50-18-0 Usage
Uses
Used in Anticancer Applications:
Cyclophosphamide is used as an anticancer agent for the treatment of acute and chronic lymphocytic leukemia, lung cancer, rhabdomyosarcoma, neuroblastoma, ovarian and mammary carcinoma, multiple myeloma, lymphosarcoma, Burkitt’s lymphoma, Hodgkin’s disease, retinoblastoma, and mycosis fungoides. It is also used as an anti-proliferative agent that regulates Bax and Bcl-2 expression.
Used in Kidney Disease Treatment:
Cyclophosphamide is used in the treatment of minimal change disease of the kidney in children, a disease that causes nephrotic syndrome.
Used in Autoimmune Disorders and BMT:
Although not officially approved for these indications, Cyclophosphamide is widely used in the treatment of various autoimmune disorders and as a part of the conditioning regimen for bone marrow transplantation.
Used in Drug Delivery Systems:
Cyclophosphamide is also used in the development of novel drug delivery systems to enhance its applications and efficacy against cancer cells. Various organic and metallic nanoparticles have been employed as carriers for Cyclophosphamide delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.
Brand Names:
Cyclophosphamide is available under the brand names Cytoxan (Bristol-Myers Squibb) and Neosar (Sicor).
History
An alkylating anticancer agent with another strategy to lower the toxicities on normal cells and increase the specifi city for cancer cells was attempted by O.M. Friedman and A.M. Seligman at Harvard University in 1949. Based on the previous fi nding that cancer cells have higher phosphamidase activity, they predicted that if the activity of this enzyme were used to develop a drug that existed as an innocuous prodrug that becomes activated by phosphoamidases inside the cancer cells, this could specifi cally eliminate cancer cells [12]. However, it was later determined that this active form is generated by a different drug metabolic pathway, contrary to the initial assumption that phosphamidases would be involved. In other words, cyclophosphamide is mostly activated to 4-hydroxycyclophosphamide by cytochrome P450 enzymes in the liver microsomes, secreted to the bloodstream, and absorbed by cancer cells.With the therapeutic effect of cyclophosphamide verifi ed in clinical tests on patients with malignant lymphoma, it was registered as an FDA-approved lymphoma anticancer agent in 1959. Later, cyclophosphamide has been widely used in anticancer treatment for not only lymphocytic leukemia such as Hodgkin’s lymphoma, Burkitt lymphoma, childhood acute lymphoblastic leukemia, chronic granulocytic leukemia, acute myeloid leukemia, and multiple myeloma, but also solid cancers such as breast cancer, ovarian cancer, and sarcoma.
Mode of action and resistance
The chemical design of cyclophosphamide—substitution of an oxazaphosphorine ring for the methyl group of nitrogen mustard—was based on the rationale that some cancer cells express high levels of phosphamidase, which is capable of cleaving the phosphorus–nitrogen (P–N) bond, releasing nitrogen mustard.[3] Thus, cyclophosphamide was one of the first agents rationally designed to selectively target cancer cells. Although cyclophosphamide is in fact a prodrug that requires metabolic activation, the original hypothesis that it would function as targeted anticancer therapy via phosphamidase activation proved to be inaccurate.
The cytotoxic action of nitrogen mustard is closely related to the reactivity of the 2chloroethyl groups attached to the central nitrogen atom. Under physiological conditions, nitrogen mustards undergo intramolecular cyclizations through elimination of chloride to form a cyclic aziridinium (ethyleneiminium) cation.
This highly unstable cation is readily attacked on one of the carbon atoms of the three-member aziridine ring by several nucleophiles, such as DNA guanine residues (Figure 1). [5] This reaction releases the nitrogen of the alkylating agent and makes it available to react with the second 2chloroethyl side chain, forming a second covalent linkage with another nucleophile, thus interfering with DNA replication by forming intrastrand and interstrand DNA crosslinks. In contrast to aliphatic (or open chain) nitrogen mustards, cyclophosphamide is an inactive prodrug that requires enzymatic and chemical activation to release active phosphoramide mustard. Hydroxylation on the oxazaphosphorine ring by the hepatic cytochrome P450 system generates 4-hydroxycyclophosphamide, which coexists with its tautomer, aldophosphamide.
