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

1718 basilar infiltrates on X-ray and may progress to life-threatening pulmonary
fibrosis. Radiological changes of bleomycin-induced lung
disease may be indistinguishable from interstitial infection or tumor,
and show strong PET-positivity, but may progress from patchy infiltrates
to dense fibrosis, cavitation and pneumothorax, atelectasis, or
lobar collapse. Approximately 5-10% of patients receiving
bleomycin develop clinically apparent pulmonary toxicity, and ~1%
die of this complication (O’Sullivan et al., 2003). Most who recover
experience a significant improvement in pulmonary function, but
fibrosis may be irreversible. Pulmonary function tests are not of predictive
value for detecting early onset of this complication. The CO
diffusion capacity declines in patients receiving doses >250 mg. The
risk of pulmonary toxicity is related to total dose, with a significant
increase in risk in total doses >250 mg and in patients >40 years of
age, in those with a CrCl of <80 mL/min, and in those with underlying
pulmonary disease; single doses of ≥30 mg/m 2 also are associated
with an increased risk of pulmonary toxicity. Administration
of high inspired O 2
concentrations during anesthesia or respiratory
therapy may aggravate or precipitate pulmonary toxicity in patients
previously treated with the drug. There is no known specific therapy
for bleomycin lung injury except for symptomatic management
and standard pulmonary care. Steroids are of variable benefit, with
greatest effectiveness in the earliest inflammatory stages of the
lesion.
The etiology of bleomycin pulmonary toxicity has been
investigated in rodent models (Moeller et al., 2008). These studies
implicate various factors secreted by macrophages, including
cytokines (such as transforming growth factor β [TGFβ] and tumor
necrosis factor α [TNFα]), and chemokines (such as CCL2 and
CXCLI2), as causative factors in leading to fibrosis in response to
epithelial damage. Other contributing factors may be disordered
coagulation cascades and imbalances in eicosanoids, leading to overproduction
of profibrotic leukotrienes and underproduction of antifibrotic
prostaglandins. Fibroblasts are recruited to the site of injury
by release of lysophosphatide acid from inflammatory cells and contribute
to the development of fibrosis (Tager et al., 2008). Various
agents (e.g., thalidomide, anti-Her 2 antibodies, PPAR-γ agonists,
N-acetylcysteine, anticoagulants, pirfenidone, and bosentan) have
attenuated bleomycin toxicity in the animal model, given either
before or after the toxic agent. The last four agents are being evaluated
in clinical trials for the treatment of idiopathic pulmonary fibrosis
(Walter et al., 2006), for which bleomycin lung disease in rodents
is the primary disease model.
Other toxic reactions to bleomycin include hyperthermia,
headache, nausea and vomiting, and a peculiar acute fulminant reaction
observed in patients with lymphomas. This reaction is characterized
by profound hyperthermia, hypotension, and sustained
cardiorespiratory collapse; it does not appear to be a classical anaphylactic
reaction and possibly may be related to release of an
endogenous pyrogen. This reaction has occurred in ~1% of patients
with lymphomas or testicular cancer.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Mitomycin
This antibiotic was isolated from Streptococcus caespitosus
by Wakaki and associates in 1958. It has limited
clinical utility, having been replaced by less toxic and
more effective drugs in most settings, with the exception
of anal cancers, for which it is curative.
Mitomycin contains an azauridine group and a
quinone group in its structure, as well as a mitosane
ring, and each of these participates in the alkylation
reactions with DNA.
Mechanism of Action. After intracellular enzymatic or spontaneous
chemical reduction of the quinone and loss of the methoxy group,
mitomycin becomes a bifunctional or trifunctional alkylating agent.
Reduction occurs preferentially in hypoxic cells in some experimental
systems. The drug inhibits DNA synthesis and cross-links DNA
at the N6 position of adenine and at the O6 and N7 positions of guanine.
Attempts to repair DNA lead to strand breaks. Mitomycin is a
potent radiosensitizer, teratogen, and carcinogen in rodents.
Resistance has been ascribed to deficient activation, intracellular
inactivation of the reduced quinone, and P-glycoprotein-mediated
drug efflux (Dorr, 1988).
Absorption, Fate, and Excretion. Mitomycin is administered intravenously.
It disappears rapidly from the blood after injection, with a
t 1/2
of 25-90 minutes. Peak concentrations in plasma are 0.4 μg/mL
after doses of 20 mg/m 2 (Dorr, 1988). The drug distributes widely
throughout the body but is not detected in the CNS. Inactivation
occurs by hepatic metabolism or chemical conjugation with
sulfhydryls. Less than 10% of the active drug is excreted in the urine
or the bile.
Therapeutic Uses. Mitomycin (mitomycin-C; MUTAMYCIN, others) is
administered by intravenous infusion; extravasation may result in
severe local injury. The usual dose (6-20 mg/m 2 ) is given as a single
bolus every 6-8 weeks. Dosage is modified based on hematological
recovery. Mitomycin also may be used by direct instillation into the
bladder to treat superficial carcinomas (Boccardo et al., 1994).
Mitomycin is used in combination with 5-FU and cisplatin,
for anal cancer. Mitomycin is used off label (in the form of an extemporaneously
compounded eye drop) as an adjunct to surgery to
inhibit wound healing and reduce scarring; it appears to have benefit
in the management of malignant and nonmalignant ophthalmic
pathologies (see the review by Abraham, 2006).
Clinical Toxicities. The major toxic effect is myelosuppression,
characterized by marked leukopenia and thrombocytopenia; after
higher doses, the nadirs may be delayed and cumulative, with
recovery only after 6-8 weeks of pancytopenia. Nausea, vomiting,
diarrhea, stomatitis, rash, fever, and malaise also are observed. A
hemolytic uremic syndrome represents the most dangerous toxic
manifestation of mitomycin and is believed to result from druginduced
endothelial damage. Patients who have received >50
mg/m 2 total dose may acutely develop hemolysis, neurological
abnormalities, interstitial pneumonia, and glomerular damage
resulting in renal failure. The incidence of renal failure increases
to 28% in patients who receive total doses of ≥70 mg/m 2 . There is
no effective treatment for the disorder. It must be recognized early,