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

and mitomycin must be discontinued immediately. Mitomycin
causes interstitial pulmonary fibrosis, and total doses >30 mg/m 2
have infrequently led to congestive heart failure. It also may potentiate
the cardiotoxicity of doxorubicin when used in combination
with this drug.
Mitotane
Mitotane (o,p′-DDD), a compound chemically similar
to the insecticides DDT and DDD, is used in the treatment
of neoplasms derived from the adrenal cortex. In
studies of the toxicology of related insecticides in
dogs, it was noted that the adrenal cortex was severely
damaged, an effect caused by the presence of the o,p′
isomer of DDD.
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Cytotoxic Action. The mechanism of action of mitotane
has not been elucidated, but its relatively selective
destruction of adrenocortical cells, normal or neoplastic,
is well established. Thus, administration of the drug
causes a rapid reduction in the levels of adrenocorticosteroids
and their metabolites in blood and urine, a
response that is useful in both guiding dosage and following
the course of hyperadrenocorticism (Cushing’s
syndrome) resulting from an adrenal tumor or adrenal
hyperplasia. It does not damage other organs.
Absorption, Fate, and Excretion. Approximately 40% of mitotane
is absorbed after oral administration. After daily doses of 5-15 g,
concentrations of 10-90 μg/mL of unchanged drug and 30-50 μg/mL
of a metabolite are present in the blood. After discontinuation of
therapy, plasma concentrations of mitotane are still measurable for
6-9 weeks. Although the drug is found in all tissues, fat is the primary
site of storage. A water-soluble metabolite of mitotane found
in the urine constitutes 25% of an oral or parenteral dose. About 60%
of an oral dose is excreted unchanged in the stool.
Therapeutic Uses. Mitotane (LYSODREN) is administered in initial
daily oral doses of 2-6 g, usually in three or four divided portions,
and usually increased to 9-10 g/day if tolerated. The maximal tolerated
dose may vary from 2-16 g/day. Treatment should continue
for at least 3 months; if beneficial effects are observed, therapy
should be maintained indefinitely. Spironolactone should not be
administered concomitantly, because it interferes with the adrenal
suppression produced by mitotane (Wortsman and Soler, 1977).
Treatment with mitotane is indicated for the palliation of
inoperable adrenocortical carcinoma, producing symptomatic benefit
in 30-50% of such patients.
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MITOTANE (o,p′ DDD)
Clinical Toxicity. Although the administration of mitotane produces
anorexia and nausea in most patients, somnolence and lethargy in
~34%, and dermatitis in 15-20%, these effects do not contraindicate
the use of the drug at lower doses. Because this drug damages the
adrenal cortex, administration of replacement doses of adrenocorticosteroids
is necessary (Hogan et al., 1978).
Trabectedin
Trabectedin (YONDELIS) is the only drug used clinically
that is derived from a sea animal. It was isolated from
the marine tunicate, Ecteinascidin turbinate, as part of
the National Cancer Institute’s natural products discovery
program. Trabectedin is designated as an orphan
drug in the U.S. for ovarian cancer, sarcoma, and pancreatic
cancer and is approved in the E.U. for secondline
treatment of soft-tissue sarcomas and ovarian
cancer.
H 3 C
H 3 C
H 3 C
O
N
O
HO
OH
HN
O
N
H
TRABECTEDIN
OH
CH 3
CH 3
CH 3
Mechanism of Action. This large structure binds to the
minor groove of DNA, allowing the alkylation of the N2
position of guanine and bending the helix toward the
major groove (Tavecchio et al., 2008). A portion of the
molecule protrudes from the minor groove and may play
a role in attracting repair or transcription complexes. The
bulky DNA adduct is recognized by the transcriptioncoupled
nucleotide excision repair complex, and these
proteins initiate attempts to repair the damaged strand,
converting the adduct to a double-stranded break.
Tumor cell sensitivity to trabectedin exhibits interesting
molecular features. Trabectedin has particular cytotoxic
effects on cells that lack components of the Fanconi
anemia complex or those that lack the ability to repair
S
O
O
O
O
O
1719
CHAPTER 61
CYTOTOXIC AGENTS