The major mechanism of cyclophosphamide detoxification is oxidation of aldophosphamide to carboxyphosphamide by cellular aldehyde dehydrogenase (AlDH). [7] withdrawal of the hydrogen adjacent to the aldehyde, by a base, is a necessary step for decomposition of aldophosphamide. Conversion of the aldehyde to carboxylic acid by AlDH makes this hydrogen less acidic for removal,[8]?subsequently releasing the active phosphoramide mustard. Thus, cellular concentrations of AlDH are serendipitously responsible for many of the differential activities of cyclophosphamide in cells. [9] Carboxyphosphamide and its degradation products are the major metabolites found in urine. [10]
Although AlDH1A1 expression is the major determinant of normal cellular sensitivity to cyclophosphamide and is associated with resistance to cyclophosphamide in tumor cell lines, [11] it has a minor role in the clinical response of cancer cells to cyclophosphamide[9, 12]. In particular, leukemia and lymphoma specimens from newly diagnosed patients rarely express high levels of AlDH isozymes[9] Increased cellular levels of glutathione and glutathione S-transferases have been shown to cause cyclophosphamide resistance in tumor cell lines, but the lack of a similar correlation in vivo suggests that this is not the major mechanism contributing to cyclophosphamide resistance[12]. The inherent sensitivity of cancer cells to undergo apoptosis following DNA damage is the most important determinant of the clinical sensitivity of cancer cells to cyclophosphamide[13, 14].
Toxicity effect
Bone marrow suppression is the most common toxic effect of cyclophosphamide. Neutropenia is dose dependent. Patients treated with low-dose cyclophosphamide should be monitored closely, although they rarely develop significant neutropenia. Leukopenia, thrombocytopenia and anemia are common after high dose cyclophosphamide administration. Rapid hematologic recovery invariably occurs within 2–3 weeks in patients with normal bone marrow reserve, regardless of the dose.
Cardiotoxicity is the dose limiting toxic effect of cyclophosphamide, and is observed only after administration of high doses. The cardiac manifestations that result from high dose cyclophosphamide are heterogeneous and range from innocuous to fatal. The most severe form is hemorrhagic necrotic perimyocarditis, with a reported incidence of <1–9% after the most commonly used high doses of cyclophosphamide (60 mg/kg daily × 2 days or 50 mg/kg daily × 4 days) [15, 16]. However, in most transplant centers the rate of hemorrhagic myocarditis is less than 0.1%. This clinical syndrome occurs abruptly within days of drug infusion and is fatal. Perimyocarditis is manifested by severe congestive heart failure accompanied by electro cardiographic findings of diffuse voltage loss, cardio megaly, pleural and pericardial effusions. Postmortem findings reveal hemorrhagic cardiac necrosis.
Gonadal failure is a major complication of cyclophosphamide administration, especially in females. The patient’s age at treatment, the cumulative dose, and the administration schedule are major determinants for this adverse effect. The risk for sustained amenorrhea in patients with lupus receiving monthly intermediate dose cyclophosphamide is 12% for women under 25 years of age, and greater than 50% for women over 30 years of age. The risk for ovarian failure following high dose cyclophosphamide administration seems to be less than that of intermediate dose.
Hemorrhagic cystitis is the most common form of cyclophosphamide bladder toxicity,[17] but bladder fibrosis and transitional or squamous cell carcinoma can also occur. Hemorrhagic cystitis can occur early or late after cyclophosphamide administration. Early onset disease, in the first few days after cyclophosphamide administration, seems to be caused by acrolein[18]. Vigorous hydration, forced diuresis and MESNA, which interacts with acrolein to form nontoxic adducts, can prevent acute hemorrhagic cystitis by limiting uroepithelial exposure to acrolein[19]. Hemorrhagic cystitis can develop weeks to months after treatment in 20–25% of patients who receive high dose cyclophosphamide.
Cyclophosphamide is carcinogenic. In addition to bladder cancer, secondary acute leukemia (often preceded by myelodysplastic syndrome) and skin cancer are the most common malignancies after cyclophosphamide therapy. The probability of acquiring a therapy-related malignancy is proportional to the length of drug exposure and cumulative dose. Therapy-related leukemia occurs in roughly 2% of patients treated with chronic cyclophosphamide, primarily in patients who have received the drug for more than 1 year[20].
Clinical efficacy
Cyclophosphamide is one of the few drugs with a broad indication for cancer. Although it is effective as a single agent in malignancies, it is usually used in combination with other antineoplastic agents. Even though it has been substituted by newer agents (such as platinums, taxanes and targeted therapies) for the treatment of many solid tumors, it is quite active for many of these indications, and there often remains limited evidence for the superiority of the newer approaches.
