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

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Mechanism of Action. Bortezomib binds to the β5 subunit of
the 20S core of the 26S proteasome and reversibly inhibits its
chymotrypsin-like activity (Adams, 2004). This event disrupts multiple
intracellular signaling cascades, leading to apoptosis. A most
important consequence of proteasome inhibition is its effect on NF-κB,
a key transcription factor that promotes cell damage response and
cell survival. Most NF-κB is found in the cytosol bound to IκB; in
this form, NF-κB is restricted to the cytosol and cannot enter to the
nucleus to regulate transcription. In response to stress signals resulting
from hypoxia, chemotherapy, and DNA damage, IκB becomes
ubiquitinated and then degraded via the proteasome. Its degradation
releases NF-κB, which enters the nucleus, where it transcriptionally
activates a host of genes involved in cell survival (e.g., cell adhesion
proteins E-selectin, ICAM-1, and VCAM-1), as well as proliferative
(e.g., cyclin-D1) or anti-apoptotic molecules (e.g., cIAPs, BCL-2).
NF-κB is highly expressed in many human tumors, including MM,
and may be a key factor in tumor cell survival in a hypoxic environment
and during chemotherapy. Bortezomib blocks proteasomal
degradation of IκB, thereby preventing the transcriptional activity
of NF-κB and downregulating survival responses.
NF-κB inhibition may not account for the full spectrum of
effects triggered by proteasome inhibition, because bortezomib also
disrupts the ubiquitin-proteasomal degradation of p21, p27, p53,
and other key regulators of the cell cycle and initiators of apoptosis.
Bortezomib activates the cell’s stereotypical “unfolded protein
response” or UPR, in which abnormal protein conformation activates
adaptive signaling pathways in the cell. The composite effect
leads to irreversible commitment of MM cells to apoptosis
(Mitsiades et al., 2002). In clinical trials, bortezomib also sensitizes
tumor cells to cytotoxic drugs, including alkylators and anthracyclines,
and to IMiDs and inhibitors of histone deacetylase (Orlowski
et al., 2007).
Absorption, Fate, and Excretion. The recommended starting dose
of bortezomib is 1.3 mg/m 2 given as an intravenous bolus on days 1,
4, 8, and 11 of every 21-day cycle (with a 10-day rest period per
cycle). At least 72 hours should elapse between doses. Drug administration
should be withheld until resolution of any grade 3 nonhematological
toxicity or grade 4 hematological toxicity, and subsequent
doses should be reduced 25%.
After intravenous administration of 1-1.3 mg/m 2 of bortezomib,
the drug exhibits a terminal t 1/2
in plasma of 5.5 hours
(Papandreou et al., 2004). The median peak plasma concentration
averages 509 ng/mL after a 1.3-mg/m 2 bolus injection. Peak proteasome
inhibition reaches 60% within 1 hour and declines thereafter,
with a t 1/2
of ~24 hours.
Bortezomib clearance results from the deboronation of
90% of the parent compound, followed by hydroxylation of the
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BORTEZOMIB
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boron-free product by CYPs 3A4 and 2D6; administration of this
drug with potent inducers or inhibitors/substrates of CYP3A4
requires caution. No dose adjustment is required for patients with
renal dysfunction.
Therapeutic Uses and Toxicity. Bortezomib is FDA approved as
initial therapy for MM and as therapy for MM after relapse from
other drugs (Kane et al., 2003). It also has received approval for
relapsed or refractory mantle cell lymphoma. The drug is active in
myeloma, including the induction of complete responses in up to
30% of patients when used in combination with other drugs (i.e.,
thalidomide, lenalidomide, liposomal doxorubicin, or dexamethasone)
(San Miguel et al., 2008).
Bortezomib toxicities include thrombocytopenia (28%),
fatigue (12%), peripheral neuropathy (12%), and neutropenia, anemia,
vomiting, diarrhea, limb pain, dehydration, nausea, or weakness.
Peripheral neuropathy, the most chronic of the toxicities,
develops most frequently in patients with a prior history of neuropathy
secondary to prior drug treatment (e.g., thalidomide) or diabetes
or with prolonged use. Dose reductions or discontinuation of bortezomib
ameliorates the neuropathic symptoms. Injection of bortezomib
may precipitate hypotension, especially in volume-depleted
patients, in those who have a history of syncope, or in patients taking
antihypertensive medications. High-dose bortezomib causes
hypotension and congestive heart failure in animals; cardiac toxicity
occurs rarely in humans, but congestive failure and prolonged
QT-interval have been reported.
mTOR INHIBITORS: RAPAMYCIN
ANALOGS
Rapamycin (sirolimus) is a fungal fermentation product
that inhibits the proper functioning of a serine/threonine
protein kinase in mammalian cells eponymously
named mammalian target of rapamycin, or mTOR, an
effector PI3 kinase signaling. The PI3K/PKB(Akt)/
mTOR pathway responds to a variety of signals from
growth factors (e.g., insulin, interleukins, EGF) that
modulate cell growth, translation, metabolism, and
apoptosis. The activation of the PI3K pathway is
opposed by the phosphatase activity of the tumor suppressor,
PTEN. Activating mutations and amplification
of genes in the receptor-PI3K pathway, and loss of
function alterations in PTEN, occur frequently in cancer
cells, with the result that PI3K signaling is exaggerated
and cells lose growth control and exhibit enhanced
survival (decreased apoptosis).
Rapamycin and its congeners, temsirolimus and
everolimus, are well-established first-line drugs in posttransplant
immunosuppression. More recently, mTOR
inhibitors have found important applications in oncology
for treatment of renal and hepatocellular cancer and
mantle cell lymphomas.
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CHAPTER 62
TARGETED THERAPIES: TYROSINE KINASE INHIBITORS, MONOCLONAL ANTIBODIES, AND CYTOKINES