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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Antimetabolites
Cytidine Analogues:
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Cytarabine (ara-C) is a deoxycytidine nucleoside analog, isolated from the sponge Cryptotethya crypta.
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Cytarabine/Daunorubicin is
a prominent, standard induction treatment for acute myeloid leukemia (AML) by infusion,
overlapping and sequential.
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Cytarabine also exhibits activity against other hematologic cancers including non-Hodgkin's lymphoma, chronic myelogenous leukemia and acute lymphocytic leukemia.
Cytarabine (ara-C), however, does not exhibit antineoplastic activity against solid tumors.
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Ara-C utilizes nucleoside transporter systems to gain cell entry.
The most important system is the "equilibrative inhibitor-sensitive" (ES) receptor.
Inside the cell, cytarabine must be activated to achieve its antineoplastic, cytotoxic activity.
The first step involves enzyme catalyzed conversion of ara-C to the monophosphate form, ara-cytidine monophosphate (ara-CMP).
The enzyme that catalyzes the step is deoxycytidine kinase (dCK).
Additional phosphorylation steps yield di-and triphosphate metabolites.
Ara-cytidine
triphosphate (ara-CTP) is an important inhibitor of several DNA polymerases,
DNA polymerase α, β, γ.
Inhibition of these DNA polymerases limits DNA chain elongation, DNA synthesis and DNA repair.
Also, ara-CTP is incorporated into DNA, resulting in DNA chain termination as well as interference with chain elongation.
If DNA breaks are not repaired utilizing DNA polymerase -dependent repair enzyme systems, apoptosis (programmed cell death) is initiated.1
Ara-C cytotoxicity appears associated with a total number of ara-C incorporated into DNA.1
Degradation of ara-C depends on two enzymes: cytidine deaminase and deoxycytidylate deaminase.
These enzymes catalyze conversion to inactive metabolites
Interplay between intracellular drug activation and inactivation is determinative of the ara-CTP concentration, the mediator of cytotoxic and antitumor effects.6
In infants and
adults with acute lymphocytic leukemia and multilineage leukemia (t4; 11)
MLL translocation, high-dose cytarabine is notably effective.1
In this patient subgroup, the nucleoside transporter, ENT1, is significantly expressed with expression correlating with ara-C sensitivity.1
High-dose ara-C administration may allow intracellular drug concentrations to exceed 10 μM.1
At that concentration, the nucleoside transporter is not rate determining for drug accumulation.
Instead intracellular metabolism to the triphosphate form becomes rate limiting and it is the triphosphate form that exhibits potent DNA polymerase inhibtion.
High-dose ara-C treatment appears of particular benefit to patients with certain AML subtypes.
Furthermore,
about 1 in 5 of patients with AML exhibit leukemic cells characterized by a
K-ras mutation.
This patient group appears to especially benefit from high-dose ara-C protocols compared to patients with wild-type K-ras.1
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Absorption, Distribution, Biotransformation, Excretion:1
Cytarabine (ara-C) has limited systemic bioavailability following oral administration.1
This limitation is due to inactivating cytidine deaminase located in the G.I. mucosa and liver.
Because of enzymatic inactivation, systemic availability of oral cytarabine may be limited to about 20% of an administered dose.
Therefore,
cytarabine is typically given intravenously.
Peak cytarabine concentrations in the plasma (20-50 μM) following IV administration of 30-300 mg/m2 rapidly declines with a half-life of about 10 minutes (t1/2 approximates 10 minutes).
Of an injected dose, a small proportion, 10%, is found excreted unchanged in the urine within a day.
The inactivated deaminated product, ara-U, is much more prominent (80%).1,6
At higher ara-C concentrations administered by continuous infusion, drug levels can be identified in the cerebrospinal fluid (CSF).
These levels, however, may be only 10% (7%-14%)6 that observed in plasma.1
Higher CSF
concentrations may be obtained following intrathecal drug
administration.
Sustained-release into the CSF is available by depot liposomal ara-C formulations. Liposomal ara-C allows for cytotoxic CSF ara-C concentrations to be maintained for about 10 days.1
Cytarabine (ara-C) is the standard induction chemotherapy for acute myeloid leukemia (AML), often in combination with an anthracycline, such as doxorubicin.
Ara-C has activity against other hematological malignancies including non-Hodgkin's lymphoma, acute lymphocytic leukemia and chronic myelogenous leukemia.
Treatment typically involves continuous DNA synthesis inhibition for a length of time equivalent to at least one cell-cycle (24 hours).
This duration is thought sufficient to ensure that most tumor cells will encounter cytarabine during the S-phase of the cell cycle.
Subsequently,
for bolus dosing, a treatment schedule is developed that maintains
intracellular ara-CTP concentrations at inhibitory levels.
Intrathecal use of liposomal cytarabine is an alternative to the use of the standard agent.
High-dose protocols appear required to ensure that drug levels do not fall below concentrations required to saturate both transport and support intracellular drug activation.
Finally the liposomal cytarabine agent is considered appropriate for intrathecal management of lymphomatous meningitis.
Myelosuppression due to cytarabine can result in acute, severe leukopenia, anemia, and thrombocytopenia.1
Intrathecal administration of ara-C (either is free drug or as the liposomal preparation) can result in arachnoiditis, seizures, myelopathy, delirium or coma.1
These effects may be more likely if the patient is also receiving systemic, high-dose methotrexate or systemic ara-C.
Intrathecal administration or high-dose systemic administration may induce neurological side effects including ataxia with slurred speech as well as cerebral toxicity manifest as seizures, dementia and coma.1
High-dose ara-C presents with numerous neurological toxicities even when the drug is administered systemically (not only following intrathecal administration).6
Seizures, cerebral and cerebellar abnormalities along with peripheral neuropathy have been identified.
With respect to cerebellar dysfunction, up to 15% of patients may present with dysarthria, dysmetria and ataxia.6,13
Cerebral toxicities manifest in both alertness changes and changes in cognitive ability including memory loss.6
Frontal lobe release signs indicate cerebral toxicity. Frontal lobe release signs reflect reemergence of primitive reflexes typically noted in infants.12
Frontal release signs include grasp, snout, route and suck reflexes. In evaluating frontal lobe dysfunction the grasp reflex appears most useful.12
Numerous other toxicities have also been identified.1
These include:
Stomatitis (inflamed and sore mouth)
G.I. pathologies
Conjunctivitis
Noncardiogenic pulmonary edema and
Dermatitis.1
Following high-dose ara-C, dyspnea, fever, along with pulmonary infiltrates described on chest CT scans may present 1-2 weeks following initial treatment.1
Pulmonary complications associated with cytarabine (ara-C) may include:
Noncardiogenic pulmonary edema
Acute respiratory distress, and
Pneumonia (Streptococcus viridans).
High-dose cytarabine related pulmonary pathology may be due to cytokine-related mechanisms.
Pulmonary complication
due to high-dose ara-C can be fatal in about 10%-20% of individuals.1
Such pulmonary toxicity requires cytarabine (ara-C) discontinuation.1
Ara-C induced pulmonary toxicity in leukemic patients is considered likely due to a cytokine-mediated mechanism.9
This toxicity is considered under-recognized, requiring an early diagnosis which may improve clinical management.9
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