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Revision as of 10:15, 7 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL').← Previous edit		Latest revision as of 07:12, 9 December 2024 edit undoCitation bot (talk | contribs)Bots5,391,794 edits Added bibcode. | Use this bot. Report bugs. | Suggested by Abductive | Category:Prodrugs | #UCB_Category 296/338
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			{{short description|Medication used as chemotherapy and to suppress the immune system}}
	{{Drugbox		{{Drugbox
	| Watchedfields = changed		| Watchedfields = changed
	| verifiedrevid = 451983040		| verifiedrevid = 459435450
	| IUPAC_name = (''RS'')-''N'',''N''-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide		| IUPAC_name = (''RS'')-''N'',''N''-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
	| image = Cyclophosphamid.svg		| image = Cyclophosphamide.svg
	| width = 96		| width = 125
	| image2 = R-cyclophosphamide-from-xtal-1996-3D-balls.png		| image2 = R-cyclophosphamide-from-xtal-1996-3D-balls.png
	| width2 = 150
	<!--Clinical data-->		<!--Clinical data-->
			| pronounce = {{IPAc-en|ˌ|s|aɪ|k|l|oʊ|ˈ|f|ɒ|s|f|ə|ˌ|m|aɪ|d|,_|-|l|ə|-}}{{refn|{{cite web |url=https://www.oxforddictionaries.com/definition/english/cyclophosphamide |archive-url=https://web.archive.org/web/20120825000014/http://oxforddictionaries.com/definition/english/cyclophosphamide |url-status=dead |archive-date=August 25, 2012 |title=cyclophosphamide – definition of cyclophosphamide in English from the Oxford dictionary |publisher=] |access-date=2016-01-20 }} }}{{refn|{{MerriamWebsterDictionary|cyclophosphamide}}}}
	| tradename = Lyophilizedcytoxan
			| tradename = Lyophilized Cytoxan, Endoxan, Cytoxan, Neosar, Procytox, Revimmune, Cycloblastin
	| Drugs.com = {{drugs.com|monograph|cyclophosphamide}}		| Drugs.com = {{drugs.com|monograph|cyclophosphamide}}
	| MedlinePlus = a682080		| MedlinePlus = a682080
	| pregnancy_AU = D		| pregnancy_AU = D
	| pregnancy_US = D		| pregnancy_US = D
	| pregnancy_category =		| pregnancy_category =
			| legal_AU = S4
			| legal_CA = Rx-only
			| legal_UK = POM
			| legal_US = Rx-only
	| legal_status = Rx-only		| legal_status = Rx-only
	| dependency_liability =		| dependency_liability =
	| routes_of_administration = Oral, ]		| routes_of_administration = ], ]
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability = >75% (oral)		| bioavailability = >75% (by mouth)
	| protein_bound = >60%		| protein_bound = >60%
	| metabolism = ]		| metabolism = ]
	| elimination_half-life = 3-12 hours		| elimination_half-life = 3–12 hours
	| excretion = ]		| excretion = ]
	<!--Chemical data-->		<!--Chemical data-->
	| C=7 | H=15 | Cl=2 | N=2 | O=2 | P=1		| C=7 | H=15 | Cl=2 | N=2 | O=2 | P=1
			| SMILES = O=P1(OCCCN1)N(CCCl)CCCl
	| molecular_weight = 261.086 ]/]
	| smiles = O=P1(OCCCN1)N(CCCl)CCCl
	| InChI = 1/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12)
	| InChIKey = CMSMOCZEIVJLDB-UHFFFAOYAB
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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	| KEGG = D07760		| KEGG = D07760
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
			| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 88		| ChEMBL = 88
	| ChemSpiderID = 2804		| ChemSpiderID = 2804
	| CAS_number_Ref = {{cascite|correct|??}}		| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 50-18-0		| CAS_number = 50-18-0
			| ATC_prefix=L01
			| ATC_suffix=AA01
			| ATC_supplemental=
			| PubChem = 2907
	| StdInChI = 1S/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12)		| StdInChI = 1S/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12)
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = CMSMOCZEIVJLDB-UHFFFAOYSA-N		| StdInChIKey = CMSMOCZEIVJLDB-UHFFFAOYSA-N
	| density =		| density =
	| melting_point = 2		| melting_point = 2
	| boiling_point =		| boiling_point =
	| solubility =		| solubility =
	| specific_rotation =		| specific_rotation =
	| sec_combustion =
	}}		}}
			<!-- Definition and medical uses -->
	'''Cyclophosphamide''' (], trade names '''Endoxan''', '''Cytoxan''', '''Neosar''', '''Procytox''', '''Revimmune'''), also known as '''cytophosphane''',<ref>National Cancer Dictionary: </ref> is a ] ],<ref>Takimoto CH, Calvo E. in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) . 11 ed. 2008.</ref> from the ]s group.