Cyclophosphamide based therapy is used extensively for lymphomas and is often curative for aggressive non-Hodgkin lymphoma, with Burkitt lymphoma being particularly sensitive. Although modern therapeutic regimens employ intensive cyclophosphamide based combination chemotherapy[21], in the 1960s durable complete remissions were reported following a single course of cyclophosphamide.[22] RCHoP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) remains the most commonly employed regimen for aggressive non-Hodgkin lymphoma, with cure rates of 30–40%. Many newer cyclophosphamide based multidrug combinations have been developed for aggressive non-Hodgkin lymphoma, but none have proven to be superior to CHoP.[23] Myeloablative therapy, usually including high dose cyclophosphamide, followed by BMT is the most effective treatment for relapsed aggressive non-Hodgkin lymphoma.
Cyclophosphamide, in combination with other agents, has been the mainstay of adjuvant and metastatic breast cancer chemotherapy regimens such as CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and FEC (5-fluorouracil, epirubicin, cyclophosphamide) for decades. AC (doxorubicin, cyclophosphamide) was demonstrated to be equivalent to 6 months of classic CMF in two separate National surgical Adjuvant Breast and Bowel Project (NsABP) studies[24, 25]. The addition of a sequential taxane to this adjuvant regimen further improved outcomes and has since become the standard of care for human epidermal growth factor receptor 2 (HER2) negative early-stage breast cancer.
Cyclophosphamide is the cornerstone of curative chemotherapy regimens for numerous newly diagnosed and recurrent pediatric malignancies. Combinations of carboplatin and etoposide, and vincristine, cyclophosphamide and doxorubicin (CAdo), showed 5 year overall and event free survival rates of over 90% in infants with initial localized and unresectable neuroblastoma as well as allowance for subsequent surgical excision.[27] Cyclophosphamide in combination chemotherapy regimens as an adjunct to surgery and radiation has also been used in a variety of rare cancers such as retinoblastoma, wilms tumor, and rhabdomyosarcoma as well as Ewing sarcoma.
References
Brock, N. & Wilmanns H. Effect of a cyclic nitrogen mustard-phosphamidester on experimentally induced tumors in rats; chemotherapeutic effect and pharmacological properties of B518 ASTA [German]. Dtsch. Med. Wochenschr. 83, 453–458 (1958).
Gross, R. & Wulf, G. Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren [German]. Strahlentherapie 41, 361–367 (1959).
Friedman, O. M. & Seligman, A. M. Preparation of N-phosphorylated derivatives of bis-P-chloroethylamine. J. Amer. Chem. Soc. 76, 655–658 (1954).
Arnold, H., Bourseaux, F. & Brock, N. Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B 518-ASTA) in experimental tumours of the rat. Nature 181, 931 (1958).
Dong, Q. et al. A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC). Proc. Natl Acad. Sci. USA 92, 12170–12174 (1995).
Boddy, A. v. & Yule, S. M. Metabolism and pharmacokinetics of oxazaphosphorines. Clin. Pharmacokinet. 38, 291–304 (2000).
Chen, T. L. et al. Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Drug Metab. Dispos. 25, 544–551 (1997).
Silverman, R. B. The Organic Chemistry of Enzyme-catalyzed Reactions (Academic Press, 2002).
Russo, J. E., Hilton, J. & Colvin, O. M. The role of aldehyde dehydrogenase isozymes in cellular resistance to the alkylating agent cyclophosphamide. Prog. Clin. Biol. Res. 290, 65–79 (1989).
Joqueviel, C. et al. Urinary excretion of cyclophosphamide in humans, determined by phosphorus-31 nuclear magnetic resonance spectroscopy. Drug Metab. Dispos. 26, 418–428 (1998).
Sladek, N. E. Leukemic cell insensitivity to cyclophosphamide and other oxazaphosphorines mediated by aldehyde dehydrogenase(s). Cancer Treat. Res. 112, 161–175 (2002).
Tanner, B. et al. Glutathione, glutathione S-transferase alpha and pi, and aldehyde dehydrogenase content in relationship to drug resistance in ovarian cancer. Gynecol. Oncol. 65, 54–62 (1997).
