Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Cyclophosphamide cyc is an alkylating agent that was introduced into clinical practice as a chemotherapeutic agent but has also been used to treat a number of systemic autoimmune diseases. Pdf cyclophosphamide mechanism of action in preclinical tecemotide studies find, read and cite all the research you need on researchgate. Cyclophosphamide mechanism of action in preclinical tecemotide studies ken hance1, robert tighe1, jin qi1, william hastings1, guozhong qin1, bo marelli1, hong wang1, huakui yu1, yanping zhang1, xiaomei xu1, wilson guzman1, masie wong1, giorgio kradjian1, beatrice brunkhorst1, helen sabzevari1, yan lan1, robert hofmeister1, michael wolf2 from. Rituximab versus cyclophosphamide for ancaassociated. Cyclophosphamide is commonly used with doxorubicin hydroxydaunorubicin, vincristine oncovin, and prednisone known as the chop regimen, with or without other agents, in the treatment of various types of intermediategrade nonhodgkin lymphoma. An activated form of cyclophosphamide, phosphoramide mustard, alkylates, or binds, to dna. Pdf cyclophosphamide cpa is a nitrogen alkylating agent used for.
The activation mechanism is believed to require an initial oxidative. Cyclophosphamide exhibit the bimodal mechanism of antitumor action with cardiotoxic effect and immunomodulatory effects. Cyclophosphamide is the generic name of the prescription drug cytoxan, a chemotherapy drug for people with certain cancers. In order to work, cyclophosphamide first is converted by the liver into two chemicals, acrolein and phosphoramide. Caution should be exercised when handling and preparing cyclophosphamide for injection, usp lyophilized powder, or bottles containing cyclophosphamide tablets. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. Jun 21, 2019 cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by cyp2b6. Nov 01, 2019 women treated with cyclophosphamide injection may go through menopause at a younger age than normal. Cyclophosphamide is an alkylating drug indicated for treatment of.
In the liver, cyclophosphamide is converted to active metabolites including phosphoramide mustard, which binds to and crosslinks dna and rna, thereby inhibiting dna. These findings establish that cyclophosphamide treatment can modulate hepatic p450 activities through multiple mechanisms and in a manner that may alter p450 metabolism of cyclophosphamide and perhaps other anticancer drugs. All of the available evidence indicates that cyclophosphamide exerts its carcinogenic activity via a genotoxic mechanism. Effects of cyclophosphamide on b and tlymphocytes in. Jun 26, 2017 considering the data from human case reports, animal studies and the mechanism of action of cyclophosphamide, its use during pregnancy, in particular during the first trimester, is not recommended. Therapeutic use of cyclophosphamide and its cytotoxic. Cyclophosphamide injectable solution is a prescription medication used to treat many types of cancer.
This medicine may cause harm to the unborn baby or loss of the unborn baby if you take it while you are pregnant. Cyclophosphamide in its parent form does not have direct cytotoxic effects. The mechanism of action is thought to involve crosslinking of tumor cell dna. Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. Cyclophosphamide tablets, usp are for oral use and contain 25 mg or 50 mg cyclophosphamide anhydrous. Although women taking cyclophosphamide can stop having periods, they can still become pregnant, so an effective form of birth control to prevent pregnancy should be used while taking this medication. Cyclophosphamide side effects, warnings, dosage, and more.
Aldophosphamide undergoes nonenzymatic breakdown into both acrolein and phosphoramide mustard which are also. Cyclophosphamide is used to treat breast cancer, lung cancer, leukaemia, lymphoma, and myeloma. Cyclophosphamide for injection, usp is a sterile white powder containing cyclophosphamide monohydrate. Clinical pharmacology of cyclophosphamide cancer research. It is one of the most potent immunosuppressive drugs available. Fidanze, in comprehensive medicinal chemistry ii, 2007. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cytoxan cyclophosphamide for injection, usp cytoxan.
Ndechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via cyp3a4. Cyclophosphamide is bio transformed principally in the liver to active alkylating metabolites by microsomal oxidase system. Phosphoramide mustard forms dna crosslinks both between and within dna strands at guanine n7 positions known as interstrand and intrastrand crosslinkages, respectively. The unchanged drug has an elimination halflife of 3 to 12 hours. Cyclophosphamide cyc is an alkylating agent that was introduced into clinical practice as a chemotherapeutic agent but has also been used to treat a number of.
The difference in pharmacological effect depends on the metabolism of the drug, the dose administered, dosing schedule and timing of the dosing. Molecular mechanism involved in cyclophosphamideinduced. Cyclophosphamide for injection, usp is a sterile white powder containing. Cyclophosphamide is used to treat various types of cancer.
Taking cyclophosphamide during pregnancy is very dangerous to an unborn child. Cyclophosphamide fda prescribing information, side effects. Cyclophosphamide is an alkylating cytotoxic drug that is toxic not only to. Carcinogenesis, mutagenesis, impairment of fertility. A course of cyclophosphamide administered to guinea pigs after immunization with mycobacteria led to a transient inhibition of cutaneous hypersensitivity to tuberculin protein. Following activation of cyclophosphamide in the liver, multiple metabolites appear in the circulation with varying degrees of immunosuppressive action and toxicity. Jun, 20 cyclophosphamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and published reports of effects in pregnant patients or animals. Cyclophosphamide cp, also known as cytophosphane among other names, is a medication. It is transformed via hepatic and intracellular enzymes to active alkylating metabolites. Theres also a slightly increased risk of certain types of cancer, particularly bladder cancer, but cyclophosphamide will not be recommended for you unless the benefits of treatment are thought to be much greater than the risks. Pdf cyclophosphamide mechanism of action in preclinical. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. This metabolite is only formed in cells that have low levels of aldh. Pdf therapeutic use of cyclophosphamide and its cytotoxic action.