			'''Cyclophosphamide''' ('''CP'''), also known as '''cytophosphane''' among other names,<ref>{{cite web|title=NCI Drug Dictionary|url=http://www.cancer.gov/drugdictionary/?CdrID=39748|website=National Cancer Institute|date = 2 February 2011|access-date=20 December 2016|url-status=live|archive-url=https://web.archive.org/web/20150425042348/http://www.cancer.gov/drugdictionary?CdrID=39748|archive-date=25 April 2015}}</ref> is a medication used as ] and to ].<ref name=AHFS2016/> As chemotherapy it is used to treat ], ], ], ], ], ], ], and ].<ref name=AHFS2016/> As an immune suppressor it is used in ], ], and following ], among other conditions.<ref name=AHFS2016/><ref name="Pagnoux">{{cite journal | vauthors = Pagnoux C | title = Updates in ANCA-associated vasculitis | journal = European Journal of Rheumatology | volume = 3 | issue = 3 | pages = 122–133 | date = September 2016 | pmid = 27733943 | pmc = 5058451 | doi = 10.5152/eurjrheum.2015.0043 }}</ref> It is taken by mouth or ].<ref name=AHFS2016/>
			<!-- Side effects and mechanism -->
	An alkylating agent adds an alkyl group (C<sub>n</sub>H<sub>2n+1</sub>) to DNA. It attaches the alkyl group to the ] base of DNA, at the number 7 nitrogen atom of the imidazole ring.
			Most people develop side effects.<ref name=AHFS2016/> Common side effects include ], loss of appetite, vomiting, ], and ].<ref name=AHFS2016/> Other severe side effects include an increased future risk of cancer, ], ], and ].<ref name=AHFS2016/> Cyclophosphamide is in the ] and ] family of medications.<ref name=AHFS2016/> It is believed to work by interfering with the duplication of ] and the creation of ].<ref name=AHFS2016/>
			<!-- History and culture -->
	It is used to treat various types of ] and some ]s. It is a "]"; it is converted in the ] to active forms that have ] activity.
			Cyclophosphamide was approved for medical use in the United States in 1959.<ref name=AHFS2016>{{cite web|title=Cyclophosphamide|url=https://www.drugs.com/monograph/cyclophosphamide.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20170102075231/https://www.drugs.com/monograph/cyclophosphamide.html|archive-date=2 January 2017}}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref>
	==Uses==		==Medical uses==
			Cyclophosphamide is used to treat cancers and ]s. 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 ].{{cn|date=May 2024}}
	The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of ]s, some forms of ]<ref name="pmid17514743">{{cite journal |author=Shanafelt TD, Lin T, Geyer SM, ''et al.'' |title=Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia |journal=Cancer |volume=109 |issue=11 |pages=2291–8 |year=2007 |month=June |pmid=17514743 |doi=10.1002/cncr.22662}}</ref> and some solid tumors.<ref name="pmid16707607">{{cite journal |author=Young SD, Whissell M, Noble JC, ''et al.'' |title=Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors and |journal=Clinical Cancer Research |volume=12 |issue=10 |pages=3092–8 |year=2006 |pmid=16707607 |doi=10.1158/1078-0432.CCR-05-2255}}</ref> It is a chemotherapy drug that works by slowing or stopping cell growth.
	]
	Cyclophosphamide also ] to various diseases and conditions. Therefore, it has been used in various non-neoplastic ]s where ]s (DMARDs) have been ineffective. For example, ] (SLE) with severe ]<ref name="pmid4104337">{{cite journal |author=Steinberg AD, Kaltreider HB, Staples PJ, ''et al.'' |title=Cyclophosphamide in lupus nephritis: a controlled trial |journal=Annals of Internal Medicine |volume=75 |issue=2 |pages=165–71 |month=August |year=1971 |pmid=4104337}}</ref> may respond to pulsed cyclophosphamide (in 2005, however, standard treatment for lupus nephritis changed to ] (MMF) from cyclophosphamide). Cyclophosphamide is also used to treat ],<ref>Brenner and Rector's The Kidney: Volume 8</ref> severe ],<ref name="pmid779796">{{cite journal |doi=10.1002/art.1780190308 |author=Townes AS, Sowa JM, Shulman LE |title=Controlled trial of cyclophosphamide in rheumatoid arthritis |journal=Arthritis & Rheumatism |volume=19 |issue=3 |pages=563–73 |month=May–June |year=1976 |pmid=779796}}</ref> ]<ref name="pmid5551803">{{cite journal |doi=10.1056/NEJM197104292841703 |author=Novack SN, Pearson CM. |title=Cyclophosphamide therapy in Wegener's granulomatosis |journal=New England Journal of Medicine |volume=284 |issue=17 |pages=938–42 |year=1971 |month=April |pmid=5551803}}</ref> (with trade name Cytoxan), and ]<ref name="pmid19439723">{{cite journal |author=Makhani N, Gorman MP, Branson HM, ''et al.'' |title=Cyclophosphamide therapy in pediatric multiple sclerosis |journal=Neurology |issue=24 |pages=2076–82 |month=June |year=2009 |pmid=19439723 |pmc=2923592 |volume=72 |doi=10.1212/WNL.0b013e3181a8164c}}</ref> (with trade name Revimmune).
