Cyclophosphamide ( CP), also known as cytophosphane among other names,[ As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma.][ As an immune suppressor it is used in nephrotic syndrome, ANCA-associated vasculitis, and following organ transplant, among other conditions.][
]
Most people develop side effects.[ Common side effects include leukopenia, loss of appetite, vomiting, hair loss, and bleeding from the bladder.][ Other severe side effects include an increased future risk of cancer, infertility, allergic reactions, and pulmonary fibrosis.][ Cyclophosphamide is in the alkylating agent and nitrogen mustard family of medications.][ It is believed to work by interfering with the duplication of DNA and the creation of RNA.][
]
Cyclophosphamide was approved for medical use in the United States in 1959.
Medical uses
Cyclophosphamide is used to treat cancers and autoimmune diseases. It is used to quickly control the disease. Due to its toxicity, it is replaced as soon as possible by less toxic drugs. Regular and frequent laboratory evaluations are required to monitor kidney function, avoid drug-induced bladder complications and screen for bone marrow toxicity.
Cancer
The main use of cyclophosphamide is with other chemotherapy agents in the treatment of , some forms of brain cancer, neuroblastoma, leukemia and some solid tumors.
Autoimmune diseases
Cyclophosphamide decreases the immune system's response, and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat minimal change disease,
Because of its potential side effects such as amenorrhea or ovarian failure, cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or azathioprine.
AL amyloidosis
Cyclophosphamide, used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as an Off-label use of AL amyloidosis. It appears to be an alternative to the more traditional treatment with melphalan in people who are ill-suited for autologous stem cell transplant.
Graft-versus-host disease
Graft-versus-host disease (GVHD) is a major barrier for allogeneic stem cell transplant because of the immune reactions of donor T cell against the person receiving them. GVHD can often be avoided by T-cell depletion of the graft.
Contraindications
Like other alkylating agents, cyclophosphamide is teratogenic and contraindicated in pregnant women (pregnancy category D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide include lactation, active infection, neutropenia or bladder toxicity.
Cyclophosphamide is a pregnancy category D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including growth restriction, ear and facial abnormalities, absence of digits and hypoplasia.
Side effects
Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting,
Pulmonary injury appears rare,
High-dose intravenous cyclophosphamide can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by intravenous fluids administered to prevent drug-induced cystitis.
Bladder bleeding
Acrolein is toxic to the urinary bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria.
Infection
Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial, mycosis and opportunistic infections.
Infertility
Cyclophosphamide has been found to significantly increase the risk of premature menopause in females and of infertility in males and females, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary, but can be permanent.
Cancer
Cyclophosphamide is and may increase the risk of developing , leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies.
This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including radiotherapy), treatment length and intensity. For some regimens, it is rare. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) carries an AML risk of less than 1/2000, with some studies finding no increased risk compared to background. Other treatment regimens involving higher doses may carry risks of 1–2% or higher.
Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk falls to background. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML.
Pharmacology
Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase (cytochrome P450 system) in the liver to active metabolites.
It is specifically in the oxazaphosphorine group of medications.
Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction.
Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine.
Mechanism of action
The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.
Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestine epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation.
Cyclophosphamide induces beneficial effects in adaptive immunotherapy. Suggested mechanisms include:
-
Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
-
Induction of T cell growth factors, such as type I IFNs, and/or
-
Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.
Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity.
History
As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications,
Cyclophosphamide and the related nitrogen mustard–derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology).
Society and culture
The abbreviation CP is common, although abbreviating drug names is not best practice in medicine.
Research
Because of its impact on the immune system, it is used in animal studies. Rodents are injected intraperitoneally with either a single dose of 150 mg/kg or two doses (150 and 100 mg/kg) spread over two days.
-
The EPA may be concerned about potential human pathogenicity of an engineered microbe when conducting an MCAN review. Particularly for bacteria with potential consumer exposure they require testing of the microbe on immuno-compromised rats.
-
Cyclophosphamide provides a positive control when studying immune-response of a new drug.
External links
-
Novel cyclic phosphoric acid ester amides, and the production thereof. (patent for cyclophosphamide).
