It07:Cylcophosphamide

Cyclophosphamide

Cyclophosphamide is a nitrogen mustard alkylating agant, and is used to treat many cancers and a few autoimmune disorders.

Image of Cyclophosphamide

Main Uses

Cyclophosphamide is used in chemotherapy to fight against certain types of leukemia, solid tumours and lymphomas. It works by slowing or stopping cell growth and decreasing the immune systems response to diseases. For autoimmune disorders, it can be used when disease-modifying antirheumatic drugs have not been successful.

It can be administered via injection into a vein, an intravenous drip or oral tablets. As a solution it appears colourless from a white powder, and the tablets can be white or pink.

Possible side effects include lowered resistance to infection (due to a decrease in production of white blood cells from the bone marrow), bruising and bleeding (due to a decrease in production in platelets, which help blood clot), anaemia (low number of red blood cells), nausia, vomiting, loss of appetite, irritation to the bladder and hair loss.

Interactions with other drugs can cause more problems. The effect of reducing the production of red blood cells from the bone marrow is increased by allopurinol. Cyclophosphamide can also increase the risk of heart failure from taking doxorubicin, as well as increasing the action of blood thinners and decreasing the effect of quinolone antibiotics.

How it works

Cyclophosphamide is converted in the liver by mixd function oxidase enzymes. The product of this is active metabolites, mainly 4-hydroxycyclophosphamide. This exists in equilibrium with aldophosphamide (its tautomer). The enzyme aldehyde dehydrogenase (ALDH) oxidises this tautomer to produce carboxyphosphamide. A little of the aldophosphamide is converted into acrolein and phosphoramide mustard. Acreolein is an unwanted side product as it is toxic to the bladder epithelium and can lead to hemorrhagic cystitis, this is prevented by hydration and mesna. The phosphoramide mustard causes the most the main effect of cyclophosphamide, and is only formed in cells with low levels of ALDH. It works by forming DNA crosslinks at guanine N-7 positions, between and within DNA strands (interstrand and intrastrand crosslinkages, respectively). This leads to cell death.

Cyclophosphamide (CPA) is the prototypical antitumor agent activated by oxidation in situ. CPA is a modified nitrogen mustard (n,N-bis(2-chloroethyl)amine). CPA is stable to cellular nucleophiles as the electron density at the mustard nitrogen is decreased due to the cyclic phosphamide and this decreases the alkylation reactivity of the agent. If there is enough electron density present at the nitrogen, the nitrogen mustard is an active alkylation agent as aziridinium ino formation can be induced. The in situ activation begins in the liver, where the CPA is hydroxylated at C4 by the cytochrome P450. An equilibrium of hydroxy-CPA and its ring-opened isomer is generated. The hydoxy-CPA converts reversibly to thio-CPA with free thiols of plasma proteins to be transported from the liver. In the cells, 3’,5’-exonucleases (in particular those associated with DNA polymerase) catalyses the conversion of ring-opened hydroxyl-CPA to the active alkylating form. Greater concentrations of phosphoramide mustard are formed in rapidly dividing tumor cells as there is a greater rate of DNA synthesis. The mustard nitrogen now has an increased electron density so the formation of aziridinium alkylating agents, which react with DNA bases, can be induced.

Mechanism for Activation

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References

1. http://organicdivision.org/essays_2001/wolkenberg.pdf
2. http://en.wikipedia.org/wiki/Cyclophosphamide
3. http://www.cancerbackup.org.uk/Treatments/Chemotherapy/Individualdrugs/Cyclophosphamide
4. http://www.medicinenet.com/cyclophosphamide/article.htm
5. http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s052cycl.pdf

It07:Cylcophosphamide
General
Systematic name	N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
Other names	Cytoxan, Neosar, Cytophosphane
Molecular formula	C7H15CL2N2O2P
SMILES	{{{SMILES}}}
Molar mass	261.085 gmol-1
Appearance	{{{Appearance}}}
CAS number	{{{CASNo}}}
Properties
Density & phase	{{{Density}}} g/cm³
Solubility in water	{{{Sol_Water}}} g/100 ml (25°C)
Melting point	45.5-53 degrees C
Boiling point	{{{Bp}}} K
Acidity (pKa)	{{{pKa}}}
Basicity (pKb)	{{{pKb}}}
Chiral rotation [α]D	{{{Rotation}}}°
Viscosity	{{{Viscosity}}} cP at 25°C
Hazards
MSDS	http://www.sciencelab.com/xMSDS-Cyclophosphamide_Monohydrate-9923635
Main hazards	{{{Hazards}}}
NFPA 704	{{{NFPA}}}
Flash point	{{{Fp}}}°C
R/S statement	R: {{{R-S}}} S: ?
RTECS number	{{{RTECS}}}
Supplementary data page
Structure and properties	n, εr, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references