			===Cancer===
	A 2004 study<ref name="2004-HRPC-Study">{{cite journal | author=Nicolini A, Mancini P, Ferrari P, ''et al'' | title=Oral dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC). | journal=Biomed Parmacother. | volume=58 | pages=447–50 | year=2004 |pmid=15464874 |url=http://linkinghub.elsevier.com/retrieve/pii/S0753-3322(04)00118-0 | doi=10.1016/j.biopha.2004.08.006}}</ref> showed that the biological actions of cyclophosphamide are dose-dependent. At higher doses, it is associated with increased cytotoxicity and immunosuppression, while at low continuous dosage it shows immunostimulatory and antiangiogenic properties. A 2009 study of 17 patients with ]-resistant metastatic hormone refractory prostate cancer showed a ] (PSA) decrease in 9 of the 17 patients. Median survival was 24 months for the entire group, and 60 months for those with a PSA response. The study concluded that low-dose cyclophosphamide "might be a viable alternative" treatment for docetaxel-resistant MHRPC and "is an interesting candidate for combination therapies, e.g., immunotherapy, tyrosine kinase inhibitors, and antiangiogenisis."<ref name="2009-HRPC-Study">{{cite journal | author= Nelius T, Klatte T, ''et al'' | title=Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy | journal=Medical Oncology | pmid= 19365737 | doi=10.1007/s12032-009-9218-8 | year=2009 | month=April | volume= 27 | issue= 2 | pages= 363 |url=https://commerce.metapress.com/content/1p65963mhu095415/resource-secured/?target=fulltext.pdf |format=PDF}}</ref>
			]
			The main use of cyclophosphamide is with other ] agents in the treatment of ]s, some forms of ], ], ] and some solid tumors.<ref name="MD">{{cite web|title=Cyclophosphamide: Martindale: The Complete Drug Reference|website=MedicinesComplete|date=9 January 2017|access-date=12 August 2017|publisher=Pharmaceutical Press|url=https://www.medicinescomplete.com/mc/martindale/current/1825-k.htm|editor=Brayfield, A|location=London, UK}}</ref>
			===Autoimmune diseases===
	==Pharmacokinetics/Pharmacodynamics==
			Cyclophosphamide ], and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening ]s where ]s (DMARDs) have been ineffective. For example, ] with severe ] may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat ],<ref>{{cite book |title=Brenner & Rector's The Kidney |date=2020 |publisher=Elsevier |location=Philadelphia |isbn=978-0-323-53265-5 |pages=1007–1091 |edition=11th}}</ref> severe ], ],<ref name="Pagnoux"/> ]<ref>{{cite book| vauthors = DeVrieze BW, Hurley JA|title=StatPearls|chapter=Goodpasture Syndrome (Anti-glomerular Basement Membrane Antibody Disease)|year=2019|pmid=29083697|publisher=StatPearls Publishing|location=Treasure Island, USA|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK459291/}}</ref> and ].<ref>{{cite journal | vauthors = La Mantia L, Milanese C, Mascoli N, D'Amico R, Weinstock-Guttman B | title = Cyclophosphamide for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 1 | pages = CD002819 | date = January 2007 | pmid = 17253481 | pmc = 8078225 | doi = 10.1002/14651858.CD002819.pub2 }}</ref>
	Cyclophosphamide is converted by mixed function ] ]s in the liver to active metabolites.<ref name="pmid4393764">{{cite journal |author=Cohen JL, Jao JY |title=Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat. |journal=Journal of Pharmacology and Experimental Therapeutics |volume=174 |issue=2 |pages=206–10 |year=1970 |pmid=4393764}}</ref> The main active metabolite is ], which exists in ] with its ], aldophosphamide. Most of the aldophosphamide is oxidised by the enzyme ] (ALDH) to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard and ]. Acrolein is toxic to the ] ] and can lead to ]. This can be prevented through the use of aggressive hydration and/or ].
	Recent clinical studies have shown that cyclophosphamide induce beneficial ]y effects in the context of adaptive immunotherapy. Although the mechanisms underlying these effects are not fully understood, several mechanisms have been suggested based on potential modulation of the host environment, including{{Citation needed|date=February 2007}}:
	# Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
	# Induction of T cell growth factors such as type I IFNs, and/or
	# Enhanced grafting of adoptively transferred tumor-reactive effector T cells by the creation of an immunologic space niche.
			Because of its potential side effects such as ] or ], cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as ] or ].<ref>{{cite journal | vauthors = Davis LS, Reimold AM | title = Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus | journal = Rheumatology | volume = 56 | issue = suppl_1 | pages = i100–i113 | date = April 2017 | pmid = 28375452 | pmc = 5850311 | doi = 10.1093/rheumatology/kew417 }}</ref><ref>{{cite journal | vauthors = Singh JA, Hossain A, Kotb A, Wells GA | title = Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis | journal = Systematic Reviews | volume = 5 | issue = 1 | pages = 155 | date = September 2016 | pmid = 27619512 | pmc = 5020478 | doi = 10.1186/s13643-016-0328-z | doi-access = free }}</ref>
	Thus, cyclophosphamide pre-conditioning 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 anti-tumor immunity.
