Cyclophosphamide
Encyclopedia
Cyclophosphamide 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.
s, some forms of brain cancer 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 disease
s where disease-modifying antirheumatic drug
s (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."
enzyme
s 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 immunomodulator
y 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:
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.
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 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)..
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 carcinogen
ic, 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:
-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.
Nitrogen mustard
The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, in principle these compounds can also be deployed as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by...
alkylating agent
Alkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....
, from the oxazophorines group.
An alkylating agent adds an alkyl group (CnH2n+1) to DNA. It attaches the alkyl group to the guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
base of DNA, at the number 7 nitrogen atom of the imidazole ring.
It is used to treat various types of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and some autoimmune disorders. It is a "prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
"; it is converted in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
to active forms that have chemotherapeutic
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
activity.
Uses
The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of lymphomaLymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s, some forms of brain cancer leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
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
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
to various diseases and conditions. Therefore, it has been used in various non-neoplastic autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s where disease-modifying antirheumatic drug
Disease-modifying antirheumatic drug
Disease-modifying antirheumatic drugs is a category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression...
s (DMARDs) have been ineffective. For example, systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(SLE) with severe lupus nephritis
Lupus nephritis
Lupus nephritis is an inflammation of the kidney caused by systemic lupus erythematosus , a disease of the immune system. Apart from the kidneys, SLE can also damage the skin, joints, nervous system and virtually any organ or system in the body....
may respond to pulsed cyclophosphamide (in 2005, however, standard treatment for lupus nephritis changed to mycophenolic acid
Mycophenolic acid
Mycophenolic acid INN or mycophenolate is an immunosuppressant drug used to prevent rejection in organ transplantation. It inhibits an enzyme needed for the growth of T cells and B cells. It was initially marketed as the prodrug mycophenolate mofetil to improve oral bioavailability. More...
(MMF) from cyclophosphamide). Cyclophosphamide is also used to treat minimal change disease
Minimal change disease
Minimal Change Disease is a disease of the kidney that causes nephrotic syndrome and usually affects children .-Epidemiology:...
, severe rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, Wegener's granulomatosis
Wegener's granulomatosis
Wegener's granulomatosis , more recently granulomatosis with polyangiitis , is an incurable form of vasculitis that affects the nose, lungs, kidneys and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression...
(with trade name Cytoxan), and multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
(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 oxidaseOxidase
An oxidase is any enzyme that catalyzes an oxidation-reduction reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water or hydrogen peroxide ....
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s in the liver to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide
4-Hydroxycyclophosphamide
4-Hydroxycyclophosphamide is the main, active metabolite of cyclophosphamide....
, which exists in equilibrium
Chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which the concentrations of the reactants and products have not yet changed with time. It occurs only in reversible reactions, and not in irreversible reactions. Usually, this state results when the forward reaction proceeds at the same...
with its tautomer
Tautomer
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...
, aldophosphamide. Most of the aldophosphamide is oxidised by the enzyme aldehyde dehydrogenase
Aldehyde dehydrogenase
Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes.- Function :Aldehyde dehydrogenase is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized by the body’s muscle and heart...
(ALDH) to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard and acrolein
Acrolein
Acrolein is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity...
. Acrolein is toxic to the bladder
Urinary bladder
The urinary bladder is the organ that collects urine excreted by the kidneys before disposal by urination. A hollow muscular, and distensible organ, the bladder sits on the pelvic floor...
epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
and can lead to hemorrhagic cystitis
Hemorrhagic cystitis
Hemorrhagic cystitis or Haemorrhagic cystitis is diffuse inflammation of the bladder leading to dysuria, hematuria, and hemorrhage. The disease can occur as a complication of cyclophosphamide, ifosfamide and radiation therapy...
. This can be prevented through the use of aggressive hydration and/or mesna
Mesna
Mesna is an organosulfur compound. It is used in cancer chemotherapy involving cyclophosphamide and ifosfamide as an adjuvant. It is marketed by Baxter as Uromitexan and Mesnex...
.
Recent clinical studies have shown that cyclophosphamide induce beneficial immunomodulator
Immunomodulator
An immunomodulator, also known as an immunotherapy is a substance which has an effect on the immune system.- Immunosuppressants :Inhibits immune response in organ transplantation and autoimmune diseases.- Immunostimulants :...
y 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:
- 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.
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 death.
Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and intestinal
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. 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-effectsAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
include chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea...
(CINV), bone marrow suppression
Bone marrow suppression
Bone marrow suppression or myelotoxicity or myelosuppression, is the decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...
, stomach ache, diarrhea, darkening of the skin/nails, alopecia
Alopecia
Alopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...
(hair loss) or thinning of hair, changes in color and texture of the hair, and lethargy. Hemorrhagic cystitis
Hemorrhagic cystitis
Hemorrhagic cystitis or Haemorrhagic cystitis is diffuse inflammation of the bladder leading to dysuria, hematuria, and hemorrhage. The disease can occur as a complication of cyclophosphamide, ifosfamide and radiation therapy...
is a frequent complication, but this is prevented by adequate fluid intake and Mesna
Mesna
Mesna is an organosulfur compound. It is used in cancer chemotherapy involving cyclophosphamide and ifosfamide as an adjuvant. It is marketed by Baxter as Uromitexan and Mesnex...
(sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds acrolein
Acrolein
Acrolein is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity...
.
Cyclophosphamide is itself carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic, potentially causing transitional cell carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
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
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
, 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
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
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 hematuriaHematuriaIn medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
, - 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 mustardNitrogen mustard
The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, in principle these compounds can also be deployed as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by...
-derived alkylating agent ifosfamide
Ifosfamide
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
were developed by Norbert Brock and ASTA (now Baxter
Baxter International
Baxter International Inc. , is an American health care company with headquarters in Deerfield, Illinois. The company primarily focuses on products to treat hemophilia, kidney disease, immune disorders and other chronic and acute medical conditions...
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
Active transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
into the cancer cells. Once in the cells, the pro-drug was enzymatically
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
converted into the active, toxic form.
The first clinical trials were published at the end of the 1950s.