Cyclophosphamide

Cyclophosphamide

Systematic (IUPAC) name
(RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
Clinical data
Trade names	Lyophilizedcytoxan
AHFS/Drugs.com	monograph
MedlinePlus	a682080
Pregnancy cat.	D(AU) D(US)
Legal status	℞ Prescription only
Routes	Oral, intravenous
Pharmacokinetic data
Bioavailability	>75% (oral)
Protein binding	>60%
Metabolism	Hepatic
Half-life	3-12 hours
Excretion	Renal
Identifiers
CAS number	50-18-0 Y
ATC code	?
DrugBank	DB00531
ChemSpider	2804 Y
UNII	6UXW23996M Y
KEGG	D07760 Y
ChEBI	CHEBI:4027 Y
ChEMBL	CHEMBL88 Y
Chemical data
Formula	C7H15Cl2N2O2P
Mol. mass	261.086 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12) Y Key:CMSMOCZEIVJLDB-UHFFFAOYSA-N Y
Physical data
Melt. point	2 °C (36 °F)
Y(what is this?)  (verify)

Cyclophosphamide (INN, trade names Endoxan, Cytoxan, Neosar, Procytox, Revimmune), also known as cytophosphane,^[1] is a nitrogen mustard alkylating agent,^[2] from the oxazophorines group.

An alkylating agent adds an alkyl group (C_nH_2n+1) to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring.

It is used to treat various types of cancer and some autoimmune disorders. It is a "prodrug"; it is converted in the liver to active forms that have chemotherapeutic activity.

Uses

The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of lymphomas, some forms of leukemia^[3] and some solid tumors.^[4] It is a chemotherapy drug that works by slowing or stopping cell growth.

Cyclophosphamide IV drip

Cyclophosphamide also decreases the immune system's response to various diseases and conditions. Therefore, it has been used in various non-neoplastic autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus (SLE) with severe lupus nephritis^[5] may respond to pulsed cyclophosphamide (in 2005, however, standard treatment for lupus nephritis changed to mycophenolic acid (MMF) from cyclophosphamide). Cyclophosphamide is also used to treat minimal change disease,^[6] severe rheumatoid arthritis,^[7] Wegener's granulomatosis^[8] (with trade name Cytoxan), and multiple sclerosis^[9] (with trade name Revimmune).

A 2004 study^[10] 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 docetaxel-resistant metastatic hormone refractory prostate cancer showed a Prostate-specific antigen (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."^[11]

Pharmacokinetics/Pharmacodynamics

Cyclophosphamide is converted by mixed function oxidase enzymes in the liver to active metabolites.^[12] The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard and acrolein. Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis. This can be prevented through the use of aggressive hydration and/or mesna.

Recent clinical studies have shown that cyclophosphamide induce beneficial immunomodulatory 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]}:

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 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.

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 death.

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 phosphoramide mustard and acrolein by converting aldophosphamide to carboxyphosphamide that does not give rise to the toxic metabolites (phosphoramide mustard and acrolein)..

Side-effects

Many people taking cyclophosphamide do have serious side effects. Side-effects include chemotherapy-induced nausea and vomiting (CINV), bone marrow suppression, stomach ache, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, and lethargy. Hemorrhagic cystitis is a frequent complication, but this is prevented by adequate fluid intake and Mesna (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds acrolein.

Cyclophosphamide is itself carcinogenic, potentially causing transitional cell carcinoma 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 Acute Myeloid Leukemia, 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 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 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.

Other (serious) side effects include:

• gross and microscopic hematuria,
• unusual decrease in the amount of urine,
• mouth sores,
• unusual tiredness or weakness,
• joint pain,
• easy bruising/bleeding,
• existing wounds that are slow healing.

History

Cyclophosphamide and the related nitrogen mustard-derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.^[13] They converted the base nitrogen mustard into a non-toxic "transport form". This transport form was a pro-drug, subsequently actively transported into the cancer cells. Once in the cells, the pro-drug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.^[14][15][16]

References

1. ^ National Cancer Dictionary: cyclophosphamide
2. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
3. ^ Shanafelt TD, Lin T, Geyer SM, et al. (June 2007). "Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia". Cancer 109 (11): 2291–8. doi:10.1002/cncr.22662. PMID 17514743. 
4. ^ Young SD, Whissell M, Noble JC, et al. (2006). "Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors and". Clinical Cancer Research 12 (10): 3092–8. doi:10.1158/1078-0432.CCR-05-2255. PMID 16707607. 
5. ^ Steinberg AD, Kaltreider HB, Staples PJ, et al. (August 1971). "Cyclophosphamide in lupus nephritis: a controlled trial". Annals of Internal Medicine 75 (2): 165–71. PMID 4104337. 
6. ^ Brenner and Rector's The Kidney: Volume 8
7. ^ Townes AS, Sowa JM, Shulman LE (May–June 1976). "Controlled trial of cyclophosphamide in rheumatoid arthritis". Arthritis & Rheumatism 19 (3): 563–73. doi:10.1002/art.1780190308. PMID 779796. 
8. ^ Novack SN, Pearson CM. (April 1971). "Cyclophosphamide therapy in Wegener's granulomatosis". New England Journal of Medicine 284 (17): 938–42. doi:10.1056/NEJM197104292841703. PMID 5551803. 
9. ^ Makhani N, Gorman MP, Branson HM, et al. (June 2009). "Cyclophosphamide therapy in pediatric multiple sclerosis". Neurology 72 (24): 2076–82. doi:10.1212/WNL.0b013e3181a8164c. PMC 2923592. PMID 19439723. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2923592. 
10. ^ Nicolini A, Mancini P, Ferrari P, et al (2004). "Oral dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC).". Biomed Parmacother. 58: 447–50. doi:10.1016/j.biopha.2004.08.006. PMID 15464874. http://linkinghub.elsevier.com/retrieve/pii/S0753-3322(04)00118-0. 
11. ^ Nelius T, Klatte T, et al (April 2009). "Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy" (PDF). Medical Oncology 27 (2): 363. doi:10.1007/s12032-009-9218-8. PMID 19365737. https://commerce.metapress.com/content/1p65963mhu095415/resource-secured/?target=fulltext.pdf. 
12. ^ Cohen JL, Jao JY (1970). "Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat.". Journal of Pharmacology and Experimental Therapeutics 174 (2): 206–10. PMID 4393764. 
13. ^ Brock N (1996). "The history of the oxazaphosphorine cytostatics". Cancer 78 (3): 542–7. doi:10.1002/(SICI)1097-0142(19960801)78:3<542::AID-CNCR23>3.0.CO;2-Y. PMID 8697402. 
14. ^ Wilmanns, H. (1958). Asta-Forschung und Therapie. 
15. ^ Gross, R., and Wulf, G. (1959). "Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren". Strahlentherapie 41 (Sonderband III): 361–367. 
16. ^ Brock N (1989). "Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture" (PDF). Cancer Res. 49 (1): 1–7. PMID 2491747. http://cancerres.aacrjournals.org/cgi/reprint/49/1/1. 

External links

• U.S. National Library of Medicine: Drug Information Portal - Cyclophosphamide