			===AL amyloidosis===
	==Mechanism of action==
			Cyclophosphamide, used in combination with ] or ] and ] has documented efficacy as an ] of ]. It appears to be an alternative to the more traditional treatment with ] in people who are ill-suited for autologous stem cell transplant.<ref>{{cite journal | vauthors = Gertz MA | title = Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatment | journal = American Journal of Hematology | volume = 89 | issue = 12 | pages = 1132–40 | date = December 2014 | pmid = 25407896 | doi = 10.1002/ajh.23828 | s2cid = 85480421 | doi-access = }}</ref><ref name="MD"/>
	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.
			===Graft-versus-host disease===
	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 death.
			] (GVHD) is a major barrier for ] because of the immune reactions of donor ] against the person receiving them. GVHD can often be avoided by ] of the graft.<ref>{{cite journal | vauthors = Or-Geva N, Reisner Y | title = The evolution of T-cell depletion in haploidentical stem-cell transplantation | journal = British Journal of Haematology | volume = 172 | issue = 5 | pages = 667–84 | date = March 2016 | pmid = 26684279 | doi = 10.1111/bjh.13868 | s2cid = 1093277 | doi-access = free }}</ref> The use of a high dose cyclophosphamide post-transplant in a half matched or haploidentical donor ] reduces GVHD, even after using a reduced ].<ref>{{cite journal | vauthors = Fuchs EJ | title = HLA-haploidentical blood or marrow transplantation with high-dose, post-transplantation cyclophosphamide | journal = Bone Marrow Transplantation | volume = 50 | issue = Suppl 2 | pages = S31–6 | date = June 2015 | pmid = 26039204 | pmc = 4634886 | doi = 10.1038/bmt.2015.92 }}</ref><ref>{{cite journal | vauthors = Robinson TM, O'Donnell PV, Fuchs EJ, Luznik L | title = Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide | journal = Seminars in Hematology | volume = 53 | issue = 2 | pages = 90–7 | date = April 2016 | pmid = 27000732 | pmc = 4806368 | doi = 10.1053/j.seminhematol.2016.01.005 }}</ref>
			==Contraindications==
	Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in ], ] and ] ]. ALDHs protect these actively proliferating tissues against toxic effects phosphoramide mustard and acrolein by converting aldophosphamide to carboxyphosphamide that does not give rise to the toxic metabolites (phosphoramide mustard and acrolein)..
			Like other alkylating agents, cyclophosphamide is ] and contraindicated in pregnant women (] D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide include ], active infection, ] or bladder toxicity.<ref name="MD"/>
			Cyclophosphamide is a ] D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment of ] or ] displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including ], ear and facial abnormalities, absence of digits and ].<ref>{{cite journal | vauthors = Enns GM, Roeder E, Chan RT, Ali-Khan Catts Z, Cox VA, Golabi M | title = Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? | journal = American Journal of Medical Genetics | volume = 86 | issue = 3 | pages = 237–41 | date = September 1999 | pmid = 10482872 | doi = 10.1002/(SICI)1096-8628(19990917)86:3<237::AID-AJMG8>3.0.CO;2-V | doi-access = free }}</ref>
	==Side-effects==
	Many people taking cyclophosphamide do have serious side effects. ] include ] (CINV), ], stomach ache, diarrhea, darkening of the skin/nails, ] (hair loss) or thinning of hair, changes in color and texture of the hair, and ]. ] is a frequent complication, but this is prevented by adequate fluid intake and ] (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds ].
			==Side effects==
	Cyclophosphamide is itself ]ic, potentially causing transitional cell ] of the bladder as a long-term complication. It can lower the body's ability to fight an infection. It can cause temporary or (rarely) permanent sterility. A serious potential side-effect is ], referred to as secondary AML, due to it occurring secondarily to the primary disease being treated. The risk may be dependent on dose and a number of other factors, including the condition being treated, other agents or treatment modalities used (including radiotherapy), treatment intensity and length of treatment. For some regimens it is a very rare occurrence. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20&nbsp;grams of cyclophosphamide) seems to carry an AML risk of less than 1/2000th, with some studies even finding no increased risk compared to the background population. Other treatment regimens involving higher doses may carry risks of 1-2% or higher, depending on regimen. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After 9 years, the risk has fallen to the level of the regular population. When AML occurs, it is often preceded by a ] phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML.
