocytic leukaemia.[1]

  • Neuroblastoma, retinoblastoma, ovarian and breast cancer, mycosis fungoides

    The 2013 US label lists disseminated neuroblastoma, retinoblastoma, adenocarcinoma of the ovary, breast carcinoma and advanced mycosis fungoides.[1]

  • Hodgkin disease (early clinical report)

    A 1960 British Medical Journal paper reports cyclophosphamide in Hodgkin disease and related disorders (from its title; no abstract).[9]

Family and partners

Drugs derived from it: Ifosfamide

Worth knowing

  • The 2013 US label also lists biopsy-proven minimal change nephrotic syndrome in children who did not respond adequately to, or could not tolerate, corticosteroid therapy.[1]
  • A 2009 review says the hypothesised tumour-specific activation by phosphamidases proved irrelevant, and that its metabolism and inactivation by aldehyde dehydrogenase explain its cytotoxic properties.[6]
  • Brock's 1989 lecture names cyclophosphamide, ifosfamide and trofosfamide as the oxazaphosphorine cytostatics designed on the transport-form and active-form idea.[4]
  • Brock's 1989 lecture says mesna, introduced as a regional uroprotector, removes the risk of therapy-limiting urotoxic effects of oxazaphosphorines, so higher doses can be given with more safety.[4]

On this site

References

  1. U.S. Food and Drug Administration. Cyclophosphamide, prescribing information, NDA 012141 supplement 090 and NDA 012142 supplement 112 (action date 7 May 2013). Source
  2. Arnold H, Bourseaux F. Synthese und Abbau cytostatisch wirksamer cyclischer N‐Phosphamidester des Bis‐(β‐chloräthyl)‐amins. Angewandte Chemie. 1958;70(17-18):539-544. DOI
  3. Arnold H, Bourseaux F, Brock N. Neuartige Krebs-Chemotherapeutika aus der Gruppe der zyklischen N-Lost-Phosphamidester. Die Naturwissenschaften. 1958;45(3):64-66. DOI
  4. Brock N. Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture. Cancer Res. 1989;49(1):1-7. PubMed
  5. Brock N. Ideas and reality in the development of cancer chemotherapeutic agents, with particular reference to oxazaphosphorine cytostatics. J Cancer Res Clin Oncol. 1986;111(1):1-12. PubMedDOI
  6. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6(11):638-47. 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 012141 (Cytoxan tablets, cyclophosphamide); the injection, NDA 012142, shows the same original action date. Page read 2026-10-26. Source
  9. MATTHIAS JQ, MISIEWICZ JJ, SCOTT RB. Cyclophosphamide in Hodgkin's disease and related disorders. Br Med J. 1960;2(5216):1837-40. PubMedDOI