Cyclophosphamide: Effects, Uses & Risks

Cyclophosphamide is a drug in the cytostatic drug class. It is used to treat cancer and to treat severe autoimmune diseases.

What is cyclophosphamide?

Cyclophosphamide is used to treat cancers and to treat severe autoimmune diseases. Cyclophosphamide is a drug with alkylating activity. Alkylating agents are chemical substances that can introduce alkyl groups into DNA. Cyclophosphamide belongs to the group of mustard gas-nitrogen compounds and thus to the cytostatics. Cytostatics are drugs that inhibit cell growth and/or cell division. They are used in particular to treat cancer as part of chemotherapy. In their search for a cancer drug, chemists at the pharmaceutical company Asta Medica produced a derivative of phosphamide mustard. Based on this, cyclophosphamide was discovered in 1956. The drug was finally patented in 1962. Today, cyclophosphamide is produced from bisamine and phosphorus oxychloride. Phosphoric acid amide dichloride is formed in the process. In the reaction with 3-amino-1-propanol, in the presence of the basic solvent triethylamine, the substance mixture cyclophosphamide is formed.

Pharmacological action

Cyclophosphamide belongs to the class of prodrugs. Prodrugs are inactive precursors of drugs that develop their effects only through various metabolic processes in the body. The cytotoxic effect of cyclophosphamide is only activated in the liver. Thus, cyclophosphamide is in itself a substance that does not initially have a cytostatic effect. The bioavailability after oral administration is over 75 percent. The half-life is between three and twelve hours. In the cells of the liver, hydroxylation of the drug occurs by the cytochrome P450 system. This produces 4-hydroxycyclophosphamide aldophosphamide. This cleaves acrolein, thereby becoming phosphoramide mustard. Phosphoramide mustard is an alkylane with an active bifunction. It damages the DNA of the cells by so-called cross links. Cross links are cross connections between the individual DNA strands. Due to the DNA damage, the cells can no longer divide. The proliferation of the cells is thus inhibited.

Medical application and use

Cyclophosphamide is used to treat various cancers as a cytostatic drug. Usually, the drug is combined with other cytostatic drugs in therapy. In adults, cyclophosphamide is used to treat Hodgkin’s and non-Hodgkin’s lymphomas. Hodgkin’s and non-Hodgkin’s lymphomas are malignant diseases of the lymphatic system. In combination with methotrexate and 5-fluorouracil, cyclophosphamide is administered in the so-called CMF regimen in the treatment of breast cancer (mammary carcinoma). Other indications for cyclophosphamide include soft tissue sarcomas and Ewing’s sarcoma. Ewing’s sarcoma is the second most common form of bone cancer in children. Cyclophosphamide is also used to mobilize stem cells for stem cell apheresis and as a conditioning treatment prior to immunotherapies and stem cell transplants. In children, not only Ewing’s sarcoma is treated with cyclophosphamide. Other indications for the drug include medulloblastoma, neuroblastoma, retinoblastoma, and severe aplastic anemia. However, cyclophosphamide is not used exclusively in cancer therapy. Severe courses of autoimmune diseases such as granulomatosis, rheumatoid arthritis or systemic lupus erythematosus (SLE) are also treated with cyclophosphamide. Several studies have also shown an improvement of symptoms in multiple sclerosis. Currently, however, there is no approval for the treatment of multiple sclerosis.

Risks and side effects

Cyclophosphamide should not be used during pregnancy. Adequate contraception should be used during therapy so that pregnancy does not occur under any circumstances. In addition, vaccinations with live vaccines must not be given during treatment with cyclophosphamide. Otherwise, potentially life-threatening infections could occur due to the immunosuppressive effect of the drug. In the course of therapy with cyclophosphamide, a reduction in white blood cells (leukocytes) may occur. Common side effects also include nausea and hair loss. Cumulative doses of cyclophosphamide increase the risk of leukemia and bladder tumors.Hemorrhagic inflammation of the bladder (cystitis) may occur in the course of chemotherapy with the drug. For this reason, the drug mercapto-ethanesulfonate sodium (mesna) is administered in parallel with cyclophosphamide. Whether this administration is really helpful is currently still controversial. Especially in the case of lower doses of cyclophosphamide, for example in the therapy of autoimmune diseases, the administration of mesna is usually not necessary. Following the administration of cyclophosphamide, infertility may occur in both men and women. Therefore, prior to therapy, cryopreservation of eggs and sperm is recommended for patients who wish to have children.