			]s from cyclophosphamide are related to the cumulative medication dose and include ],<ref>{{cite journal | vauthors = Singh G, Fries JF, Williams CA, Zatarain E, Spitz P, Bloch DA | title = Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis | journal = The Journal of Rheumatology | volume = 18 | issue = 2 | pages = 188–94 | date = February 1991 | pmid = 1673721 }}</ref> ],<ref>{{cite journal | vauthors = Lohrmann HP | title = The problem of permanent bone marrow damage after cytotoxic drug treatment | journal = Oncology | volume = 41 | issue = 3 | pages = 180–4 | year = 1984 | pmid = 6374556 | doi = 10.1159/000225819 }}</ref> ], ], ], darkening of the skin/nails, ] (hair loss) or thinning of hair, changes in color and texture of the hair, ], 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|date=May 2014}} Potential side effects also include leukopenia, infection, bladder toxicity, and cancer.<ref>{{cite journal | vauthors = Singh JA, Hossain A, Kotb A, Wells G | title = Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis | journal = BMC Medicine | volume = 14 | issue = 1 | pages = 137 | date = September 2016 | pmid = 27623861 | pmc = 5022202 | doi = 10.1186/s12916-016-0673-8 | doi-access = free }}</ref>
			Pulmonary injury appears rare,<ref>{{cite journal | vauthors = Twohig KJ, Matthay RA | title = Pulmonary effects of cytotoxic agents other than bleomycin | journal = Clinics in Chest Medicine | volume = 11 | issue = 1 | pages = 31–54 | date = March 1990 | doi = 10.1016/S0272-5231(21)00670-5 | pmid = 1691069 }}</ref> but can present with two clinical patterns: an early, acute ] and a chronic, progressive ].<ref>{{cite journal | vauthors = Malik SW, Myers JL, DeRemee RA, Specks U | title = Lung toxicity associated with cyclophosphamide use. Two distinct patterns | journal = American Journal of Respiratory and Critical Care Medicine | volume = 154 | issue = 6 Pt 1 | pages = 1851–6 | date = December 1996 | pmid = 8970380 | doi = 10.1164/ajrccm.154.6.8970380 }}</ref> ] is a major problem with people treated with higher dose regimens.<ref>{{cite journal | vauthors = Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC | title = Cardiotoxicity of cancer therapy | journal = Journal of Clinical Oncology | volume = 23 | issue = 30 | pages = 7685–96 | date = October 2005 | pmid = 16234530 | doi = 10.1200/JCO.2005.08.789 }}</ref>
	Other (serious) side effects include:
	* gross and microscopic ],
			High-dose intravenous cyclophosphamide can cause the ] (SIADH) and a potentially fatal ] when compounded by intravenous fluids administered to prevent drug-induced cystitis.<ref>{{cite journal | vauthors = Bressler RB, Huston DP | title = Water intoxication following moderate-dose intravenous cyclophosphamide | journal = Archives of Internal Medicine | volume = 145 | issue = 3 | pages = 548–9 | date = March 1985 | pmid = 3977522 | doi = 10.1001/archinte.145.3.548 }}</ref> 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.<ref>{{cite journal | vauthors = Salido M, Macarron P, Hernández-García C, D'Cruz DP, Khamashta MA, Hughes GR | title = Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus | journal = Lupus | volume = 12 | issue = 8 | pages = 636–9 | year = 2003 | pmid = 12945725 | doi = 10.1191/0961203303lu421cr | s2cid = 26125211 }}</ref>
	* unusual decrease in the amount of urine,
	* mouth sores,
			===Bladder bleeding===
	* unusual tiredness or weakness,
			] is toxic to the ] ] and can lead to ], which is associated with microscopic or gross ] and occasionally ].<ref name="pmid19786984" /> Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage and ] (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein.<ref>{{cite journal | vauthors = Monach PA, Arnold LM, Merkel PA | title = Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review | journal = Arthritis and Rheumatism | volume = 62 | issue = 1 | pages = 9–21 | date = January 2010 | pmid = 20039416 | doi = 10.1002/art.25061 }}</ref> Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management of ].<ref>{{cite journal | vauthors = Boumpas DT, Austin HA, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, Balow JE | title = Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis | journal = Lancet | volume = 340 | issue = 8822 | pages = 741–5 | date = September 1992 | pmid = 1356175 | doi = 10.1016/0140-6736(92)92292-n | s2cid = 8800101 | url = https://zenodo.org/record/1258313 }}</ref>
	* joint pain,
	* easy bruising/bleeding,
			===Infection===
	* existing wounds that are slow healing.
			] or ] arising secondary to cyclophosphamide usage can predispose people to a variety of ], ] and ]s.<ref>{{cite journal | vauthors = Pryor BD, Bologna SG, Kahl LE | title = Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus | journal = Arthritis and Rheumatism | volume = 39 | issue = 9 | pages = 1475–82 | date = September 1996 | pmid = 8814058 | doi = 10.1002/art.1780390906 | doi-access = }}</ref> No published guidelines cover ] prophylaxis for people with ] receiving ], but some advocate its use when receiving high-dose medication.<ref>{{cite journal | vauthors = Suryaprasad A, Stone JH | title = When is it safe to stop Pneumocystis jiroveci pneumonia prophylaxis? Insights from three cases complicating autoimmune diseases | journal = Arthritis and Rheumatism | volume = 59 | issue = 7 | pages = 1034–9 | date = July 2008 | pmid = 18576286 | doi = 10.1002/art.23822 }}</ref><ref name="Kronbichler2015">{{cite journal | vauthors = Kronbichler A, Jayne DR, Mayer G | title = Frequency, risk factors and prophylaxis of infection in ANCA-associated vasculitis | journal = European Journal of Clinical Investigation | volume = 45 | issue = 3 | pages = 346–68 | date = March 2015 | pmid = 25627555 | doi = 10.1111/eci.12410 | s2cid = 870510 | type = Review | doi-access = free }}</ref>
