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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Alkylating Agents (Continued)
Classification8
Nitrogen Mustards
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Overview: Cyclophosphamide (Cytoxan)
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Cyclophosphamide (Cytoxan) is a prodrug, requiring an activation process to exert its therapeutic effect.24
Cyclophosphamide
can be used in treating breast cancer, lymphomas, leukemias,
numerous solid tumors and as part of
protocols for treating Ewing sarcoma.
Activation of cyclophosphamide to 4-hydroxycyclophosphamide depends on the liver microsomal cytochrome P450 drug metabolizing system.24
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The cytochrome P450 system involves a number of isoforms or isozymes.
The prominent isoforms involved in hepatic activation include CYP2B6, CYP2C9, and CYP3A4.
Other forms making lesser contributions are CYP2A6, CYP2C8, and CYP2C19.
Cyclophosphamide can undergo sidechain oxidation mainly catalyzed by CYP3A4 and to a lesser extent by CYP2B6.
This
reaction (~10%) results in an N-dechloroethylation
metabolite and formation of chloroacetaldehyde, a neurotoxin.24
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Cyclophosphamide is likely the most versatile of the alkylating drugs.8
Aborption, Metabolism and Excretion
Cyclophosphamide is well absorbed following oral administration and subsequently activated to the 4-hydroxyl intermediate.4
Metabolic activation of cyclophosphamide exhibits both interpatient variability and tends to increase with repetitive dosing in high-dose protocols.
The 4-hydroxylcyclophosphamide intermediate undergoes additional oxidative metabolism (aldehyde oxidase) leading to therapeutically inactive metabolites.
Antitumor effects are attributed to phosphoramide mustard; whereas, bladder toxicity (hemorrhagic cystitis) associated with cyclophosphamide therapy is likely due to acrolein.
Cystitis may be either prevented or mitigated by parenteral co-administration of an organosulfur compound, 2-mercaptoethane sulfonate (Mesna).4
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With high-dose cyclophosphamide intravenous hydration is required.4
Significant
hematuria for patients receiving daily oral administration is cause for
immediate cyclophosphamide discontinuation.4
Sometimes bladder hemorrhage may be refractory to treatment and can become a life-threatening complication.
Cystectomy is sometimes required for bleeding control.
Cyclophosphamide
at higher doses may also lead to abnormal ADH (antidiuretic hormone)
secretion.4
In this case, patients being aggressively hydrated to mitigate bladder toxicity may be susceptible to water intoxication.
Cyclophosphamide
is eliminated by hepatic metabolism; therefore, even patients with
renal dysfunction may receive full cyclophosphamide dosages.4
However, if patient exhibited more than mild hepatic dysfunction, reduced cyclophosphamide dosing should be considered.
Urinary and fecal cyclophosphamide (parent compound) is limited following IV administration.4
Well absorbed following oral administration, cyclophosphamide (100-mg doses) exhibits comparable systemic drug availability when comparing oral versus intravenous injection.27,26
Oral versus intravenous cyclophosphamide administered to the same individual resulted in no apparent difference in area-under-the-curve (AUC) for either primary cytotoxic metabolite, i.e. hydroxycyclophosphamide and phosphoramide mustard.27
Variability (3-10 hours) has been observed in the terminal-phase t½ (time required for drug concentration to exhibit a 50% decline).
Highest levels of alkylating activity are noted about 2-3 hours following drug administration.27
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Bone
Marrow:8
Bone marrow toxicity associated with cyclophosphamide administration can affect red cell, platelet, and leukocyte blood elements.8
Relative platelet sparing has been described.
When cyclophosphamide is used as part of protocol for bone marrow transplantation, hemopoietic partial recovery can occur within three weeks to a month.
This recovery is consistent with a "stem cell-sparing" property..
The stem cell-sparing cyclophosphamide effect may be related to high levels of aldehyde dehydrogenase associated with bone marrow progenitor cells.
Aldehyde dedydrogenase is an important enzyme in cyclophosphamide detoxification.8
Aldehyde dehydrogenase catalyzes oxidation of aldehydes to carboxylic acids.29,30
Both constitutive and induced forms exist with ALDH1 and ALDH2 considered most important for aldehyde oxidation.
