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

most potent antitumor agents known. The drug may produce alopecia
and, when extravasated subcutaneously, causes marked local
inflammation. Erythema, sometimes progressing to necrosis, has
been noted in areas of the skin exposed to X-ray radiation before,
during, or after administration of dactinomycin.
Absorption, Fate, and Excretion. Dactinomycin is administered
by intravenous injection. Metabolism of the drug is minimal. The
drug is excreted in both bile and urine and disappears from plasma
with a terminal t 1/2
of 36 hours. Dactinomycin does not cross the
blood-brain barrier.
Therapeutic Uses. A wide variety of single-agent and combination
chemotherapy regimens with dactinomycin (actinomycin D; COSMEGEN)
are employed. The usual daily dose of dactinomycin is 10-15 μg/kg;
this is given intravenously for 5 days; if no manifestations of toxicity are
encountered, additional courses may be given at intervals of 2-4 weeks.
In other regimens, 3-6 μg/kg/day, for a total of 125 μg/kg, and weekly
maintenance doses of 7.5 μg/kg have been used. If infiltrated during
administration, the drug is extremely corrosive to soft tissues.
The most important clinical use of dactinomycin is in the
treatment of rhabdomyosarcoma and Wilms tumor in children, where
it is curative in combination with primary surgery, radiotherapy, and
other drugs, particularly vincristine and cyclophosphamide. Ewing,
Kaposi, and soft-tissue sarcomas also respond. Dactinomycin and
methotrexate form a curative therapy for choriocarcinoma.
Clinical Toxicities. Toxic manifestations include anorexia, nausea,
and vomiting, usually beginning a few hours after administration.
Hematopoietic suppression with pancytopenia may occur in the first
week after completion of therapy. Proctitis, diarrhea, glossitis, cheilitis,
and ulcerations of the oral mucosa are common; dermatological
manifestations include alopecia, as well as erythema, desquamation,
and increased inflammation and pigmentation in areas previously or
concomitantly subjected to X-ray radiation. Severe injury may occur
as a result of local drug extravasation.
Anthracyclines and Anthracenediones
Anthracyclines are derived from the fungus Streptomyces
peucetius var. caesius. Idarubicin and epirubicin are
analogs of the naturally produced anthracyclines doxorubicin
and daunorubicin, differing only slightly in chemical
structure, but having somewhat distinct patterns of
clinical activity. Daunorubicin and idarubicin primarily
have been used in the acute leukemias, whereas doxorubicin
and epirubicin display broader activity against
human solid tumors. These agents, which all possess
potential for generating free radicals, cause an unusual
and often irreversible cardiomyopathy, the occurrence of
which is related to the total dose of the drug. The structurally
similar agent mitoxantrone has useful activity
against prostate cancer and AML, and is used in highdose
chemotherapy, but has less cardiotoxicity.
Chemistry. The anthracycline antibiotics have a tetracyclic ring
structure attached to an unusual sugar, daunosamine. Cytotoxic
agents of this class all have quinone and hydroquinone moieties on
adjacent rings that permit the gain and loss of electrons. Although
there are marked differences in the clinical uses of daunorubicin and
doxorubicin, their chemical structures differ only by a single
hydroxyl group on C-14 (substituent R 4
on the diagram below).
Idarubicin is 4-demethoxydaunorubicin (alteration in substituent R 1
),
a synthetic derivative of daunorubicin; epirubicin is an epimer at the
4′ position of the sugar. Mitoxantrone, an anthracenedione, lacks a
glycosidic side group.
Mechanism of Action. A number of important biochemical effects
have been described for the anthracyclines and anthracenediones, all
of which could contribute to their therapeutic and toxic effects. These
compounds can intercalate with DNA, directly affecting transcription
and replication. A more important action is the ability to form
a tripartite complex with topoisomerase II and DNA. Topoisomerase
II is an ATP-dependent enzyme that binds to DNA and produces
double-strand breaks at the 3′-phosphate backbone, allowing strand
passage and uncoiling of super-coiled DNA. Following strand passage,
topoisomerase II re-ligates the DNA strands. This enzymatic
function is essential for DNA replication and repair. Formation of
the tripartite complex with anthracyclines or with etoposide inhibits
the re-ligation of the broken DNA strands, leading to apoptosis.
Defects in DNA double-strand break repair sensitize cells to damage
by these drugs, while overexpression of transcription-linked DNA
repair may contribute to resistance.
Anthracyclines, by virtue of their quinone groups, also generate
free radicals in solution and in both normal and malignant tissues
(Myers, 1988). Anthracyclines can form semiquinone radical
intermediates that can react with O 2
to produce superoxide anion
radicals. These can generate both hydrogen peroxide and hydroxyl
radicals, which attack DNA (Serrano et al., 1999) and oxidize DNA
bases. The production of free radicals is significantly stimulated by
the interaction of doxorubicin with iron (Myers, 1988). Enzymatic
defenses such as superoxide dismutase and catalase protect cells
against the toxicity of the anthracyclines, and these defenses can be
augmented by exogenous antioxidants such as alpha tocopherol or
by an iron chelator, dexrazoxane (ZINECARD, others), which protects
against cardiac toxicity (Swain et al., 1997).
Exposure of cells to anthracyclines leads to apoptosis; mediators
of this process include the p53 DNA-damage sensor and activated
caspases (proteases), although ceramide, a lipid breakdown
product, and the Fas receptor-ligand system also have been implicated
(Friesen et al., 1996).
1713
CHAPTER 61
CYTOTOXIC AGENTS