			===Infertility===
			Cyclophosphamide has been found to significantly increase the risk of ] in females and of ] 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.<ref>{{cite journal | vauthors = Balow JE, Austin HA, Tsokos GC, Antonovych TT, Steinberg AD, Klippel JH | title = NIH conference. Lupus nephritis | journal = Annals of Internal Medicine | volume = 106 | issue = 1 | pages = 79–94 | date = January 1987 | pmid = 3789582 | doi = 10.7326/0003-4819-106-1-79 }}</ref> The use of ] in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.<ref>{{cite journal | vauthors = Periti P, Mazzei T, Mini E | title = Clinical pharmacokinetics of depot leuprorelin | journal = Clinical Pharmacokinetics | volume = 41 | issue = 7 | pages = 485–504 | year = 2002 | pmid = 12083977 | doi = 10.2165/00003088-200241070-00003 | s2cid = 10873321 }}</ref>
			===Cancer===
			Cyclophosphamide is ]ic and may increase the risk of developing ]s, ], ], ] of the bladder or other malignancies.<ref>{{cite journal | vauthors = Bernatsky S, Clarke AE, Suissa S | title = Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis | journal = Archives of Internal Medicine | volume = 168 | issue = 4 | pages = 378–81 | date = February 2008 | pmid = 18299492 | doi = 10.1001/archinternmed.2007.107 | doi-access = free }}</ref> ], including ], ] and ], occurred in 5 of 119 ] patients within the first decade after receiving cyclophosphamide, compared with one case of ] in 119 rheumatoid arthritis patients with no history.<ref>{{cite journal | vauthors = Radis CD, Kahl LE, Baker GL, Wasko MC, Cash JM, Gallatin A, Stolzer BL, Agarwal AK, Medsger TA, Kwoh CK | title = Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study | journal = Arthritis and Rheumatism | volume = 38 | issue = 8 | pages = 1120–7 | date = August 1995 | pmid = 7639809 | doi = 10.1002/art.1780380815 }}</ref> Secondary ] (therapy-related AML, or "t-AML") is thought to occur either by cyclophosphamide-inducing mutations or selecting for a high-risk myeloid clone.<ref>{{cite journal | vauthors = Larson RA | title = Etiology and management of therapy-related myeloid leukemia | journal = Hematology. American Society of Hematology. Education Program | volume = 2007 | pages = 453–9 | year = 2007 | pmid = 18024664 | doi = 10.1182/asheducation-2007.1.453 | doi-access = free }}</ref>
			This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including ]), treatment length and intensity. For some regimens, it is rare. For instance, ] for ] (where the cumulative dose is typically less than 20&nbsp;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 ] phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex ], which carries a worse prognosis than ''de novo'' AML.{{citation needed|date=May 2014}}
			==Pharmacology==
			Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function ] ]s (] system) in the liver to active metabolites.<ref name="pmid4393764">{{cite journal | vauthors = Cohen JL, Jao JY | title = Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 174 | issue = 2 | pages = 206–10 | date = August 1970 | pmid = 4393764 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=4393764 | access-date = 2014-05-02 | archive-date = 2021-08-28 | archive-url = https://web.archive.org/web/20210828052431/https://jpet.aspetjournals.org/content/174/2/206.long | url-status = dead }}</ref><ref>{{cite journal | vauthors = Huttunen KM, Raunio H, Rautio J | title = Prodrugs--from serendipity to rational design | journal = Pharmacological Reviews | volume = 63 | issue = 3 | pages = 750–71 | date = September 2011 | pmid = 21737530 | doi = 10.1124/pr.110.003459 | s2cid = 25381232 }}</ref> The main active metabolite is ], which exists in ] with its ], aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme ] (ALDH) to make ]. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein.<ref name="pmid10803453">{{cite journal | vauthors = Boddy AV, Yule SM | title = Metabolism and pharmacokinetics of oxazaphosphorines | journal = Clinical Pharmacokinetics | volume = 38 | issue = 4 | pages = 291–304 | date = April 2000 | pmid = 10803453 | doi = 10.2165/00003088-200038040-00001 | s2cid = 39787288 }}</ref> The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the ] and are known to be present in ].<ref>{{cite journal | vauthors = Wiernik PH, Duncan JH | title = Cyclophosphamide in human milk | journal = Lancet | volume = 1 | issue = 7705 | pages = 912 | date = May 1971 | pmid = 4102054 | doi = 10.1016/s0140-6736(71)92474-3 }}</ref>
			It is specifically in the oxazaphosphorine group of medications.<ref name="pmid_20446865">{{cite journal | vauthors = Giraud B, Hebert G, Deroussent A, Veal GJ, Vassal G, Paci A | title = Oxazaphosphorines: new therapeutic strategies for an old class of drugs | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 6 | issue = 8 | pages = 919–938 | date = August 2010 | pmid = 20446865 | doi = 10.1517/17425255.2010.487861 | s2cid = 695545 }}</ref>
			Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction.<ref>{{cite journal | vauthors = Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D | title = Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency | journal = Kidney International | volume = 61 | issue = 4 | pages = 1495–501 | date = April 2002 | pmid = 11918757 | doi = 10.1046/j.1523-1755.2002.00279.x | doi-access = free }}</ref> Drugs altering hepatic microsomal enzyme activity (e.g., ], ], ], or ]) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of the drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g. ], ]s, or ]) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.<ref>{{cite journal | vauthors = Donelli MG, Bartosek I, Guaitani A, Martini A, Colombo T, Pacciarini MA, Modica R | title = Importance of pharmacokinetic studies on cyclophosphamide (NSC-26271) in understanding its cytotoxic effect | journal = Cancer Treatment Reports | volume = 60 | issue = 4 | pages = 395–401 | date = April 1976 | pmid = 1277213 }}</ref>
			Cyclophosphamide reduces plasma ] activity and may result in prolonged ] when administered concurrently with ].<ref>{{cite journal | vauthors = Koseoglu V, Chiang J, Chan KW | title = Acquired pseudocholinesterase deficiency after high-dose cyclophosphamide | journal = Bone Marrow Transplantation | volume = 24 | issue = 12 | pages = 1367–8 | date = December 1999 | pmid = 10627651 | doi = 10.1038/sj.bmt.1702097 | s2cid = 22946564 | doi-access = }}</ref><ref>{{cite journal | vauthors = Vigouroux D, Voltaire L | title = | language = fr | journal = Annales Françaises d'Anesthésie et de Réanimation | volume = 14 | issue = 6 | pages = 508–10 | year = 1995 | pmid = 8745976 | doi = 10.1016/S0750-7658(05)80493-9 | trans-title = Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide | id = {{INIST|2947795}} }}</ref> Tricyclic antidepressants and other ] agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein.{{citation needed|date=May 2014}}
			==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 ]. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at ] N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell ].<ref>{{cite journal | vauthors = Hall AG, Tilby MJ | title = Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies | journal = Blood Reviews | volume = 6 | issue = 3 | pages = 163–73 | date = September 1992 | pmid = 1422285 | doi = 10.1016/0268-960X(92)90028-O }}</ref>
			Cyclophosphamide has relatively little typical ] toxicity as ALDHs are present in relatively large concentrations in ], ] and ] ]. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting ] to ] 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 ].<ref name="pmid19786984">{{cite journal | vauthors = Emadi A, Jones RJ, Brodsky RA | title = Cyclophosphamide and cancer: golden anniversary | journal = Nature Reviews. Clinical Oncology | volume = 6 | issue = 11 | pages = 638–47 | date = November 2009 | pmid = 19786984 | doi = 10.1038/nrclinonc.2009.146 | s2cid = 18219134 }}</ref><ref name="pmid2996550">{{cite journal | vauthors = Kohn FR, Sladek NE | title = Aldehyde dehydrogenase activity as the basis for the relative insensitivity of murine pluripotent hematopoietic stem cells to oxazaphosphorines | journal = Biochemical Pharmacology | volume = 34 | issue = 19 | pages = 3465–71 | date = October 1985 | pmid = 2996550 | doi = 10.1016/0006-2952(85)90719-1 }}</ref><ref name="pmid1277209">{{cite journal | vauthors = Friedman OM, Wodinsky I, Myles A | title = Cyclophosphamide (NSC-26271)-related phosphoramide mustards- recent advances and historical perspective | journal = Cancer Treatment Reports | volume = 60 | issue = 4 | pages = 337–46 | date = April 1976 | pmid = 1277209 }}</ref>
			Cyclophosphamide induces beneficial ]y effects in adaptive ]. Suggested mechanisms include:<ref>{{cite journal | vauthors = Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L | title = Immunomodulatory effects of cyclophosphamide and implementations for vaccine design | journal = Seminars in Immunopathology | volume = 33 | issue = 4 | pages = 369–83 | date = July 2011 | pmid = 21611872 | doi = 10.1007/s00281-011-0245-0 | s2cid = 3360104 }}</ref>
			# Elimination of T regulatory cells (CD4<sup>+</sup>CD25<sup>+</sup> T cells) in naive and tumor-bearing hosts
			# Induction of T cell growth factors, such as type I IFNs, and/or
			# Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.
			Thus, cyclophosphamide ] 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 ] strategies, inducing objective antitumor immunity.
	==History==		==History==
			As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications,
	Cyclophosphamide and the related ]-derived alkylating agent ] were developed by Norbert Brock and ASTA (now ] Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.<ref>{{cite journal |author=Brock N |title=The history of the oxazaphosphorine cytostatics |journal=Cancer |volume=78 |issue=3 |pages=542–7 |year=1996 |pmid=8697402 |doi=10.1002/(SICI)1097-0142(19960801)78:3<542::AID-CNCR23>3.0.CO;2-Y }}</ref> They converted the base nitrogen mustard into a non-toxic "transport form". This transport form was a pro-drug, subsequently ] into the cancer cells. Once in the cells, the pro-drug was ] converted into the active, toxic form.
