Cytarabine
ara-C
deoxycytidine kinase cytidine deaminase
ara-U ara-CMP
dCMP kinase
ara-CDP
ara-CTP
NDP kinase
ara-UMP
dCMP deaminase
NH2
N CH
CH C O
C
N
H H
H
HO
HO
H
HOCH2 O
Trade Names
Cytosine arabinoside, Ara-C
Classification
Antimetabolite
Category
Chemotherapy drug
Drug Manufacturer
Bedford Laboratories
Mechanism of Action
Deoxycytidine analog originally isolated from the sponge
Cryptothethya crypta .
Cell cycle–specific with activity in the S-phase.
Requires intracellular activation to the nucleotide metabolite ara-CTP.
Antitumor activity of cytarabine is determined by a balance between
intracellular activation and degradation and the subsequent formation
of cytotoxic ara-CTP metabolites.
Incorporation of ara-CTP into DNA resulting in chain termination
and inhibition of DNA synthesis and function.
Ara-CTP inhibits several DNA polymerases _, , and _, which then
interferes with DNA chain elongation, DNA synthesis, and DNA
repair.
Ara-CTP inhibits the enzyme ribonucleotide reductase, resulting in
decreased levels of essential deoxyribonucleotides required for DNA
synthesis and function.
Mechanism of Resistance
Decreased activation of drug through decreased expression of the
anabolic enzyme deoxycytidine kinase.
Increased breakdown of drug by the catabolic enzymes, cytidine
deaminase and deoxycytidylate (dCMP) deaminase.
Decreased transport of drug into cells.
Increased expression of CTP synthetase activity resulting in
increased concentrations of competing physiologic nucleotide substrate
dCTP.
Absorption
Poor oral bioavailability (~20%) as a result of extensive deamination
within the GI tract.
Distribution
Rapidly cleared from the bloodstream after IV administration. Distributes
rapidly into tissues and total body water. Crosses the blood-brain barrier with
CSF levels reaching 20%–40% of those in plasma. Binding to plasma proteins
has not been well characterized.
Metabolism
Undergoes extensive metabolism, with approximately 70%–80% of
drug being recovered in the urine as the ara-U metabolite within 24 hours.
Deamination occurs in liver, plasma, and peripheral tissues. The principal
enzyme involved in drug catabolism is cytidine deaminase, which converts
ara-C into the inactive metabolite ara-U. dCMP-deaminase converts ara-CMP
into ara-UMP, and this represents an additional catabolic pathway of the
drug. The terminal elimination half-life is 2–6 hours. The half-life of ara-C
in CSF is somewhat longer, ranging from 2 to 11 hours, due to the relatively
low activity of cytidine deaminase present in CSF.
Indications
Acute myelogenous leukemia.
Acute lymphocytic leukemia.
Chronic myelogenous leukemia.
Leptomeningeal carcinomatosis.
Non-Hodgkin’s lymphoma.
DosageRange
Several different doses and schedules have been used:
Standard dose: 100 mg/m 2 /day IV on days 1–7 as a continuous IV
infusion, in combination with an anthracycline as induction chemotherapy
for AML.
High-dose: 1.5–3.0 g/m 2 IV q 12 hours for 3 days as a high-dose,
intensification regimen for AML.
SC: 20 mg/m 2 SC for 10 days per month for 6 months, associated
with IFN-_ for treatment of CML.
Intrathecal: 10–30 mg intrathecal (IT) up to three times weekly in the
treatment of leptomeningeal carcinomatosis secondary to leukemia
or lymphoma.
Drug Interaction 1
Gentamicin—Cytarabine antagonizes the efficacy of gentamicin.
Drug Interaction 2
5-Fluorocytosine—Cytarabine inhibits the efficacy of 5-fluorocytosine by
preventing its cellular uptake.
Drug Interaction 3
Digoxin—Cytarabine decreases the oral bioavailability of digoxin, thereby
decreasing its efficacy. Digoxin levels should be monitored closely while on
therapy.
Drug Interaction 4
Alkylating agents, cisplatin, and ionizing radiation—Cytarabine enhances
the cytotoxicity of various alkylating agents (cyclophosphamide, carmustine),
cisplatin, and ionizing radiation by inhibiting DNA repair mechanisms.
Concurrent use of high-dose cytarabine and cisplatin may increase risk of
ototoxicity.
Drug Interaction 5
Methotrexate—Pretreatment with methotrexate enhances the formation
of ara-CTP metabolites resulting in enhanced cytotoxicity.
Drug Interaction 6
Fludarabine, hydroxyurea—Pretreatment with fludarabine and/or
hydroxyurea potentiates the cytotoxicity of cytarabine by enhancing the formation
of cytotoxic ara-CTP metabolites.
Drug Interaction 7
GM-CSF, interleukin-3—Cytokines including GM-CSF and interleukin-3
enhance cytarabine-mediated apoptosis mechanisms.
Drug Interaction 8
L-Asparaginase—Increased risk of pancreatitis when L-asparaginase is
given before cytarabine.
Special Considerations
Monitor CBCs on a regular basis during therapy.
Use with caution in patients with abnormal liver and/or renal function.
Dose modification should be considered in this setting as
patients are at increased risk for toxicity. Monitor hepatic and renal
function during therapy.
Alkalinization of the urine (pH _7.0), allopurinol, and vigorous IV
hydration are recommended to prevent tumor lysis syndrome in
patients with acute myelogenous leukemia.
High-dose therapy should be administered over a 1- to 2-hour period.
Conjunctivitis is observed with high-dose therapy as the drug is
excreted in tears. Patients should be treated with hydrocortisone eye
drops (2 drops OU qid for 10 days) on the night before the start of
therapy.
Pregnancy category D.
Toxicity 1
Myelosuppression is dose-limiting. Leukopenia and thrombocytopenia
are common. Nadir usually occurs by days 7–10, with recovery by days 14–21.
Megaloblastic anemia has also been observed.
Toxicity 2
Nausea and vomiting. Mild to moderate emetogenic agent with increased
severity observed with high-dose therapy. Anorexia, diarrhea, and mucositis
usually occur 7–10 days after therapy.
Toxicity 3
Cerebellar ataxia, lethargy, and confusion. Neurotoxicity develops in up
to 10% of patients. Onset usually 5 days after drug treatment and lasts up to
1 week. In most cases, CNS toxicities are mild and reversible. Risk factors for
neurotoxicity include high-dose therapy, age older than 40, abnormal renal
function with serum creatinine 1.2 mg/dL, and abnormal liver function.
Toxicity 4
Transient hepatic dysfunction with elevation of serum transaminases and
bilirubin. Most often associated with high-dose therapy.
Toxicity 5
Acute pancreatitis.
Toxicity 6
Ara-C syndrome. Described in pediatric patients and represents an allergic
reaction to cytarabine
Characterized by fever, myalgia, malaise, bone
pain, maculopapular skin rash, conjunctivitis, and occasional chest pain.
Usually occurs within 12 hours of drug infusion. Steroids appear to be effective
in treating and/or preventing the onset of this syndrome.
Toxicity 7
Pulmonary complications include non-cardiogenic pulmonary edema,
acute respiratory distress, and Streptococcus viridans pneumonia. Observed
with high-dose therapy.
Toxicity 8
Erythema of skin, alopecia, and hidradenitis are usually mild and selflimited.
Hand-foot syndrome observed rarely with high-dose therapy.
Toxicity 9
Conjunctivitis and keratitis. Associated with high-dose regimens.
Toxicity 10
Seizures, alterations in mental status, and fever may be observed within
the first 24 hours after IT administration.