Cyclophosphamide
Synonym(s):2-[Bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide;Cyclophosphamide monohydrate;Cytoxan
- CAS NO.:50-18-0
- Empirical Formula: C7H15Cl2N2O2P
- Molecular Weight: 261.09
- MDL number: MFCD00005978
- EINECS: 200-015-4
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-20 11:41:24
What is Cyclophosphamide?
Absorption
After oral administration, peak concentrations occur at one hour.
Toxicity
Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.
Chemical properties
Endoxan is a white crystalline powder (monohydrate). It may be used or shipped in solution. Darkens on exposure to light. Odorless
Originator
Cytoxan,Mead Johnson,US,1959
The Uses of Cyclophosphamide
Cyclophosphamide USP is used to treat acute and chronic lymphocytic leukemia; lung cancer; rhabdomyosarcoma; neuroblastoma; ovarian and mammary carcinoma; multiple myeloma; lymphosarcoma; Burkitt’s lymphoma; Hodgkin’s disease; retinoblastoma; mycosis fungoides
The Uses of Cyclophosphamide
Oncology
The Uses of Cyclophosphamide
An anti-proliferative agent that regulates Bax and Bcl-2 expression.
Background
Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.
Indications
Cyclophosphamide is indicated for the treatment of malignant lymphomas, multiple myeloma, leukemias, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. It is also indicated for the treatment of biopsy-proven minimal change nephrotic syndrome in pediatric patients.
What are the applications of Application
Cyclophosphamide is an anti-proliferative agent that regulates Bax and Bcl-2 expression
Definition
ChEBI: Cyclophosphamide is a phosphorodiamide that is 1,3,2-oxazaphosphinan-2-amine 2-oxide substituted by two 2-chloroethyl groups at the amino nitrogen atom. It is an alkylating agent used in the treatment of several forms of cancer including leukemias, lymphomas and breast cancer.
Indications
Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mustards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated metabolically by microsomal enzymes of the cytochrome P450 system before ionization of the chloride atoms and formation of the cyclic ethylenimmonium ion can occur. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moiety derived from cyclophosphamide.
Manufacturing Process
A solution of 7.5 g (0.1 mol) of 1,3-propanolamine and 20.2 g of triethylamine in 100 cc of absolute dioxane is added dropwise at 25°C to 30°C while stirring well to a solution of 25.9 g (0.1 mol) of N,N-bis-(β-chloroethyl)- phosphoric acid amide dichloride in 100 cc of absolute dioxane. After the reaction is complete, the product is separated from the precipitated triethylamine hydrochloride and the filtrate is concentrated by evaporation in waterjet vacuum at 35°C. The residue is dissolved in a large amount of ether and mixed to saturation with water. The N,N-bis-(β-chloroethyl)-N,O-propylene phosphoric acid diamide crystallizes out of the ethereal solution, after it has stood for some time in a refrigerator, in the form of colorless water-soluble crystals. MP 48°C to 49°C. Yield: 65% to 70% of the theoretical.
brand name
Cytoxan (Bristol-Myers Squibb); Neosar (Sicor).
Therapeutic Function
Antineoplastic
Synthesis Reference(s)
The Journal of Organic Chemistry, 43, p. 1111, 1978 DOI: 10.1021/jo00400a019
General Description
Cyclophosphamide is a fine white crystalline powder. Odorless with a slightly bitter taste. Melting point 41-45 °C. A 2% solution has pH of 4 to 6. Used medicinally as an antineoplastic agent.
Air & Water Reactions
Water soluble.
Reactivity Profile
Cyclophosphamide is sensitive to exposure to light (darkens). Also sensitive to oxidation. Aqueous solutions may be kept for a few hours at room temperature, but hydrolysis occurs at temperatures above 86°F. Solutions in DMSO, 95% ethanol or acetone are stable for 24 hours under normal lab conditions. Incompatible with benzyl alcohol. Undergoes both acid and base hydrolysis at extreme pHs
Fire Hazard
Flash point data for Cyclophosphamide are not available; however, Cyclophosphamide is probably combustible.
Biological Activity
cyclophosphamide, an inactive prodrug, is a kind of nitrogen mustard alkylating agent. cyclophosphamide requires enzymatic and chemical activation. as a result, nitrogen mustard is produced. it causes dna cross-linking that accounts for its cytotoxic properties. [1] ic50 of cytotoxicity in mouse embryo balb/c 3t3 cells is 37.6 μm, [2] ic50 of cytotoxicity against human hl60 cells is 8.79 μm measured by mtt assay. [3]cyclophosphamide attaches the alkyl group to the guanine base of dna causing its crosslinking, strand breakage and inducing mutations.[1] emadi a, jones rj, brodsky ra. cyclophosphamide and cancer: golden anniversary. nat rev clin oncol. 2009 nov; 6 (11):638-47.[2] moon ky, kwon ch. n3-methyl-mafosfamide as a chemically stable, alternative prodrug of mafosfamide. bioorg med chem lett. 1998 jul 7; 8 (13):1673-8.[3] patel mm, mali md, patel sk. bernthsen synthesis, antimicrobial activities and cytotoxicity of acridine derivatives. bioorg med chem lett. 2010 nov 1; 20 (21):6324-6.[4] lutsiak me, semnani rt, de pascalis r,et al. inhibition of cd4(+)25+ t regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. blood. 2005 apr 1; 105 (7):2862-8. epub 2004 dec 9.[5] chang tk, yu l, maurel p, waxman dj. enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome p-450 inducers and autoinduction by oxazaphosphorines. cancer res. 1997 may 15; 57 (10):1946-54.[6] anderson d, bishop jb, garner rc, et al. cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks. mutat res. 1995 aug; 330 (1-2):115-81.