	The first clinical trials were published at the end of the 1950s.<ref>{{cite journal|author=Wilmanns, H.|journal= Asta-Forschung und Therapie|year= 1958}}</ref><ref>{{ cite journal|author=Gross, R., and Wulf, G. |title=Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren|journal=Strahlentherapie|volume= 41 (Sonderband III)|pages= 361–367|year= 1959}}</ref><ref>{{cite journal |author=Brock N |title=Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture |journal=Cancer Res. |volume=49 |issue=1 |pages=1–7 |year=1989 |pmid=2491747 |doi= | url=http://cancerres.aacrjournals.org/cgi/reprint/49/1/1 | format=PDF}}</ref>
			{{blockquote|Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954<ref>{{cite journal | vauthors = Friedman OM, Seligman AM |year=1954 |title=Preparation of N-Phosphorylated Derivatives of Bis-β-chloroethylamine1a |journal=Journal of the American Chemical Society |volume=76 |issue=3 |pages=655–8 |doi=10.1021/ja01632a006 |bibcode=1954JAChS..76..655F }}</ref> ...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''.<ref>{{cite journal | vauthors = Colvin OM | title = An overview of cyclophosphamide development and clinical applications | journal = Current Pharmaceutical Design | volume = 5 | issue = 8 | pages = 555–60 | date = August 1999 | doi = 10.2174/1381612805666230110214512 | pmid = 10469891 }}</ref>}}
	==References==
	{{reflist|2}}
			Cyclophosphamide and the related ]–derived alkylating agent ] were developed by Norbert Brock and ASTA (now ] Oncology).<ref>{{US patent|3018302}}</ref> Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.<ref>{{cite journal | vauthors = Brock N | title = The history of the oxazaphosphorine cytostatics | journal = Cancer | volume = 78 | issue = 3 | pages = 542–7 | date = August 1996 | pmid = 8697402 | doi = 10.1002/(SICI)1097-0142(19960801)78:3<542::AID-CNCR23>3.0.CO;2-Y | doi-access = free }}</ref> They converted the base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequently ] into cancer cells. Once in the cells, the prodrug was ] converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.<ref>{{cite book | vauthors = Wilmanns H |title=Chemotherapie maligner Tumoren |trans-title=Chemotherapy of malignant tumors |language=de |series=Asta-Forschung und Therapie |year=1958 |oclc=73296245}}{{page needed|date=May 2014}}</ref><ref>{{cite journal |vauthors=Gross R, Wulf G |year=1959 |title=Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren |trans-title=Clinical and experimental experiences with metallic cyclical and non-cyclical Phosphamidestern the N-losl in the chemotherapy of tumors |language=de |journal=Strahlentherapie |volume=41 |pages=361–7}}</ref><ref>{{cite journal | vauthors = Brock N | title = Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture | journal = Cancer Research | volume = 49 | issue = 1 | pages = 1–7 | date = January 1989 | pmid = 2491747 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=2491747 }}</ref> In 1959 it became the eighth cytotoxic anticancer agent to be approved by the ].<ref name="pmid19786984" />
	== External links==
	*
			==Society and culture==
			The abbreviation CP is common, although abbreviating drug names is not ] in medicine.<ref name="ISMP_list_do_not_abbreviate">{{Citation |author=Institute for Safe Medication Practices |title=ISMP's List of Error-Prone Abbreviations, Symbols, and Dose Designations |url=http://www.ismp.org/tools/errorproneabbreviations.pdf |postscript=. |url-status=live |archive-url=https://web.archive.org/web/20111027133115/http://www.ismp.org/tools/errorproneabbreviations.pdf |archive-date=2011-10-27 }}</ref>
			==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&nbsp;mg/kg or two doses (150 and 100&nbsp;mg/kg) spread over two days.<ref>{{cite journal | vauthors = Zuluaga AF, Salazar BE, Rodriguez CA, Zapata AX, Agudelo M, Vesga O | title = Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases | language = En | journal = BMC Infectious Diseases | volume = 6 | issue = 1 | pages = 55 | date = March 2006 | pmid = 16545113 | pmc = 1434751 | doi = 10.1186/1471-2334-6-55 | doi-access = free }}</ref> This can be used for applications such as:
			* The ] 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.<ref>{{cite web |url=http://www.epa.gov/biotech_rule/pubs/submiss.htm |title=EPA: Notifications, FY 1998 to Present - Biotechnology Program under the Toxic Substances Control Act (TSCA) &#124; New Chemicals Program &#124; US EPA |access-date=2015-07-01 |url-status=live |archive-url=https://web.archive.org/web/20150621202223/http://www.epa.gov/biotech_rule/pubs/submiss.htm |archive-date=2015-06-21 }}</ref>
			* Cyclophosphamide provides a positive control when studying immune-response of a new drug.<ref>{{cite journal | vauthors = Huyan XH, Lin YP, Gao T, Chen RY, Fan YM | title = Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice | journal = International Immunopharmacology | volume = 11 | issue = 9 | pages = 1293–7 | date = September 2011 | pmid = 21530682 | doi = 10.1016/j.intimp.2011.04.011 | url = https://zenodo.org/record/895552 }}</ref>
			== References ==
			{{reflist|32em}}
			==External links==
			* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/Cyclophosphamide+(anhydrous) | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Cyclophosphamide }}
			* {{US patent|3018302}} Novel cyclic phosphoric acid ester amides, and the production thereof. (patent for cyclophosphamide).
	{{Chemotherapeutic agents}}		{{Chemotherapeutic agents}}
			{{Xenobiotic-sensing receptor modulators}}
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