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

1700 the liposomal formulation is indicated for the intrathecal treatment
of lymphomatous meningitis.
Clinical Toxicities. Cytarabine is a potent myelosuppressive
agent capable of producing acute, severe
leukopenia, thrombocytopenia, and anemia with striking
megaloblastic changes. Other toxic manifestations
include GI disturbances, stomatitis, conjunctivitis,
reversible hepatic enzyme elevations, noncardiogenic
pulmonary edema, and dermatitis.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Onset of dyspnea, fever, and pulmonary infiltrates on chest
computed tomography scans may follow 1-2 weeks after high-dose
Ara-C and may be fatal in 10-20% of patients, especially in patients
being treated for relapsed leukemia (Forghieri et al., 2007).
Infectious or other causes of pulmonary infiltrates must be excluded
in evaluating such patients. No specific therapy, other than Ara-C
discontinuation, is indicated. Intrathecal Ara-C, either the free drug
or the liposomal preparation, may cause arachnoiditis, seizures,
delirium, myelopathy, or coma, especially if given concomitantly
with systemic high-dose methotrexate or systemic Ara-C (Jabbour
et al., 2007).
Cerebellar toxicity, manifesting as ataxia and slurred speech,
and cerebral toxicity (seizures, dementia, and coma) may follow
intrathecal administration or high-dose systemic administration,
especially in patients >40 years of age and/or patients with poor renal
function.
Azacitidine (5-Azacytidine)
5-Azacytidine (Figure 61–8) and the closely related
decitabine (2′-deoxy-5-azacytidine) have antileukemic
activity and induce differentiation by virtue of their
inhibition of DNA cytosine methyltransferase activity.
Both drugs are approved for treatment of myelodysplasia,
for which they induce normalization of bone marrow
in 15-20% of patients and reduce transfusion
requirement in one-third of patients. 5-Azacytidine
improves survival.
The aza-nucleosides enter cells by the human equilibrative
transporter, the presence of which correlates with sensitivity of cell
lines (Stresemann and Lyko, 2008). The drugs incorporate into
DNA, where they become covalently bound to the methyltransferase
through their N-5 position, depleting intracellular enzyme
and leading to global demethylation of DNA and tumor cell differentiation
and apoptosis. Decitabine also induces double-strand
DNA breaks, perhaps as a consequence of the effort to repair the
protein-DNA adduct. The azacytidine ring spontaneously opens in
alkaline solution and has greater stability (t 1/2
of 7 hours) at neutral
pH. After subcutaneous administration of the standard dose of
75 mg/m 2 , 5-azacytidine achieves peak drug levels of 10 μM and
undergoes very rapid deamination by cytidine deaminase (plasma
t 1/2
of 20-40 minutes), with the product hydrolyzing to inactive
metabolites. Due to the formation of intracellular nucleotides, which
become incorporated into DNA, the effects of the aza-nucleosides
persist for many hours.
The major toxicities of the aza-nucleosides include myelosuppression
and mild GI symptoms. 5-Azacytidine produces
rather severe nausea and vomiting when given intravenously in
large doses (150-200 mg/m 2 /day for 5 days). The usual regimen for
5-azacytidine in myelodysplastic syndrome (MDS) is 75 mg/m 2 /day
for 7 days every 28 days, while decitabine is given in a dose of
20 mg intravenously every day for 5 days every 4 weeks (Oki et al.,
2007). Best responses may become apparent only after two to five
courses of treatment.
Gemcitabine
Gemcitabine (2′,2′-difluorodeoxycytidine; dFdC)
(Figure 61–8), a difluoro analog of deoxycytidine, has
become an important drug for patients with metastatic
pancreatic; non-squamous, non–small cell lung; ovarian;
and bladder cancer.
Mechanism of Action. Gemcitabine is carried into cells by three
distinct nucleoside transporters: hENT, hCNT, and a nucleobase
transporter found in malignant mesothelioma cells. The hENT transporter
appears to be the major carrier. Intracellularly, deoxycytidine
kinase phosphorylates gemcitabine to produce difluorodeoxycytidine
monophosphate (dFdCMP), from which point it is converted to
difluorodeoxycytidine di- and triphosphate (dFdCDP and dFdCTP).
Although gemcitabine’s anabolism and effects on DNA in general
mimic those of cytarabine, there are distinct differences in kinetics
of inhibition, additional enzymatic sites of action, different effects of
incorporation into DNA, and a distinct spectrum of clinical activity.
Unlike that of cytarabine, the cytotoxicity of gemcitabine is not confined
to the S phase of the cell cycle, and the drug is equally effective
against confluent cells and cells in logarithmic growth phase.
The cytotoxic activity may be a result of several actions on DNA
synthesis. dFdCTP competes with dCTP as a weak inhibitor of DNA
polymerase. dFdCDP is a stoichiometric inhibitor of RNR (Wang et al.,
2007). It forms a complex with the RNR subunits and with ATP,
resulting in depletion of deoxyribonucleotide pools necessary for
DNA synthesis. Most important, dFdCTP incorporates into DNA
and, after the incorporation of one more nucleotide, causes DNA
strand termination (Heinemann et al., 1988). This “extra” nucleotide
may be important in hiding the dFdCTP from DNA repair enzymes,
as the incorporated dFdCMP appears resistant to repair. The ability
of cells to incorporate dFdCTP into DNA is critical for gemcitabineinduced
apoptosis. Gemcitabine is inactivated by cytidine deaminase,
which is found both in tumor cells and throughout the body.
Preliminary evidence suggests that response to gemcitabine
in pancreatic carcinoma tumors correlates positively with high
expression of hENT (Giovannetti et al., 2006) and low expression
of subunits of RNR, but resistance is found in tumors with low levels
of deoxycytidine kinase and high levels of cytidine deaminase,
the inactivating enzyme (Ohhashi et al., 2008). In mouse tumors,
forced expression of the HMGA1 transcription factor also caused
gemcitabine resistance (Liau and Whang, 2008), possibly through
its effect on Akt-dependent survival pathways.
Absorption, Fate, and Elimination. Gemcitabine is administered as
an intravenous infusion. The pharmacokinetics of the parent compound
are largely determined by deamination in liver, plasma, and
other organs, and the predominant urinary elimination product is