These tetrameric forms are found in highest concentration in liver.29,30
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Nausea and vomiting are side effects generally associated with alkylating drugs.8
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Cyclophosphamide at doses ≥ 1500 mg/m2 is considered highly emetic with the frequency of emesis estimated at >90%.31
At reduced doses (<1500 mg/ m2), cyclophosphamide still is associated with an emesis frequency of about 30%-90%, considered moderate.
However, when cyclophosphamide is given in combination with, for example, doxorubicin or epirubicin, the resulting protocol was considered highly emetogenic, even at the lower cyclophosphamide doses.31
Several neurotransmitter systems have been implicated in activation of the emetic reflex arc.31
Receptor stimulation both in the CNS and/or G.I. tract appear involved.
Following activation of these receptors, the medullary vomiting center is then activated.
A chemoreceptor trigger zone (CTZ) has been identified in the medulla, including a "chemoreceptor" which monitors both blood and cerebrospinal fluid. 31
Dopamine: The dopamine system has been an important focus of antiemetic research efforts, leading to use of several drugs targeting the dopamine receptors.31
These drugs include phenothiazines such as chlorpromazine and prochloperazine along with substituted benzamides, such as metoclopramide.
Serotonin: The serotonin system also appears important in the emetic response.
Furthermore, higher doses of metoclopramide are likely affected by influencing serotonin receptors.
Certain drugs appear to target a particular serotonin receptor subtype, type 3, (5-HT3).
These drugs include ondansetron, granisetron and palonosetron.
Tachykinines: Tachykinins including substance P are also important in emesis with certain new drugs such as natupitant and rolapitant.
These agents are antagonists at the neurokinin type 1 (NK1) receptors.
The combination of natupitant and palonosetron (Akyzeo) has been approved by the FDA for use in both prevention of acute as well as delayed nausea and vomiting due to administration of cancer chemotherapeutic agents.31
Antiemetic
agents useful in managing acute emesis associated with chemotherapy
using drugs with a high emetic risk include: granisetron, ondansetron,
palonosetron, dexamethasone, metoclopramide, haloperidol, droperidol,
nabilone, prochlorperazine, lorazepam (adjunct), natupitant, aprepitant/fosaprepitant.31
Both cyclophosphamide and ifosfamide (oxazaphosphorines) may cause a unique, hemorrhagic cystitis.8
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The presentation may be mild to severe with bladder pathology including significant organ damage and hemorrhage.
Toxic metabolites, especially acrolein, are likely causative.
Adequate hydration with bladder irrigation with a solution containing MESNA (2-mercaptoethane sulfonate) may mitigate both frequency and severity of this reaction.8
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With high-dose cyclophosphamide intravenous hydration is required.4
Significant
hematuria for patients receiving daily oral administration is cause for
immediate cyclophosphamide discontinuation.4
Sometimes bladder hemorrhage may be refractory to treatment and can become a life-threatening complication.
Cystectomy is sometimes required for bleeding control.
Cyclophosphamide
at higher doses may also lead to abnormal ADH (antidiuretic hormone)
secretion.4
In this case, patients being aggressively hydrated to mitigate bladder toxicity may be susceptible to water intoxication.
Pneumonitis and
Pulmonary Fibrosis:8
At high cumulative doses (>1000 mg/m2) cyclophosphamide may lead to pulmonary side effects comparable to that observed with long-term busulfan treatment.
Side effects include nonproductive cough, dyspnea with evolution to tachypnea and cyanosis.
Severe pulmonary insufficiency and death may also result.
Administration of the alkylating drugs chlorambucil, mitomycin C, or melphalan can lead to pulmonary fibrosis following treatment.
These pulmonary effects may be due to a direct cytotoxic action by alkylating agents to the pulmonary epithelium.8
Reproductive System Toxicities:
Alkylating drugs have significant toxic effects on reproductive tissue.27
For example these drugs deplete testicular germ cells with Sertoli's cells preservation.
