Cyclophosphamide#Pharmacology

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.{{cn|date=May 2024}}

File:Cyclophosphamide iv.jpg

The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas, some forms of brain cancer, neuroblastoma, leukemia and some solid tumors.{{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}}

Cyclophosphamide decreases the immune system's response, and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat minimal change disease,{{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}} severe rheumatoid arthritis, granulomatosis with polyangiitis, Goodpasture syndrome{{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/}} and multiple sclerosis.{{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 }}

Because of its potential side effects such as amenorrhea or ovarian failure, cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or azathioprine.{{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 }}{{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 }}

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.{{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 = }}

Graft-versus-host disease (GVHD) is a major barrier for allogeneic stem cell transplant because of the immune reactions of donor T cell against the person receiving them. GVHD can often be avoided by T-cell depletion of the graft.{{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 }} The use of a high dose cyclophosphamide post-transplant in a half matched or haploidentical donor hematopoietic stem cell transplantation reduces GVHD, even after using a reduced conditioning regimen.{{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 }}{{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 }}

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.

Cyclophosphamide is a pregnancy category D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including growth restriction, ear and facial abnormalities, absence of digits and hypoplastic limbs.{{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 }}

Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting,{{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 }} bone marrow suppression,{{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 }} stomach ache, hemorrhagic cystitis, diarrhea, darkening of the skin/nails, 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|date=May 2014}} Potential side effects also include leukopenia, infection, bladder toxicity, and cancer.{{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 }}

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

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.{{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 }} 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.{{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 }}

Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria. 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.{{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 }} 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.{{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 }}

Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial, fungal and opportunistic infections.{{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 = }} No published guidelines cover PCP prophylaxis for people with rheumatological diseases receiving immunosuppressive drugs, but some advocate its use when receiving high-dose medication.{{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 }}{{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 }}

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.{{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 }} The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.{{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 }}

Cyclophosphamide is carcinogenic and may increase the risk of developing lymphomas, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies.{{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 }} 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.{{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 }} 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.{{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 }}

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|date=May 2014}}

Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites.{{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 }}{{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 }} 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.{{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 }} 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.{{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 }}

It is specifically in the oxazaphosphorine group of medications.{{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 }}

Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction.{{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 }} Drugs altering hepatic microsomal enzyme activity (e.g., alcohol, barbiturates, rifampicin, or phenytoin) 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. corticosteroids, tricyclic antidepressants, or allopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.{{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 }}

Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine.{{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 = }}{{cite journal | vauthors = Vigouroux D, Voltaire L | title = [Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide] | 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}} }} Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein.{{citation needed|date=May 2014}}

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.{{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 }}

Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting 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.{{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 }}{{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 }}{{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 }}

Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:{{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 }}

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.

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

{{blockquote|Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954{{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 }} ...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.{{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 }}}}

Cyclophosphamide and the related nitrogen mustard–derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology).{{US patent|3018302}} Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.{{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 }} 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.{{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}}{{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}}{{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 }} In 1959 it became the eighth cytotoxic anticancer agent to be approved by the FDA.

The abbreviation CP is common, although abbreviating drug names is not best practice in medicine.{{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 }}

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.{{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 }} 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.{{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) | New Chemicals Program | 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 }}
• Cyclophosphamide provides a positive control when studying immune-response of a new drug.{{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 }}

{{reflist|32em}}

• {{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).

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Category:Hepatotoxins

Category:IARC Group 1 carcinogens

Category:Nitrogen mustards

Category:Oxazaphosphinans

Category:Phosphorodiamidates

Category:Prodrugs

Category:Chloroethyl compounds

Category:World Health Organization essential medicines

Category:Wikipedia medicine articles ready to translate