Banker, D. E., Groudine, M., Norwood, T. & Appelbaum, F. R. Measurement of spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. Blood 89, 243–255 (1997).
Zhang, J., Tian, Q., Chan, S. Y., Duan, W. & Zhou, S. Insights into oxazaphosphorine resistance and possible approaches to its circumvention. Drug Resist. Updat. 8, 271–297 (2005).
Murdych, T. & Weisdorf, D. J. Serious cardiac complications during bone marrow transplantation at the University of Minnesota, 1977–1997. Bone Marrow Transplant. 28, 283–287 (2001).
Cazin, B. et al. Cardiac complications after bone marrow transplantation. A report on a series of 63 consecutive transplantations. Cancer 57, 2061–2069 (1986).
Stillwell, T. J. & Benson, R. C. Jr Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer 61, 451–457 (1988).
Cox, P. J. Cyclophosphamide cystitis— identification of acrolein as the causative agent. Biochem. Pharmacol. 28, 2045–2049 (1979).
Haselberger, M. B. & Schwinghammer, T. L. Efficacy of mesna for prevention of hemorrhagic cystitis after high-dose cyclophosphamide therapy. Ann. Pharmacother. 29, 918–921 (1995)
Levine, E. G. & Bloomfield, C. D. Semin. Oncol. 19, 47–84 (1992).
Magrath, I. et al. J. Clin. Oncol. 14, 925–934 (1996).
Burkitt, D. Cancer 20, 756–759 (1967).
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Fisher, B. et al.. J. Clin. Oncol. 8, 1483–1496 (1990).
Fisher, B. et al. J. Clin. Oncol. 19, 931–942 (2001)
Rubie, H. et al. Med. Pediatr. Oncol. 36, 247–250 (2001).
Originator
Cytoxan,Mead Johnson,US,1959
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.
Therapeutic Function
Antineoplastic
Synthesis Reference(s)
The Journal of Organic Chemistry, 43, p. 1111, 1978 DOI: 10.1021/jo00400a019
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.
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.
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.
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.
Carcinogenicity
Cyclophosphamide is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
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.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 50-18-0 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 0 respectively; the second part has 2 digits, 1 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 50-18:
(4*5)+(3*0)+(2*1)+(1*8)=30
30 % 10 = 0
So 50-18-0 is a valid CAS Registry Number.
InChI:InChI=1/C7H15Cl2N2O2P.H2O/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14;/h1-7H2,(H,10,12);1H2
50-18-0Relevant articles and documents
Process for preparing cyclophosphamide, intermediates, and monohydrate thereof
-
Page/Page column 4; 5, (2019/11/28)
The present disclosure provides a process for preparing cyclophosphamide, intermediate, and the monohydrate thereof.
Synthetic method for cyclophosphoramide
-
Paragraph 0026; 0029; 0030; 0033-0037, (2019/04/11)
The invention provides a synthetic method for cyclophosphoramide. According to the synthetic method, phosphorus oxychloride is slowly added into a mixed solution of dichloroethane, polyphosphoric acidand acetic anhydride, 3-amino propyl alcohol is dropwise added so as to prepare 2-chloro-2-oxo-[1.3.2] oxygen-nitrogen-phosphorus heterocyclic hexane; and dichloroethane and a 5a molecular sieve areadded, ammonia gas is introduced, heating is carried out at 4 atm to reach 120 DEG C, reaction is carried out for 2-2.5 hours, and treatment is carried out so as to obtain the cyclophosphoramide. Themethod has the advantages that the reaction conditions are relatively mild, and the yield and the content are high.
Cyclophosphamide synthetic method
-
Paragraph 0030; 0031; 0032, (2018/06/15)
The invention provides a cyclophosphamide synthetic method. The cyclophosphamide synthetic method is characterized by comprising the following steps: adding dichloroethane into a reaction flask; slowly adding phosphorus oxychloride; starting to drip a 3-amino propanol and triethylamine mixed solvent; performing a reaction after finish of dripping to prepare a 2-chloro-2-oxo-[1,3,2] oxaphosphorinane solution; then transferring the 2-chloro-2-oxo-[1,3,2] oxaphosphorinane solution into the pressure reaction flask; adding triethylamine; controlling the temperature; continuously pumping into ammonia gas; keeping a certain pressure for a reaction; separating an organic phase from a reaction liquid; performing vacuum concentration on the organic phase till the organic phase is dry; adding a solvent; and performing crystallization to obtain cyclophosphamide. The cyclophosphamide synthetic method is high in yield, less in byproduct, simple in step and convenient to operate and facilitates industrial production.
