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

1720 double-strand DNA breaks through homologous
recombination (Soares et al., 2007). Unlike cisplatin
and other DNA adduct– forming drugs, its activity
requires the presence of intact components of NER,
including XPG, which may be important for initiation of
single breaks and attempts at adduct removal (Stevens
et al., 2008).
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Absorption, Fate, and Excretion. Trabectedin is administered as a
24-hour infusion of 1.3 mg/m 2 every 3 weeks. Its approval in
Europe was based on a trial in soft-tissue sarcoma in which a superior
time to progression was found with the longer infusion, as compared
to a more convenient 3-hour infusion. It is administered with
dexamethasone, 4 mg BID, starting 24 hours before drug infusion to
diminish hepatic toxicity. The drug is slowly cleared by CYP3A4,
with a plasma t 1/2
of ~24-40 hours.
Therapeutic Uses. Trabectedin is approved outside the U.S. for second-line
treatment of soft-tissue sarcomas and for ovarian cancer in
combination with a doxorubicin formulation (DOXIL). It produces a
very high (>50%) disease control rate in myxoid liposarcomas, a
tumor characterized by a particular genomic translocation, although
the reasons for this sensitivity are unclear (Grosso et al., 2009).
Toxicity. Without dexamethasone pretreatment, trabectedin causes significant
hepatic enzyme elevations and fatigue in at least one-third of
patients. With the steroid, the increases in transaminase are less pronounced
and rapidly reverse (Grosso et al., 2009). Other toxicities
include mild myelosuppression and, rarely, rhabdomyolysis.
ENZYMES
L-Asparaginase
In 1953, Kidd reported that guinea pig serum had antileukemic
effects and identified L-asparaginase (L-ASP)
as the source of this activity (Kidd, 1953). Fifteen years
later, the purified enzyme from Escherichia coli proved to
have dramatic antitumor activity against malignant lymphoid
cells, based on the dependence of those tumors on
exogenous sources of L-asparagine (Broome, 1981). The
enzyme has become a standard agent for treating ALL.
Mechanism of Action. Most normal tissues are able to synthesize
L-asparagine in amounts sufficient for protein synthesis, but lymphocytic
leukemias lack adequate amounts of asparagine synthetase,
and derive the required amino acid from plasma. L-ASP, by catalyzing
the hydrolysis of circulating asparagine to aspartic acid and
ammonia, deprives these malignant cells of asparagine, leading to
cell death. L-ASP is used in combination with other agents, including
methotrexate, doxorubicin, vincristine, and prednisone for the
treatment of ALL and for high-grade lymphomas.
Resistance arises through induction of asparagine synthetase
in tumor cells. For unknown reasons, hyperdiploid ALL
cells or those with translocations involving the TEL oncogene are
particularly sensitive to L-ASP (Pui et al., 2004), while cells containing
the bcr-abl translocation, more common in adult ALL, are
more resistant.
Absorption, Fate, Excretion, and Therapeutic Use. L-Asparaginase
(ELSPAR), a 144-kDa tetramer, is given intramuscularly or intravenously,
but usually by the former route. After intravenous administration,
E. coli–derived L-ASP has a clearance rate from plasma of
0.035 mL/min/kg, a volume of distribution that approximates the
volume of plasma in humans, and a t 1/2
of 24 hours (Asselin et al.,
1993). It is given in doses of 6000-10,000 IU every third day for
3-4 weeks, although doses up to 25,000 IU once per week may be
more effective in childhood ALL (Moghrabi et al., 2007). Enzyme levels
must be maintained at >0.2 IU/mL in plasma to deplete asparagine
in the bloodstream. Pegaspargase (PEG-L-ASPARAGINASE; ONCASPAR) a
preparation in which the enzyme is conjugated to 5000-Da units of
monomethoxy polyethylene glycol, has much slower clearance from
plasma (t 1/2
of 6-7 days), and it is administered in doses of 2500 IU/m 2
intramuscularly no more frequently than every 14 days, producing
rapid and complete depletion of plasma and tumor cell asparagine
for 21 days in most patients (Appel et al., 2008). Pegaspargase has
much reduced immunogenicity (<20% of patients develop antibodies)
(Hawkins et al., 2004) and has been approved for first-line ALL
therapy.
Intermittent dosage regimens and longer durations of treatment
increase the risk of inducing hypersensitivity. In hypersensitive
patients, neutralizing antibodies inactivate L-ASP. Not all
patients with neutralizing antibodies experience clinical hypersensitivity,
although enzyme may be inactivated and therapy may be
ineffective. In previously untreated ALL, pegaspargase produces
more rapid clearance of lymphoblasts from bone marrow than does
the E. coli preparation and circumvents the rapid antibody-mediated
clearance seen with E. coli enzyme in relapsed patients (Avramis
et al., 2002). Asparaginase preparations only partially deplete CSF
asparagine.
Clinical Toxicity. L-ASP toxicities result from its antigenicity as a foreign
protein and its inhibition of protein synthesis. Hypersensitivity
reactions, including urticaria and full-blown anaphylaxis, occur in
5-20% of patients and may be fatal. These reactions usually are heralded
by the earlier appearance of circulating neutralizing antibody
and accelerated enzyme clearance from plasma. In these patients,
pegaspargase is a safe and effective alternative. So-called “silent”
enzyme inactivation by antibodies occurs in a higher percentage of
patients than overt hypersensitivity and may be associated with a
negative clinical outcome, especially in high-risk ALL patients
(Mann et al., 2007).
Other toxicities result from inhibition of protein synthesis in
normal tissues (e.g., hyperglycemia due to insulin deficiency, clotting
abnormalities due to deficient clotting factors, hypertriglyceridemia
due to effects on lipoprotein production, hypoalbuminemia).
Pancreatitis may result from extreme triglyceridemia and has been
treated by plasma exchange. The clotting problems may take the form
of spontaneous thrombosis—more frequent in thrombophilic patients
with underlying deficiencies in factor S, factor C, antithrombin III
mutation, or factor V Leiden—or, less frequently, hemorrhagic episodes
(Caruso et al., 2006). Thrombosis of cortical sinus vessels frequently
goes unrecognized. Brain magnetic resonance imaging studies should
be considered in patients treated with L-ASP who present with
seizures, headache, or altered mental status. Intracranial hemorrhage
in the first week of L-ASP treatment is an infrequent but devastating
complication. L-ASP suppresses immune function as well.