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

1724 core, allowing access for transcription factor complexes,
and thereby enhancing transcriptional activity.
Acetyl groups are added by histone acetyltransferases
and removed by histone deacetylases (HDACs). HDAC
inhibitors such as vorinostat increase histone acetylation
and thus enhance gene transcription. Many nonhistone
proteins also are subject to lysine acetylation and
thus are affected by treatment with HDAC inhibitors.
The role of their acetylation status in the antitumor
action of HDAC inhibitors is unclear.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Mechanism of Action. Vorinostat is a hydroxamic acid modeled
after hybrid polar compounds, such as hexamethylene bisacetamide
(HMBA); as a class, these compounds cause differentiation of malignant
cells in vitro, as do other classes of compounds with HDACinhibitory
activity, including cyclic tetrapeptides, benzamides, and
short-chain aliphatic acids. These compounds bind to a critical Zn ++
ion in the active site of HDAC enzymes. Vorinostat inhibits the enzymatic
activity of HDACs at micromolar concentrations. An important
distinction between vorinostat and other HDAC inhibitors is that
vorinostat and the hydroxymates are pan-HDAC inhibitors, whereas
other compounds have selectivity for HDAC isoenzyme subsets. The
biological and clinical implications of this specificity are not clear,
and the specific mechanism by which HDAC inhibitors exert their
antitumor activity is uncertain. They induce cell-cycle arrest, differentiation,
and apoptosis of cancer cells; nonmalignant cells are relatively
resistant to these effects. They increase transcription of
cell-cycle regulators, affect levels of nuclear transcription factors,
and induce pro-apoptotic genes. HDAC inhibition directly blocks
function of the chaperone HSP90 and stabilizes the tumor suppressor
p53 (Bolden et al., 2006).
Absorption, Fate, and Excretion. Vorinostat is administered as a
once-daily oral dose of 400 mg. It is inactivated by glucuronidation
of the hydroxyl amine group, followed by hydrolysis of the terminal
carboxamide bond and further oxidation of the aliphatic side chain
(Figure 61–15). The metabolites are pharmacologically inactive. The
A
B
C
H
N
H
N
H
N
O
O
O
O
OH
O
O
N
H
N
H
OH
O
OH
COOH
OH
OH
Figure 61–15. Chemical structures of vorinostat (A), and its
metabolites, vorinostat O-glucuronide (B) and 4-anilino-4-
oxobutanoic acid (C).
terminal t 1/2
of vorinostat in plasma is ~2 hours. Interestingly, histones
remain hyperacetylated up to 10 hours after an oral dose of
vorinostat, suggesting that its effects persist beyond drug metabolism
and elimination.
Therapeutic Uses. Vorinostat is approved for use in refractory cutaneous
T-cell lymphoma (CTCL). In patients with refractory CTCL,
vorinostat produced an overall response rate of 30%, with a median
time to progression of 5 months (Duvic et al., 2007). Vorinostat and
other HDAC inhibitors, including romidepsin (depsipeptide; FK228)
and MGCD 0103, have shown activity in CTCL, other B- and T-cell
lymphomas, and myeloid leukemia.
Toxicity. The most common side effects of vorinostat are fatigue,
nausea, diarrhea, and thrombocytopenia. Deep venous thrombosis
and pulmonary embolism were infrequent but serious adverse events
in CTCL patients receiving vorinostat. Most HDAC inhibitors in
development cause QTc prolongation, although no serious cardiac
toxicity has been reported with vorinostat. A small number of
patients receiving infusional depsipeptide romidepsin (see below)
and the hydroxamate dacinostat (NVP-LAQ 824) have developed
ventricular arrhythmias while on treatment, but the causal relationship
to the drugs has not been clearly established, and the cardiac
risk may be lower with orally administered and/or less potent
HDAC inhibitors (Piekarz et al., 2006). Caution is advised when
using HDAC inhibitors in patients with underlying cardiac abnormalities,
and careful monitoring of the QTc interval and correction
of electrolyte (K + , Mg ++ ) abnormalities is necessary.
Romidepsin. Romidepsin, a bicyclic polypeptide derived from a soil
bacterium, inhibits HDAC at low nanomolar concentrations and is
approved for treatment of CTCL and for peripheral T-cell lymphomas.
In a Phase II trial it produced complete responses in 4 patients with
CTCL, and partial responses in 20, from a total of 71 patients treated.
Its primary toxities include GI complaints (nausea vomiting) and transient
myelosuppression. Its administration leads to T-wave flattening,
but without clear cardiac toxicity (Piekarz et al., 2009).
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