Solvent-Free Process for the Preparation of Cyclophosphamide
-
Paragraph 0039; 0040; 0041; 0042, (2014/03/25)
This invention discloses a solvent-free process for the preparation of cyclophosphamide. According to this invention, there is no solvent used during the reaction step for preparing cyclophosphamide, so that the total volume of the reaction for preparing cyclophosphamide can be reduced and the manufacture of cyclophosphamide can become more efficient. Furthermore, the above solvent-free process for the preparation of cyclophosphamide is more simply operated, more economic, and more environmental friendly than the preparation of cyclophosphamide in the prior art.
Antitumor activities of some new 1,3,2-oxaza- and 1,3,2-diazaphosphorinanes against K562, MDA-MB-231, and HepG2 cells
Gholivand, Khodayar,Ghaziani, Fatemeh,Shariatinia, Zahra,Dorosti, Nilufar,Mirshahi, Manouchehr,Sarikhani, Sina
, p. 2185 - 2195 (2012/11/07)
New X-substituted 1,3,2-oxazaphosphorinanes, where X = NHC 6H5 (1), NHC6H4S(O) 2NH2-4 (2), NHC6 H4OCH3-4 (3), NHC6H4NO2-4 (4), OC6H 4CH3-4 (5), NHC(O)C6H4NO 2-4 (6), plus one X-substituted 1,3,2-diazaphosphorinane, where X = NHC6H4S(O)2NH2-4 (7), were synthesized and characterized by NMR, IR spectroscopy, and elemental analysis. The antitumor activities of these compounds, cyclophosphamide (CP), sulfanilamide (SA), and two X-substituted 5,5-dimethyl-1,3,2- diazaphosphorinanes, where X = NHC6H5 (8) OC 6H4CH3-4 (9), were evaluated by cell culture on K562, MDA-MB-231, and HepG2 cell lines using MTT cell proliferation assay. The IC50 values for CP and compounds 1-9 were in the range of 0.06 μM (for inhibition of HepG2 cells by compound 3) to 3.17 μM (for inhibition of HepG2 cells by compound 8). It was found that compounds 2 and 7 containing sulfonamide substituent and also SA itself are the best candidates for antitumor activity very close to CP. Springer Science+Business Media, LLC 2011.
THERAPEUTIC FOR HEPATIC CANCER
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, (2011/02/18)
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
Therapeutic use of at least one botulinum neurotoxin in the treatment of pain induced by at least one anti-neoplastic agent
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, (2010/04/23)
The present invention relates to a method of treating or preventing pain or pains induced by an anti-neoplastic agent, comprising the step of administering an effective amount of at least one botulinum neurotoxin to a patient in need thereof.
Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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, (2010/05/13)
Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
Method and compositions for the treatment of pruritus
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, (2008/06/13)
A composition for treating pruritus, comprising a compound selected from the group consisting of opioid receptor antagonists, opioid receptor agonists/antagonists, and pharmaceutically acceptable salts thereof, and a compound useful in treating the cause of the pruritus. This invention also relates to a method of treating pruritus using such compositions, and a method for preparing these compositions.
A new method for the preparation of ifosfamide and cyclophosphamide
Neda,Sonnenburg,Schmutzler,Niemeyer,Kutscher,Engel,Kleemann
, p. 943 - 946 (2007/10/03)
The reaction of 2-chloro-3-(2-chloroethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide 1 and 2-chloro-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide 2 with 2-(trimethylsilyloxy)ethylamine 3 and bis-[2-(trimethylsiloxy)ethyl]amine 4, respectively, yielded the trimethylsilylated compounds 5 and 6, analogous to ifosfamide and cyclophosphamide. The reaction of 5 and 6 with 2-chloro-1,3,5-trimethyl-1,3,5-triaza-2-phosphorin-4,6-dione 7 led to the diphosphorus compounds 8 and 9 which could be transformed to ifosfamide 11 and cyclophosphamide 12 by treatment with sulfuryl chloride. This synthesis shows that the alkylating agents 2-chloroethylammonium chloride and bis-(2-chloroethyl)ammonium chloride can be avoided and the chlorine atom can be introduced in the final reaction step of the synthesis of 11 and 12.