A challenge for researchers article pdf available in journal of pharmacy research 48. Cyclophosphamide is an alkylating agent, and prevents cell division primarily by crosslinking dna and rna strands. Mechanism of action and pharmacokinetics indications and status adverse effects dosing administration guidelines special precautions interactions recommended clinical monitoring supplementary public funding references disclaimer. Several studies have examined the mechanism of action of cyclophosphamide. This treatment resulted in generalized depletion of lymphoid cells, including lymphopenia, and a substantial reduction in the number of macrophages found in induced. The clinical significance of this interaction is unknown. This means that the alkylating action of this drug is specifically directed. Mechanism of action and toxicity of cyclophosphamide the immunosuppressive actions of cyclophosphamide are complex. Vb6bearing t cells directed to minor lymphocyte stimu. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis pdf.
Cyclophosphamide is a drug that is used primarily for treating several types of cancer. Effects of cyclophosphamide on b and tlymphocytes in rheumatoid arthritis. Cyclophosphamide 500 mg powder for solution for injection or. Cyclophosphamide mechanism, indication, contraindications. It is a chemotherapy drug that works by slowing or stopping cell growth cyclophosphamide also works by decreasing your immune. Its cytotoxic effect is mainly due to crosslinking of strands of dna and rna, and to inhibition of protein synthesis.
As a single agent for induction therapy, cyclophosphamide is typically given as a dose of 100 mg m. Cyclophosphamide is an alkylating agent of the nitrogen mustard type. Therapeutic use of cyclophosphamide and its cytotoxic action. Dailymed cyclophosphamide injection, powder, for solution. Cyclophosphamide fda prescribing information, side. Reviewing the chemistry and pharmacology of cyclophosphamide is crucial for understanding its wide therapeutic applicability.
It is considered to be cell cycle phasenonspecific. Cyclophosphamide 500 mg powder for solution for injection. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. In high doses, cyclophosphamide affects b cells by inhibiting clonal expansion and suppression of production of immunoglobulins. Cyclophosphamide is used alone or in combination with other medications to treat hodgkins lymphoma hodgkins disease and nonhodgkins lymphoma types of cancer that begin in a type of white blood cells that normally fights infection. Cyclophosphamide induced sterility may be irreversible in some patients. The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and. Mechanisms of cyclophosphamide action on hepatic p450.
Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4hydroxyl metabolites, and shortened t12 values following repeated administration. Oral cyclophosphamide dosing is usually in the range of 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing. It is a prodrug that is converted to its active metabolites in liver. Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs. Its prescribed for nonhodgkin lymphoma, hodgkin lymphoma, multiple. Cyclophosphamide mechanism of action in preclinical. It is eliminated primarily in the form of metabolites.
Cyclophosphamide was considered by previous iarc working groups in. Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. Cyclophosphamide is used in combination with busulfan as a conditioning regimen before allogeneic haematopoietic progenitor cell transplantation in patients with chronic myelogenous leukaemia. It is best to read this information with our general information about chemotherapy and the type of cancer you have your doctor will talk to you about this treatment and its possible side effects before you agree consent to have treatment. Mechanisms of action cyclophosphamide, a nitrogen mustard, is an alkylating agent from the oxazophosphorine group figure 1. Women must use birth control while taking cyclophosphamide injection and for some time after the last dose. However, several components of the expression phase are affected. Mechanism of action and pharmacokinetics indications and status adverse effects dosing administration guidelines special precautions. Cytoxan cyclophosphamide for injection, usp cytoxan tablets. At higher doses, it interrupts cell cycle by forming dna cross linking, dna lesions. Inactive ingredients in cyclophosphamide tablets are.
A healthcare provider will give you this medication. Results of this study suggest that cyclophosphamide does not impair development of a population of specifically sensitized ttype lymphocytes. Over the past 20 years, increased understanding of the mechanism of action of 5fu has led to the development of strategies that. In each individual case the potential benefit of the treatment should be weighed against the potential risk for the foetus. Acrolein and phosphoramide are the active compounds, and they slow the growth of cancer cells by interfering with the actions of deoxyribonucleic acid dna within the cancerous cells. Download fulltext pdf download fulltext pdf cyclophosphamide mechanism of action in preclinical tecemotide studies article pdf available november 20 with 601 reads. Jun 29, 2016 cyclophosphamide interferes with oogenesis and spermatogenesis. Cyclophosphamide has also been used as a single agent in the treatment of lowgrade lymphomas. Apr 07, 2014 cyclophosphamide mechanism of action the main effect of cyclophosphamide is due to its metabolite phosphoramide mustard phosphoramide mustard forms dna crosslinks between interstrand crosslinkages and within intrastrand crosslinkages dna strands at guanine n7 position, this eventually leads to cell death 4. Tecemotide is a muc1 antigenspecific therapeutic cancer vaccine. Cyclophosphamide can sometimes cause a decrease in your blood count, liver problems, hair loss and mouth ulcers. Cyclophosphamide can also cause infertility in both men and women. Cyt p450 metabolism produces 4hydroxycyclophosphamide an active metabolite which spontaneously isomerizes to aldophosphamide a second active metabolite. In phase iii clinical studies, delivery of tecemotide is preceded by a single low dose of cyclophosphamide cpa to inhibit regulatory t cells tregs and enhance the response to the tumorassociated antigen.
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