Cyclophosphamide

Uses

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.

Metabolism

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 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.

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.

History

Cyclophosphamide and the related nitrogen mustard 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.