DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

incorporation into DNA by DNA polymerases. The incorporated
Ara-CMP residue is a potent inhibitor of DNA polymerase, both in
replication and repair synthesis, and blocks the further elongation of
the nascent DNA molecule. The block in elongation activates checkpoint
kinases (ATR and chk-1), which initiate attempts to remove
the offending nucleotide. If DNA breaks are not repaired, apoptosis
ensues. Ara-C cytotoxicity correlates with the total Ara-C incorporated
into DNA. Thus, incorporation of about five molecules of
Ara-C per 10 4 bases of DNA decreases cellular clonogenicity by
~50% (Kufe et al., 1984).
Ara-C exposure activates a complex system of secondary
intracellular signals that determine whether a cell survives or undergoes
apoptosis. It activates the transcription factor AP-1 and stimulates
the formation of ceramide, a potent inducer of apoptosis. It
causes an increase in the cell damage response factor NF-κB in
leukemic cells and activates checkpoint kinases. Additionally, the
level of expression of the anti-apoptotic BCL-2 and BCL-X L
proteins
correlates inversely with relative sensitivity to Ara-C (Ibrado
et al., 1996). Thus, the lethality depends on the complex interplay of
multiple factors, including transport, intracellular metabolism, and
cellular response to DNA damage.
Low concentrations of Ara-C induce terminal differentiation
of leukemic cells in tissue culture, an effect that is accompanied by
decreased c-myc oncogene expression; molecular analysis of bone
marrow specimens from some leukemic patients in remission after
Ara-C therapy has revealed persistence of leukemic markers, suggesting
that differentiation may have occurred.
Continuous inhibition of DNA synthesis for a duration equivalent
to at least one cell cycle or 24 hours is necessary to expose
most tumor cells during the S, or DNA-synthetic, phase of the cycle.
The optimal interval between bolus doses of Ara-C is ~8-12 hours,
a schedule that maintains intracellular concentrations of Ara-CTP at
inhibitory levels during a multi-day cycle of treatment. Typical
schedules for administration of Ara-C employ bolus doses every
12 hours or continuous drug infusion for 5-7 days.
Particular subtypes of AML derive benefit from high-dose
Ara-C treatment; these include t(8;21), inv(16), t(9;16), and del(16),
all of which involve core-binding factors that regulate hematopoiesis
(Widemann et al., 1997). Approximately 20% of AML patients have
leukemic cells with a k-RAS mutation, and these patients seem to
derive greater benefit from high dose Ara-C regimens than do
patients with wild type k-RAS (Neubauer et al., 2008).
Mechanisms of Resistance to Cytarabine. Response to
Ara-C is strongly influenced by the relative activities
of anabolic and catabolic enzymes that determine the
proportion of drug converted to Ara-CTP. The ratelimiting
activating enzyme, CdK, produces Ara-CMP. It
is opposed by the degradative enzyme, cytidine deaminase,
which converts Ara-C to a nontoxic metabolite,
ara-uridine (Ara-U). Cytidine deaminase activity is
high in many normal tissues, including intestinal
mucosa, liver, and neutrophils, but lower in AML cells
and other human tumors. A second degradative enzyme,
dCMP deaminase, converts Ara-CMP to the inactive
metabolite, Ara-UMP. Increased synthesis and retention
of Ara-CTP in leukemic cells leads to a longer duration
of complete remission in patients with AML (Preisler
et al., 1985). As discussed above, the ability of cells to
transport Ara-C also may affect response. Clinical studies
have implicated a loss of deoxycytidine kinase as the
primary mechanism of resistance to Ara-C in AML (Cai
et al., 2008), although 5′ nucleotidase, which degrades
Ara-CMP, and possibly cytidine deaminase elevations,
may play a role in AML resistance to Ara-C.
Absorption, Fate, and Excretion. Due to the presence
of high concentrations of cytidine deaminase in the GI
mucosa and liver, only ~20% of the drug reaches the
circulation after oral Ara-C administration; thus, the
drug must be given intravenously. Peak concentrations
of 2-50 μM are measurable in plasma after intravenous
injection of 30-300 mg/m 2 but disappear rapidly (t 1/2
of
10 minutes) from plasma.
Less than 10% of the injected dose is excreted unchanged in
the urine within 12-24 hours, while most appears as the inactive
deaminated product, Ara-U. Higher concentrations of Ara-C are
found in CSF after continuous infusion than after rapid intravenous
injection, but are far lower (≤10%) than concentrations in plasma.
After intrathecal administration of the drug at a dose of 50 mg/m 2 ,
deamination proceeds slowly, with a t 1/2
of 3-4 hours, and peak concentrations
of 1-2 μM are achieved. CSF concentrations remain
above the threshold for cytotoxicity (0.4 μM) for ≥24 hours. A depot
liposomal formulation of Ara-C (DEPOCYT) provides sustained release
into the CSF. After a standard 50-mg dose, liposomal Ara-C remains
above cytotoxic levels for an average of 12 days, thus avoiding the
need for frequent lumbar punctures (Cole et al., 2003).
Therapeutic Uses. Two dosage schedules are recommended
for administration of cytarabine (CYTOSAR-U,
TARABINE PFS, others): 1) rapid intravenous infusion of
100 mg/m 2 every 12 hours for 5-7 days or 2) continuous
intravenous infusion of 100-200 mg/m 2 /day for
5-7 days. In general, children tolerate higher doses than
adults. Intrathecal doses of 30 mg/m 2 every 4 days have
been used to treat meningeal or lymphomatous
leukemia. The intrathecal administration of 50 mg for
adults (or 35 mg for children) of liposomal cytarabine
(DEPOCYT) every 2 weeks seems equally effective as the
every-4-days regimen with the standard drug.
Ara-C is indicated for induction and maintenance of remission
in AML and is useful in the treatment of other leukemias,
such as ALL, CML in the blast phase, acute promyelocytic
leukemia, and high-grade lymphomas. Because drug concentration
in plasma rapidly falls below the level needed to saturate
transport and intercellular activation, clinicians have employed
high-dose regimens (2-3 g/m 2 every 12 hours for 6-8 doses) to
achieve 20- to 50 times higher serum levels, with improved results
in remission induction and consolidation for AML. Injection of
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CYTOTOXIC AGENTS