Cyclophosphamide: Encyclopedia - Cyclophosphamide

Cyclophosphamide

Cyclophosphamide

Cyclophosphamide is a nitrogen mustard alkylating agent, 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.

Cyclophosphamide - Uses

The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of lymphomas, some forms of leukemia and some solid tumors.

In addition, its use is becoming more common in autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. Systemic lupus erythematosus (SLE) with severe lupus nephritis, for example, may respond to pulsed cyclophosphamide.

Cyclophosphamide - Pharmacokinetics

Cyclophosphamide is converted by mixed function oxidase enzymes in the liver to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide. 4-hydroxycyclophosphamide 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.

Cyclophosphamide - Mode of action

The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells which have low levels of aldehyde dehydrogenase.

Phosphoramide mustard forms DNA crosslinks between and within DNA strands. This leads to cell death.

Cyclophosphamide has relatively little typical chemotherapy toxicity, as ALDH is present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium, protecting these tissues against phosphoramide mustard.

Cyclophosphamide - Side-effects

Side-effects include chemotherapy-induced nausea and vomiting (CINV), bone marrow suppression, alopecia (hair loss) 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.

Cyclophosphamide - History

Cyclophosphamide and the related nitrogen mustard-derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). 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. Brock and his team synthesised more than 1,000 candidate oxazophosphorine compounds, eventually finding the drug cyclophosphamide (Brock 1996).

Cyclophosphamide - Reference

• Brock N. The history of the oxazaphosphorine cytostatics. Cancer 1996;78:542-7. PMID 8697402.

ALKYLATING AGENTS: {Busulfan} {Carboplatin} {Chlorambucil} {Cisplatin} {Cyclophosphamide} {Ifosfamide} {Melphalan} {Mechlorethamine} {Oxaliplatin} {Uramustine}

ANTI-METABOLITES: {Azathioprine} {Capecitabine} {Cytarabine} {Fludarabine} {Fluorouracil} {Gemcitabine} {Methotrexate} {Pemetrexed}

PLANT ALKALOIDS: {Docetaxel} {Etoposide} {Paclitaxel} {Vinblastine} {Vincristine} (Vinorelbine)

TOPOISOMERASE INHIBITORS: {Irinotecan} {Topotecan}

ANTITUMOUR ANTIBIOTICS: {Bleomycin} {Daunorubicin} {Doxorubicin} {Epirubicin} {Hydroxyurea} {Idarubicin} {Mitomycin} {Mitoxantrone}

Category: Chemotherapeutic agents

Adapted from the Wikipedia article "Cyclophosphamide", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki