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

L-ASP terminates the antitumor activity of methotrexate
when given shortly after the antimetabolite. By lowering serum albumin
concentrations, it may decrease protein binding and accelerate
plasma clearance of other drugs.
HYDROXYUREA
The syntheses of hydroxyurea (HU) was first reported
in 1869, but its potential anticancer activity was not recognized
until 90 years later, when the drug was found
to inhibit the growth of both leukemia and solid tumors.
This drug has unique and surprisingly diverse biological
effects as an antileukemic drug, radiation sensitizer,
and an inducer of fetal hemoglobin in patients with
sickle cell disease. The drug is orally administered, and
its toxicity in most patients is modest and limited to
myelosuppression.
Cytotoxic Action. HU inhibits the enzyme ribonucleoside
diphosphate reductase, which catalyzes the
reductive conversion of ribonucleotides to deoxyribonucleotides,
a rate-limiting step in the biosynthesis of DNA.
HU binds the iron molecules that are essential for activation
of a tyrosyl radical in the catalytic subunit (hRRM2)
of RNR. The drug is specific for the S phase of the cell
cycle, during which RNR concentrations are maximal.
It causes cells to arrest at or near the G 1
–S interface
through both p53-dependent and -independent mechanisms.
Because cells are highly sensitive to irradiation at the G 1
–S
boundary, HU and irradiation cause synergistic antitumor effects.
Through depletion of physiological deoxynucleotides, HU potentiates
the antiproliferative effects of DNA-damaging agents such as
cisplatin, alkylating agents, or topoisomerase II inhibitors and facilitates
the incorporation of antimetabolites such as Ara-C, gemcitabine,
and fludarabine into DNA. It also promotes degradation of
the p21 cell-cycle checkpoint and thereby enhances the effects of
HDAC (histone deacetylase) inhibitors in vitro (Kramer et al., 2008).
The role of nitric oxide release in its differentiating activity and in its
antitumor effects is uncertain but intriguing (Cokic et al., 2003).
HU has become the primary drug for improving the control
of sickle cell (HbS) disease in adults and is also used for inducing
fetal hemoglobin (HbF) in thalassemia HbC and HbC/S patients
(Brawley et al., 2008). It reduces vaso-occlusive events, painful
cries, hospitalizations, and the need for blood transfusions in patients
with sickle cell disease. It does so via several potential mechanisms.
Increased synthesis of HbF promotes solubility of hemoglobin and
prevents sickling. The mechanism of HbF production is uncertain. It
may simply result from suppression of erythroid precursor proliferation
with compensatory stimulation of a distinct set of fetal Hbproducing
cells. Sar1a, a specific promoter that upregulates in
response to HU, induces HbF synthesis (Kumkhaek, 2008).
Polymorphisms in this promoter may explain differential responses
to HU. An alternative mechanism for HbF production has been
offered because of the ability of HU to generate nitric oxide both in
vitro and in vivo, causing nitrosylation of small-molecular-weight
GTPases, a process that stimulate γ-globin production in erythroid
precursors. Another property of HU that may be relevant is its ability
to reduce L-selectin expression and thereby to inhibit adhesion of
red cells and neutrophils to vascular endothelium. Also, by suppressing
the production of neutrophils, it decreases their contribution to
vascular occlusion.
Tumor cells become resistant to HU through increased synthesis
of the hRRM2 subunit of ribonucleoside diphosphate reductase,
thus restoring enzyme activity.
Absorption, Fate, and Excretion. The oral bioavailability of HU is
excellent (80-100%), and comparable plasma concentrations are seen
after oral or intravenous dosing. Peak plasma concentrations are
reached 1-1.5 hours after oral doses of 15-80 mg/kg. HU disappears
from plasma with a t 1/2
of 3.5-4.5 hours. The drug readily crosses the
blood-brain barrier, and it appears in significant quantities in human
breast milk. From 40-80% of the drug is recovered in the urine within
12 hours after either intravenous or oral administration. Although precise
guidelines are not available, it is advisable to modify initial doses
for patients with abnormal renal function until individual tolerance
can be assessed. Animal studies suggest that metabolism of HU does
occur, but the extent and significance of its metabolism in humans
have not been established.
Therapeutic Uses. In cancer treatment, two dosage schedules for
HU (HYDREA, DROXIA, others), alone or in combination with other
drugs, are most commonly used in a variety of solid tumors: 1) intermittent
therapy with 80 mg/kg administered orally as a single dose
every third day or 2) continuous therapy with 20-30 mg/kg administered
as a single daily dose. In patients with essential thrombocythemia
and in sickle cell disease, HU is given in a daily dose of
15 mg/kg, adjusting that dose upward or downward according to
blood counts. The neutrophil count responds within 1-2 weeks to
discontinuation of the drug. In treating subjects with sickle cell and
related diseases, a neutrophil count of at least 2500 cells/mL should
be maintained (Platt, 2008). Treatment typically is continued for
6 weeks in malignant diseases to determine its effectiveness; if satisfactory
results are obtained, therapy can be continued indefinitely,
although leukocyte counts at weekly intervals are advisable.
The principal use of HU has been as a myelosuppressive agent
in various myeloproliferative syndromes, particularly CML, polycythemia
vera, myeloid metaplasia, and essential thrombocytosis, for
controlling high platelet or white cell counts. Many of the myeloproliferative
syndromes harbor activating mutations of JAK2, a gene that
is downregulated by HU. In essential thrombocythemia, it is the drug
of choice for patients with a platelet count >1.5 million cells/mm 3 or
with a history of arterial or venous thrombosis. In this disease, it dramatically
lowers the risk of thrombosis by lowering the platelet, neutrophil,
and red cell counts and by reducing expression of L-selectin
and increasing nitric oxide production by neutrophils.
In CML, HU has been largely replaced by imatinib.
Although it has produced anecdotal, temporary remissions in
patients with solid tumors (e.g., head and neck cancers, cervical
cancers), HU rarely is used in such patients as a single agent. HU
1721
CHAPTER 61
CYTOTOXIC AGENTS