Cyclophosphamide

Source: Wikipedia, the free encyclopedia.
Cyclophosphamide
Clinical data
Pronunciation/ˌsaɪkloʊˈfɒsfəˌmaɪd, -lə-/[1][2]
Trade namesLyophilized Cytoxan, Endoxan, Cytoxan, Neosar, Procytox, Revimmune, Cycloblastin
AHFS/Drugs.comMonograph
MedlinePlusa682080
Pregnancy
category
  • AU: D
Routes of
administration		By mouth, by injection into a vein
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability>75% (by mouth)
Protein binding>60%
MetabolismLiver
Elimination half-life3–12 hours
ExcretionKidney
Identifiers
  • (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
JSmol)
Melting point2 °C (36 °F)
  • O=P1(OCCCN1)N(CCCl)CCCl
  • InChI=1S/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12) checkY
  • Key:CMSMOCZEIVJLDB-UHFFFAOYSA-N checkY
  (verify)

Cyclophosphamide (CP), also known as cytophosphane among other names,

injection into a vein.[4]

Most people develop side effects.

allergic reactions, and pulmonary fibrosis.[4] Cyclophosphamide is in the alkylating agent and nitrogen mustard family of medications.[4] It is believed to work by interfering with the duplication of DNA and the creation of RNA.[4]

Cyclophosphamide was approved for medical use in the United States in 1959.[4] It is on the World Health Organization's List of Essential Medicines.[6]

Medical uses

Cyclophosphamide is used to treat cancers and autoimmune diseases. It is used to quickly control the disease. Due to its toxicity, it is replaced as soon as possible by less toxic drugs. Regular and frequent laboratory evaluations are required to monitor kidney function, avoid drug-induced bladder complications and screen for bone marrow toxicity.

Cancer

A Cyclophosphamide IV drip

The main use of cyclophosphamide is with other

brain cancer, neuroblastoma, leukemia and some solid tumors.[7]

Autoimmune diseases

Cyclophosphamide

systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat minimal change disease,[8] severe rheumatoid arthritis, granulomatosis with polyangiitis,[5] Goodpasture syndrome[9] and multiple sclerosis.[10]

Because of its potential side effects such as

ovarian failure, cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or ACA.[11][12]

AL amyloidosis

Cyclophosphamide, used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as an off-label treatment of AL amyloidosis. It appears to be an alternative to the more traditional treatment with melphalan in people who are ill-suited for autologous stem cell transplant.[13][7]

Graft-versus-host disease

conditioning regimen.[15][16]

Contraindications

Like other alkylating agents, cyclophosphamide is

teratogenic and contraindicated in pregnant women (pregnancy category D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide include lactation, active infection, neutropenia or bladder toxicity.[7]

Cyclophosphamide is a

lupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including growth restriction, ear and facial abnormalities, absence of digits and hypoplastic limbs.[17]

Side effects

alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, lethargy, and profound gonadotoxicity. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow-healing existing wounds, unusual decrease in the amount of urine or unusual tiredness or weakness.[citation needed] Potential side effects also include leukopenia, infection, bladder toxicity, and cancer.[20]

Pulmonary injury appears rare,[21] but can present with two clinical patterns: an early, acute pneumonitis and a chronic, progressive fibrosis.[22] Cardiotoxicity is a major problem with people treated with higher dose regimens.[23]

High-dose intravenous cyclophosphamide can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by intravenous fluids administered to prevent drug-induced cystitis.[24] While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with the lower doses used in the management of inflammatory disorders.[25]

Bladder bleeding

bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria.[26] Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage and mesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein.[27] Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management of lupus nephritis.[28]

Infection

immunosuppressive drugs, but some advocate its use when receiving high-dose medication.[30][31]

Infertility

Cyclophosphamide has been found to significantly increase the risk of

premature menopause in females and of infertility in males and females, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary, but can be permanent.[32] The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.[33]

Cancer

Cyclophosphamide is

Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients with no history.[35] Secondary acute myeloid leukemia (therapy-related AML, or "t-AML") is thought to occur either by cyclophosphamide-inducing mutations or selecting for a high-risk myeloid clone.[36]

This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including radiotherapy), treatment length and intensity. For some regimens, it is rare. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) carries an AML risk of less than 1/2000, with some studies finding no increased risk compared to background. Other treatment regimens involving higher doses may carry risks of 1–2% or higher.

Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk falls to background. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML.[citation needed]

Pharmacology

Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites.[37][38] The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxycyclophosphamide. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein.[39] The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the placenta and are known to be present in breast milk.[40]

It is specifically in the oxazaphosphorine group of medications.[41]

Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction.

corticosteroids, tricyclic antidepressants, or allopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.[43]

Cyclophosphamide reduces plasma

succinylcholine.[44][45] Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein.[citation needed
]

Mechanism of action

The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of

ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.[46]

Cyclophosphamide has relatively little typical

aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation.[26][47][48]

Cyclophosphamide induces beneficial

immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:[49]

  1. Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
  2. Induction of T cell growth factors, such as type I IFNs, and/or
  3. Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.

Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity.

History

As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications,

Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954[50] …It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content. However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxic in vitro (footnote omitted), but to have a low therapeutic index in vivo.[51]

Cyclophosphamide and the related nitrogen mustard–derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology).[52] Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.[53] They converted the base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequently actively transported into cancer cells. Once in the cells, the prodrug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.[54][55][56] In 1959 it became the eighth cytotoxic anticancer agent to be approved by the FDA.[26]

Society and culture

The abbreviation CP is common, although abbreviating drug names is not best practice in medicine.[57]

Research

Because of its impact on the immune system, it is used in animal studies. Rodents are injected intraperitoneally with either a single dose of 150 mg/kg or two doses (150 and 100 mg/kg) spread over two days.[58] This can be used for applications such as:

  • The EPA may be concerned about potential human pathogenicity of an engineered microbe when conducting an MCAN review. Particularly for bacteria with potential consumer exposure they require testing of the microbe on immuno-compromised rats.[59]
  • Cyclophosphamide provides a positive control when studying immune-response of a new drug.[60]

References

  1. OxfordDictionaries.com. Archived from the original
    on August 25, 2012. Retrieved 2016-01-20.
  2. ^ "cyclophosphamide". Merriam-Webster.com Dictionary.
  3. ^ "NCI Drug Dictionary". National Cancer Institute. 2 February 2011. Archived from the original on 25 April 2015. Retrieved 20 December 2016.
  4. ^ a b c d e f g h i j "Cyclophosphamide". The American Society of Health-System Pharmacists. Archived from the original on 2 January 2017. Retrieved 8 December 2016.
  5. ^
    PMID 27733943
    .
  6. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ a b c Brayfield, A, ed. (9 January 2017). "Cyclophosphamide: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 12 August 2017.
  8. ISBN 978-0-323-53265-5
    .
  9. PMID 29083697
    .
  10. PMID 17253481
    .
  11. PMID 28375452
    .
  12. PMID 27619512
    .
  13. S2CID 85480421
    .
  14. S2CID 1093277
    .
  15. PMID 26039204
    .
  16. PMID 27000732
    .
  17. PMID 10482872
    .
  18. PMID 1673721
    .
  19. PMID 6374556
    .
  20. PMID 27623861
    .
  21. PMID 1691069
    .
  22. PMID 8970380
    .
  23. PMID 16234530
    .
  24. PMID 3977522
    .
  25. S2CID 26125211
    .
  26. ^
    S2CID 18219134
    .
  27. PMID 20039416
    .
  28. S2CID 8800101
    .
  29. PMID 8814058
    .
  30. PMID 18576286
    .
  31. S2CID 870510
    .
  32. PMID 3789582
    .
  33. S2CID 10873321
    .
  34. PMID 18299492
    .
  35. PMID 7639809
    .
  36. PMID 18024664
    .
  37. PMID 4393764. Archived from the original
    on 2021-08-28. Retrieved 2014-05-02.
  38. S2CID 25381232
    .
  39. S2CID 39787288
    .
  40. PMID 4102054
    .
  41. S2CID 695545
    .
  42. PMID 11918757
    .
  43. PMID 1277213
    .
  44. S2CID 22946564
    .
  45. PMID 8745976. INIST 2947795
    .
  46. PMID 1422285
    .
  47. PMID 2996550
    .
  48. PMID 1277209
    .
  49. S2CID 3360104
    .
  50. doi:10.1021/ja01632a006
    .
  51. PMID 10469891
    .
  52. ^ U.S. patent 3,018,302
  53. PMID 8697402
    .
  54. OCLC 73296245.[page needed
    ]
  55. ^ Gross R, Wulf G (1959). "Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren" [Clinical and experimental experiences with metallic cyclical and non-cyclical Phosphamidestern the N-losl in the chemotherapy of tumors]. Strahlentherapie (in German). 41: 361–7.
  56. PMID 2491747
    .
  57. ^ Institute for Safe Medication Practices, ISMP's List of Error-Prone Abbreviations, Symbols, and Dose Designations (PDF), archived (PDF) from the original on 2011-10-27.
  58. PMID 16545113
    .
  59. ^ "EPA: Notifications, FY 1998 to Present - Biotechnology Program under the Toxic Substances Control Act (TSCA) | New Chemicals Program | US EPA". Archived from the original on 2015-06-21. Retrieved 2015-07-01.
  60. PMID 21530682
    .

External links

  • "Cyclophosphamide". Drug Information Portal. U.S. National Library of Medicine.
  • U.S. patent 3,018,302 Novel cyclic phosphoric acid ester amides, and the production thereof. (patent for cyclophosphamide).


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