Mechanism of action
Cyclophosphamide can be given orally, intramuscularly,
or intravenously. The plasma half-life of intact cyclophosphamide
is 6.5 hours.Only 10 to 15% of the circulating
parent drug is protein bound, whereas 50% of
the alkylating metabolites are bound to plasma proteins.
Since cyclophosphamide and its metabolites are
eliminated primarily by the kidneys, renal failure will
greatly prolong their retention.
Cyclophosphamide has a wide spectrum of antitumor
activity. In lymphomas, it is frequently used in combination
with vincristine and prednisone (CVP [or
COP] regimen) or as a substitute for mechlorethamine
in the MOPP regimen (C-MOPP). High dosages of intravenously
administered cyclophosphamide are often
curative in Burkitt’s lymphoma, a childhood malignancy
with a very fast growth rate.Oral daily dosages are useful
for less aggressive tumors, such as nodular lymphomas,
myeloma, and chronic leukemias.
Pharmacokinetics
Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.
Pharmacokinetics
The drug is metabolized in the liver and is eliminated via the kidney, with approximately 15% of a given dose being excreted unchanged. Doses should be reduced in patients with levels of creatinine clearance less than 30 mL/min. Interestingly, hepatic dysfunction does not seem to alter metabolism of this drug, but caution should be exercised in patients with inhibited cytochrome P450 (CYP450) enzymes or with a combination of factors that could negatively impact drug activation/inactivation pathways.
Pharmacology
Besides being used as an alkylating agent in cancer chemotherapy, cyclophosphamide is a
unique drug when used as an immunosuppressant. First, it is the most powerful of all such
drugs. Second, it kills proliferating cells, and evidently alkylates a certain region of remaining cells. Finally, its action on T-cells is such that despite its overall suppressive
effect, it can, in certain environments, suppress the response of these cells to antigens.
Cyclophosphamide is successfully used for bone transplants. In small doses, it is effective
for autoimmune disorders.
Clinical Use
Cyclophosphamide is a component of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and other drug combinations used in the treatment of breast cancer. Cyclophosphamide in combination may produce complete remissions in some patients with ovarian cancer and oat cell (small cell) lung cancer. Other tumors in which beneficial results have been reported include non–oat cell lung cancers, various sarcomas, neuroblastoma, and carcinomas of the testes, cervix, and bladder. Cyclophosphamide also can be employed as an alternative to azathioprine in suppressing immunological rejection of transplant organs.
Side Effects
Chloroacetaldehyde toxicity is accompanied by glutathione depletion, indicating that, as expected, this electrophilic by-product alkylates Cys residues of critical cell proteins. Alkylation of Lys, adenosine, and cytidine residues also is possible. The CYP-generated carbinolamine undergoes nonenzymatic hydrolysis to provide the aldophosphamide either in the bloodstream or inside the cell. If this hydrolysis occurs extracellularly, the aldophosphamide is still able to penetrate cell membranes to reach the intracellular space. Once inside the cell, acrolein (a highly reactive α,β-unsaturated aldehyde) splits off, generating phosphoramide mustard. With a pKa of 4.75, the mustard will be persistently anionic at intracellular pH and trapped inside the cell.
Safety Profile
Confirmed human carcinogen producing leukemia, Hodgkin's dsease, gastrointestinal and bladder tumors. Experimental carcinogenic, neoplas tigenic, and teratogenic data. A human poison by ingestion and many other routes. Human systemic effects: hdney changes (hepatic dysfunction), leukopenia (reduced white blood cell count), nausea and alopecia (loss of hair), liver changes, agranulocytosis. Human reproductive and teratogenic effects by multiple routes: spermatogenesis, testicular changes, epiddymis and sperm duct changes, menstrual cycle changes, fetal developmental abnormahties of the craniofacial area, musculoskeletal and cardiovascular systems. Experimental reproductive effects. Human mutation data reported. A powerful skin irritant. Used as an immunosuppressive agent in nonmalignant diseases. When heated to decomposition it emits hghly toxic fumes of PO,, NOx, and Cl-.
