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

discontinuation. Corticosteroids and chemotherapy sharply decrease
the occurrence of “retinoic acid syndrome,” which is characterized
by fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or
pericardial effusions. When used as a single agent for remission
induction, especially in patients with >5000 leukemic cells/mm 3 in
the peripheral blood, ATRA induces an outpouring of cytokines and
mature-appearing neutrophils of leukemic origin. These cells express
high concentrations of integrins and other adhesion molecules on
their surface and clog small vessels in the pulmonary circulation,
leading to significant morbidity in 15-20% of patients. The syndrome
of respiratory distress, pleural and pericardial effusions, and mental
status changes may have a fatal outcome. Pretreatment dexamethasone
should be given to patients with leukemic cell counts of
>5,000/mL to counteract “retinoic acid syndrome”.
Toxicity. Retinoids as a class, including ATRA, cause dry skin,
cheilitis, reversible hepatic enzyme abnormalities, bone tenderness,
pseudotumor cerebri, hypercalcemia, and hyperlipidemia, and as
mentioned in the previous paragraph, the retinoic acid syndrome.
Arsenic Trioxide (ATO)
Although recognized as a heavy metal toxin for centuries,
arsenicals attracted interest as a medicinal agent
nearly a century ago for syphilis and parasitic disease,
and eventually CML. Arsenic trioxide has become a
highly effective treatment for relapsed APL, producing
complete responses in >85% of such patients (Wang
and Chen, 2008). It now is a standard treatment for
patients who relapse after ATRA and chemotherapy,
cures a significant fraction of these patients, and has
entered trials as primary therapy in combination with
ATRA and chemotherapy. The chemistry and toxicity
of arsenic is considered in detail in Chapter 67.
The basis for its antitumor activity remains uncertain. APL
cells have high levels of reactive oxygen species (ROS) and are
quite sensitive to further ROS induction. ATO inhibits thioredoxin
reductase and thereby generates ROS. It inactivates glutathione and
other sulfhydryls that scavenge ROS and thereby aggravates ROS
damage. Cells exposed to ATO also upregulate p53, Jun kinase, and
caspases associated with the intrinsic pathway of apoptosis and
downregulate anti-apoptotic proteins such as bcl-2. Of particular
relevance to APL, it promotes the phosphorylation, sumoylation,
and degradation of the APL fusion protein (Lallemand-
Breitenbach et al., 2008), as well as the degradation of NF-κB, a
transcription factor that stimulates angiogenesis and dampens apoptotic
responses in cells with DNA damage. ATO’s cytotoxic effects
are antagonized by cell survival signals emanating from activation
of components of the PI3 kinase cell survival pathway, including
Akt kinase, S6 kinase, and mammalian target of rapamycin
(mTOR). Inhibition of mTOR by rapamycin enhances its cytotoxic
activity in culture systems.
It induces differentiation of leukemic cell lines in vitro, and
in both experimental and human leukemias in vivo, but the mechanisms
of differentiation and their relationship to the above pharmacological
activities are not known.
Clinical Pharmacology. ATO (TRISENOX) is well absorbed orally, but
in cancer treatment is administered as a 2-hour intravenous infusion
in dosages of 0.15 mg/kg/day for up to 60 days, until remission is
documented. Consolidation therapy begins after a 3-week break. It
enters cells via one of several glucose transporters. The primary
mechanism of elimination is through enzymatic methylation.
Methylated metabolites have uncertain biological effects. Peak
steady-state concentrations of arsenic in plasma reached 5-7 μM in
one study in adults, while 20-fold lower levels were reported in children
using more specific atomic absorption methods (Fox, 2008).
Multiple methylated metabolites form rapidly and are excreted in
urine. Less than 20% of administered drug is excreted unchanged in
the urine. No dose reductions are indicated for hepatic or renal
dysfunction.
Toxicity. Pharmacological doses of ATO are well tolerated.
Patients may experience reversible side effects, including hyperglycemia,
hepatic enzyme elevations, fatigue, dysesthesias, and
light-headedness. Ten percent or fewer of patients will experience
a leukocyte maturation syndrome similar to that seen with ATRA,
including pulmonary distress, effusions, and mental status changes.
Oxygen, corticosteroids, and temporary discontinuation of ATO lead
to full reversal of this syndrome (Soignet et al., 1998). Another
important and potentially dangerous side effect is lengthening of the
QT interval on the electrocardiogram in 40% of patients, but rarely
do patients develop torsades de pointes, a dangerous form of ventricular
tachycardia. Simultaneous treatment with other QT-prolonging
drugs, such as macrolide antibiotics, quinidine, or methadone,
should be avoided. QT prolongation by ATO results from inhibition
of the rapid K + efflux channels in myocardial tissue by As 2
O 3
. This
change leads to slow repolarization of myocardium, and ventricular
arrhythmias. Monitoring of serum electrolytes and repletion of
serum K + in patients with hypokalemia are precautionary measures
in patients receiving ATO therapy. In patients exhibiting a significantly
prolonged QT (>470 milliseconds), treatment should be suspended,
K + supplemented, and therapy resumed only if the QT
returns to normal. Torsades de pointes requires treatment with intravenous
magnesium sulfate, K + repletion, and defibrillation if the
arrhythmia persists (Gupta et al., 2007) (see Chapter 29).
Histone Deacetylase Inhibitors
Vorinostat. A new field of cancer research, called epigenetics,
concerns the control of cell proliferation and
differentiation by processes beyond pure genetic alterations.
These processes include cellular modification of
expression of genes by microRNAs, histones, and proteins,
and post-translational modification of proteins.
Vorinostat (ZOLINZA), also known as suberoylanilide
hydroxamic acid (SAHA), is unique as an epigenetic
modifier that directly affects histone function (Figure
61–15). To understand its action, it is important to
review the complex structure of DNA, which wraps
itself around histone proteins to form the nucleosome.
This higher-order packaging controls gene expression.
Acetylation of lysine residues on histones increases the
spatial distance between DNA strands and the protein
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CHAPTER 61
CYTOTOXIC AGENTS