Cyclophosphamide is used to treat cancers andautoimmune 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 forbone marrow toxicity.[citation needed]
Like other alkylating agents, cyclophosphamide isteratogenic and contraindicated in pregnant women (pregnancy category D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide includelactation, active infection,neutropenia or bladder toxicity.[7]
Cyclophosphamide is apregnancy category D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment ofcancer orlupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", includinggrowth restriction, ear and facial abnormalities, absence of digits andhypoplastic limbs.[17]
Pulmonary injury appears rare,[21] but can present with two clinical patterns: an early, acutepneumonitis and a chronic, progressivefibrosis.[22]Cardiotoxicity is a major problem with people treated with higher dose regimens.[23]
High-dose intravenous cyclophosphamide can cause thesyndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatalhyponatremia when compounded by intravenous fluids administered to prevent drug-induced cystitis.[24] While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with the lower doses used in the management of inflammatory disorders.[25]
Acrolein is toxic to thebladderepithelium and can lead tohemorrhagic cystitis, which is associated with microscopic or grosshematuria and occasionallydysuria.[26] Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage andmesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein.[27] Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management oflupus nephritis.[28]
Cyclophosphamide has been found to significantly increase the risk ofpremature menopause in females and ofinfertility 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.[32] The use ofleuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.[33]
This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (includingradiotherapy), treatment length and intensity. For some regimens, it is rare. For instance,CMF-therapy forbreast 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 amyelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complexcytogenetics, which carries a worse prognosis thande novo AML.[citation needed]
Oral cyclophosphamide is rapidly absorbed and then converted by mixed-functionoxidaseenzymes (cytochrome P450 system) in the liver to active metabolites.[37][38] The main active metabolite is4-hydroxycyclophosphamide, which exists inequilibrium with itstautomer, aldophosphamide. Most of the aldophosphamide is then oxidised by the enzymealdehyde dehydrogenase (ALDH) to makecarboxycyclophosphamide. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein.[39] The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross theplacenta and are known to be present inbreast milk.[40]
It is specifically in the oxazaphosphorine group of medications.[41]
Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction.[42] Drugs altering hepatic microsomal enzyme activity (e.g.,alcohol,barbiturates,rifampicin, orphenytoin) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of the drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g.corticosteroids,tricyclic antidepressants, orallopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.[43]
The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels ofALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands atguanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cellapoptosis.[46]
Cyclophosphamide has relatively little typicalchemotherapy toxicity as ALDHs are present in relatively large concentrations inbone marrow stem cells,liver andintestinalepithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by convertingaldophosphamide tocarboxycyclophosphamide 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 subsequentalkylation.[26][47][48]
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, cyclophosphamidepreconditioning 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 activevaccination strategies, inducing objective antitumor immunity.
As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications,
Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954[50] ...It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content. However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxicin vitro (footnote omitted), but to have a low therapeutic indexin vivo.[51]
Cyclophosphamide and the relatednitrogen mustard–derived alkylating agentifosfamide were developed by Norbert Brock and ASTA (nowBaxter Oncology).[52] Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.[53] They converted the base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequentlyactively transported into cancer cells. Once in the cells, the prodrug wasenzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.[54][55][56] In 1959 it became the eighth cytotoxic anticancer agent to be approved by theFDA.[26]
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.[58] This can be used for applications such as:
TheEPA 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.[59]
Cyclophosphamide provides a positive control when studying immune-response of a new drug.[60]
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