Cyclophosphamide

Cyclophosphamide (INN, trade names Endoxan, Cytoxan, Neosar, Procytox, Revimmune), also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group.

An alkylating agent adds an alkyl group (CnH2n+1) to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring.

It is 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.

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. It is a chemotherapy drug that works by slowing or stopping cell growth. Cyclophosphamide also decreases the immune system's response to various diseases and conditions. Therefore, it has been used in various non-neoplastic autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus (SLE) with severe lupus nephritis may respond to pulsed cyclophosphamide (in 2005, however, standard treatment for lupus nephritis changed to mycophenolic acid (MMF) from cyclophosphamide). Cyclophosphamide is also used to treat minimal change disease, severe rheumatoid arthritis, Wegener's granulomatosis (with trade name Cytoxan), and multiple sclerosis (with trade name Revimmune).

A 2004 study showed that the biological actions of cyclophosphamide are dose-dependent. At higher doses, it is associated with increased cytotoxicity and immunosuppression, while at low continuous dosage it shows immunostimulatory and antiangiogenic properties. A 2009 study of 17 patients with docetaxel-resistant metastatic hormone refractory prostate cancer showed a Prostate-specific antigen (PSA) decrease in 9 of the 17 patients. Median survival was 24 months for the entire group, and 60 months for those with a PSA response. The study concluded that low-dose cyclophosphamide "might be a viable alternative" treatment for docetaxel-resistant MHRPC and "is an interesting candidate for combination therapies, e.g., immunotherapy, tyrosine kinase inhibitors, and antiangiogenisis."

Pharmacokinetics/Pharmacodynamics
Cyclophosphamide is converted by mixed function oxidase enzymes in the liver to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide, which 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. Recent clinical studies have shown that cyclophosphamide induce beneficial immunomodulatory effects in the context of adaptive immunotherapy. Although the mechanisms underlying these effects are not fully understood, several mechanisms have been suggested based on potential modulation of the host environment, including:
 * 1) Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
 * 2) Induction of T cell growth factors such as type I IFNs, and/or
 * 3) Enhanced grafting of adoptively transferred tumor-reactive effector T cells by the creation of an immunologic space niche.

Thus, cyclophosphamide pre-conditioning 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 anti-tumor immunity.

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 between (interstrand crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions. This is irreversible and leads to cell death.

Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects phosphoramide mustard and acrolein by converting aldophosphamide to carboxyphosphamide that does not give rise to the toxic metabolites (phosphoramide mustard and acrolein)..

Side-effects
Many people taking cyclophosphamide do have serious side effects. Side-effects include chemotherapy-induced nausea and vomiting (CINV), bone marrow suppression, stomach ache, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, 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. It can lower the body's ability to fight an infection. It can cause temporary or (rarely) permanent sterility. A serious potential side-effect is Acute Myeloid Leukemia, referred to as secondary AML, due to it occurring secondarily to the primary disease being treated. The risk may be dependent on dose and a number of other factors, including the condition being treated, other agents or treatment modalities used (including radiotherapy), treatment intensity and length of treatment. For some regimens it is a very rare occurrence. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) seems to carry an AML risk of less than 1/2000th, with some studies even finding no increased risk compared to the background population. Other treatment regimens involving higher doses may carry risks of 1-2% or higher, depending on regimen. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After 9 years, the risk has fallen to the level of the regular population. 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.

Other (serious) side effects include:
 * gross and microscopic hematuria,
 * unusual decrease in the amount of urine,
 * mouth sores,
 * unusual tiredness or weakness,
 * joint pain,
 * easy bruising/bleeding,
 * existing wounds that are slow healing.

History
Cyclophosphamide and the related nitrogen mustard-derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds. 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. The first clinical trials were published at the end of the 1950s.