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

1722 is a potent radiosensitizer as a consequence of its inhibition of
RNR (Flanagan et al., 2007) and has been incorporated into several
treatment regimens with concurrent irradiation (i.e., cervical carcinoma,
primary brain tumors, head and neck cancer, non–smallcell
lung cancer).
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Clinical Toxicity. Leukopenia, anemia, and occasionally thrombocytopenia—are
the major toxic effects; recovery of the bone marrow is
prompt if the drug is discontinued for a few days. Other adverse reactions
include a desquamative interstitial pneumonitis, GI disturbances,
and mild dermatological reactions; more rarely, stomatitis,
alopecia, and neurological manifestations have been encountered.
Increased skin and fingernail pigmentation may occur, as well as
painful leg ulcers, especially in elderly patients or in those with renal
dysfunction. HU does not increase the risk of secondary leukemia in
patients with myeloproliferative disorders or sickle cell disease. It
is a potent teratogen in all animal species tested and should not be
used in women with childbearing potential (Platt, 2008).
DIFFERENTIATING AGENTS
One of the hallmarks of malignant transformation is a
block in differentiation. It is not clear whether the
block is complete or partial, in that tumor cells with
the features of stem cells can be found in most tumors,
while the greater bulk of tumor cells do not carry the
markers or the biological potential of continuous proliferation.
Nonetheless, there is growing evidence that
many human tumors are generated by mutations that
block specific steps in differentiation, an example
being the t(15;17) translocation in APL (acute
promyelocytic leukemia). This translocation joins the
retinoic acid receptor-α (RAR-α, a dimerizing protein
critical for differentiation) and the PML gene, which
encodes a transcription factor important in inhibiting
proliferation and promoting myeloid differentiation.
Four other translocation partners for APL have been
identified in less common varieties of APL. Under
physiological conditions, RAR-α binds retinoic acid
and regulates the expression of a number of specific
genes that control myeloid differentiation. The oncogenic
PML–RAR-α gene produces a protein that binds
retinoids with much decreased affinity, lacks PML regulatory
function, and fails to upregulate transcription
factors (C/EBP and PU.1) that promote myeloid differentiation
(Collins, 2008). The fusion protein forms
homo- and heterodimers that regulate expression of
genes that increase leukemic stem cell renewal, suppress
checkpoint and apoptotic signals, and suppress
expression of DNA repair functions, thereby enhancing
mutability of APL cells. Epigenetic regulation of
gene expression by histone acetylation and methylation
also is disrupted by the fusion protein.
A number of chemical entities (vitamin D and
its analogs, retinoids, benzamides and other inhibitors
of histone deacetylase, various cytotoxics and biological
agents, and inhibitors of DNA methylation) can
induce differentiation in tumor cell lines in vitro.
Fittingly, the first and best example of differentiating
therapy was discovered in the treatment of APL (Wang
and Chen, 2008).
Retinoids
Tretinoin. The biology and pharmacology of retinoids
and related compounds are discussed in detail in
Chapter 65. The most important of these for cancer
treatment is tretinoin (all-trans retinoic acid; ATRA),
which induces a high rate of complete remission in APL
as a single agent and, in combination with anthracyclines,
cures most patients with this disease.
Under physiological conditions, the RAR-α
receptor dimerizes with the retinoid X receptor to form
a complex that binds ATRA tightly. ATRA binding displaces
a repressor from the complex and promotes differentiation
of cells of multiple lineages. In APL cells,
physiological concentrations of retinoid are inadequate
to displace the repressor. Pharmacological concentrations,
however, are effective in activating the differentiation
program and in promoting degradation of the
PML–RAR-α fusion gene (Collins, 2008). ATRA also
binds and activates RAR-γ and thereby promotes stemcell
renewal, perhaps through its effects on the microenvironment
(Drumea et al., 2008), and this action may
help restore normal bone marrow renewal. Resistance
to ATRA arises by further mutation of the fusion gene,
abolishing ATRA binding; by induction of the
CYP26A1 in liver or leukemic cells; or by loss of
expression of the PML–RAR-α fusion gene (Roussel
and Lanotte, 2001). Sensitivity can be restored by transfection
of a functional PML–RAR-α gene.
Clinical Pharmacology. The usual dosing regimen of orally administered
ATRA (VESANOID, others) is 45 mg/m 2 /day until 30 days after
remission is achieved (maximum course of therapy is 90 days).
ATRA as a single agent reverses the hemorrhagic diathesis associated
with APL and induces a high rate of temporary remission.
However, clinical trials have clearly established the benefit of giving
ATRA in combination with an anthracycline for remission
induction, achieving ≥80% relapse-free long-term survival.
ATRA concentrations reach 400 ng/mL in plasma. ATRA is
cleared by a CYP3A4-mediated elimination with a t 1/2
of <1 hour.
Treatment with inducers of CYP3A4 leads to more rapid drug disappearance
and, in some patients, resistance to ATRA (Gallagher,
2002). Inhibitors, such as antifungal imidazoles, block its degradation
and may lead to hypercalcemia and renal failure (Cordoba et al.,
2008), which responds to diuresis, bisphosphonates, and ATRA