Synthesis
Cyclophosphamide, 2-[bis-(2-chloroethyl)amino]tetrahydro- 2H-1,3,2-oxazaphosphorin-2-oxide (30.2.1.15), is made by reacting bis(2-chloroethyl)amine with phosphorous oxychloride, giving N,N-bis-(2-chloroethyl)dichlorophosphoramide (30.2.1.14), which upon subsequent reaction with 3-aminopropanol is transformed into cyclophosphamide (30.2.1.15).
Potential Exposure
Exodan is used as an immunosuppressive agent in nonmalignant diseases; treatment of malignant lymphoma, multiple meyloma; leukemias, and other malignant diseases. Exodan has been tested as an insect chemosterilant and for use in the chemical shearing of sheep. Exodan is not produced in the United States.; manufactured in Germany and imported into the United States since1959. The FDA estimates that 200,000300,000 patients per year are treated with exodan. It is administered orally and through injection. The adult dosage is usually 15 mg/kg of body weight daily or 1015 mg/kg administered intravenous every 710 days
Veterinary Drugs and Treatments
In veterinary medicine, cyclophosphamide is used primarily in small
animals (dogs and cats) in combination with other agents both as
an antineoplastic agent (lymphomas, leukemias, carcinomas, and
sarcomas) and as an immunosuppressant (SLE, ITP, IMHA, pemphigus,
rheumatoid arthritis, proliferative urethritis, etc.). Its use in
treating acute immune-mediated hemolytic anemia is controversial;there is some evidence that it does not add beneficial effects when
used with prednisone.
Cyclophosphamide
has been used as a chemical shearing agent
in sheep.
in vitro
cyclophosphamide has a dose-dependent, bimodal effect on the immune system. low-dose cyclophosphamide not only decreases cell number but leads to decreased functionality of regulatory t cells (tregs). cyclophosphamide treatment enhances apoptosis and decreases homeostatic proliferation of these cells. expression of gitr and foxp3, which are involved in the suppressive activity of tregs, is down-regulated after cyclophosphamide administration.[4] in primary human hepatocyte cultures, cyclophosphamide increases cyp3a4, cyp2c8, and cyp2c9 protein levels, causing its 4-hydroxylation rate enhance.[5] in somatic cells, cyclophosphamide produces gene mutations, chromosome aberrations, micronuclei and sister chromatid exchanges in a variety of cultured cells in the presence of metabolic activation as well as sister chromatid exchanges without metabolic activation. [6]
in vivo
it has produced chromosome damage and micronuclei in rats, mice and chinese hamsters, and gene mutations in the mouse spot test and in the transgenic lacz construct of muta™mouse. [6]
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Cytotoxics: increased toxicity with high-dose
cyclophosphamide and pentostatin - avoid.
First aid
If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seekmedical attention immediately. If this chemical contactsthe skin, remove contaminated clothing and wash immediately with soap and water. Seek medical attention immediately. If this chemical has been inhaled, remove fromexposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing hasstopped and CPR if heart action has stopped. Transferpromptly to a medical facility. When this chemical hasbeen swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit.
Carcinogenicity
Cyclophosphamide is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
Metabolism
Metabolism and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19. The CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration.
Metabolism
The initial metabolic step is mediated primarily by CYP2B6 (and, to a much lower extent, by CYP3A4) and involves hydroxylation of the oxazaphosphorine ring to generate a carbinolamine. This hydroxylation reaction must occur before the molecule will be transported into cells. CYP3A4 (but not CYP2B6) also catalyzes an inactivating N-dechloroethylation reaction, which yields highly nephrotoxic and neurotoxic chloroacetaldehyde.
storage
Store at -20°C
Shipping
UN3464 Organophosphorus compound, solid, toxic, n.o.s, Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN1851 Medicine, liquid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials
Incompatibilities
Should be protected from exposure to temperatures above 30°C/86°F.
Waste Disposal
Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal
Properties of Cyclophosphamide
Melting point: | 41-45°C |
Boiling point: | 336.1±52.0 °C(Predicted) |
Density | 1.33±0.1 g/cm3(Predicted) |
storage temp. | Keep in dark place,Inert atmosphere,Store in freezer, under -20°C |
solubility | ≥11.85 mg/mL in H2O with gentle warming and ultrasonic; ≥13.05 mg/mL in DMSO; ≥50.8 mg/mL in EtOH |
form | solid |
pka | 2.84±0.20(Predicted) |
color | White to off-white |
Water Solubility | Soluble. 1-5 g/100 mL at 23 ºC |
Stability: | Stable, but light sensitive. Incompatible with oxidizing agents. |
CAS DataBase Reference | 50-18-0(CAS DataBase Reference) |
NIST Chemistry Reference | 2-[Bis(2-chloroethylamino)]-tetrahydro-2h-1,3,2-oxazaphosphorine-2-oxide(50-18-0) |
IARC | 1 (Vol. 26, Sup 7, 100A) 2012 |
EPA Substance Registry System | Cyclophosphamide (50-18-0) |
Safety information for Cyclophosphamide
Computed Descriptors for Cyclophosphamide
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