Everything about Cyclophosphamide totally explained
Cyclophosphamide (the generic name for Cytoxan, Neosar), also known as cytophosphane, is a
nitrogen mustard alkylating agent, from the oxazophorines group. It is used to treat various types of
cancer and some
autoimmune disorders. It is a "
prodrug"; it's 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. It also works by decreasing the immune system's response to various diseases. 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. In 2005, however, standard treatment for lupus nephritis changed to
MMF from cyclophosphamide.
Cyclophosphamide is also used to treat
Minimal Change Disease and rheumatoid arthritis. It is still used for
Wegener's granulomatosis.
The trade name is Endoxan.
Pharmacokinetics/Pharmacodynamics
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.
Recent clinical studies have shown that cyclophosphamide induce beneficial
immunomodulatory effects in the context of adoptive 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:
- 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 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.
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 ALDH.
Phosphoramide mustard forms DNA crosslinks between (interstrand crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions. This 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 doesn't give rise to the toxic metabolites (phosphoramide mustard and acrolein).
Side-effects
Many people taking cyclophosphamide don't 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), 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. Although it's used to treat cancer, it may increase the risk of developing another form of cancer, sometimes months to years after treatment.
Other (serious) side effects include:
pink/bloody urine,
unusual decrease in the amount of urine,
mouth sores,
unusual tiredness or weakness,
joint pain,
easy bruising/bleeding,
stopping of menstrual periods,
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.
Further Information
Get more info on 'Cyclophosphamide'.
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