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The likelihood of aspermia is increased as dose and cumulative dosing of the alkylating drug increases.
Patients expecting to undergo chemotherapy with alkylating agents may consider sperm banking in anticipation of a posttreatment desire to father children.27
In females both a high incidence of amenorrhea and ovarian atrophy accompanies cyclophosphamide administration.8
This effect has been described as age-related, developing following reduced doses in older patients compared with younger ones.
Furthermore, these effects in older patients were less likely reversible.8
Alkylating drugs appear teratogenic due to direct cytotoxic activity in the developing embryo.27
A
risk of a viable but malformed infant has been described for first
trimester alkylating drug administration.
Risk appears reduced at later times.
Malformation
in children whose mothers received cyclophosphamide, nitrogen
mustard, procarbazine or chlorambucil during the first
trimester has been reported in several studies.
However, birth of normal infants was found when alkylating drugs were administered to mothers during the second or third trimester.
Perhaps, however, by definition, DNA-damage resulting from alkylating agents represents a basis for expectable teratogenicity and carcinogenicity.8
Development of a second cancer as a result of an earlier therapeutic protocol involving alkylating drugs has been described.8
Acute
myeloid leukemia with an earlier myelodysplastic phase has been reported
in some patients initially treated with melphalan, cyclophosphamide,
chlorambucil and nitrosoureas.8
Cyclophosphamide appears notably less leukemogenic compared to melphalan.
The above drugs represent the most widely used alkylating drugs for cancer treatment.
In reports of leukemogenesis many patients had been treated with alkylating drugs for Hodgkin's lymphoma, ovarian carcinoma and multiple myeloma over an extended period of time, often for years.
Occurrence of acute leukemia in those patients with ovarian cancer surviving for 10 years following alkylating drug therapy may be up to 10%.
Acute leukemia the most frequently noted secondary malignancy tends to develop within a time window of 1-4 years following alkylating drug treatment.
Some solid tumors have also developed in patients previously managed with alkylating drugs.8
During the last 40 years significant enhancement in survival of children diagnosed with cancer has been reported. In this circumstance, 5-year survival is about 80%. 8
Perhaps up to two thirds of childhood cancer survivors may experience a "delayed drug toxicity" severe enough to be even life-threatening.
These toxicities which may be severe include:8
Neurocognitive abnormalities
Growth and developmental impairmen
Cardiopulmonary pathologies,
Renal impairment
G.I. dysfunction
Endocrine dysfunction, as well as
Secondary cancers8
Suppression of both humoral and cellular immunity occurs with alkylating agent administration.8
Of the
alkylating drugs, cyclophosphamide appears most immunosuppressive.8
Cyclophosphamide is associated with:
Suppression of B-cell lymphocyte function
Depletion of B lymphocytes and
Reduced T cell mediated lymphocyte functions.8
Long-term
cyclophosphamide administration may result in significant lymphocyte
depletion with marked immunosuppression.
This immunosuppression may be associated with increased susceptibility to viral, protozoal, and fungal infections.8
Immunosuppression by cyclophosphamide (and other alkylating agents) has been employed in some clinical applications.27
The initial use was suppression of recipient immune response prior to allogenic transplantation.
Cyclophosphamide at large doses, employed as pretreatment, facilitate match sibling bone marrow transplants into recipients.
Accordingly, cyclophosphamide has been one agent used for its immunosuppressive activity during bone marrow allotransplantation.
Cyclophosphamide may also be effective in management of kidney graft rejection, although azathioprine (Imuran) is more widely used.27
Management of autoimmune disorders may also involve alkylating drugs. 27
Cyclophosphamide has been shown effective in treating:27
Wegener's granulomatosis (Granulomatosis with polyangitis)
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Rheumatoid arthritis
Membranous glomerulonephritis
Idiopathic thrombocytopenic purpura.
The combination of cyclophosphamide with methylprednisolone, given as monthly pulse doses, represents the standard remission induction treatment for severe lupus nephritis.
Generally however, because of adverse side effect profiles, alkylating drugs for the treatment of nonmalignant disease should be used only with caution.27
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