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

H 2 N O
NH 2
NH
NH 2 O
N N O
CH 3 H O
N R
O HO
N
H 2 N
O
NH N S
CH 3 N
O
H N CH 3 HO CH 3 S
H
O N
HO
R
OH
O
N
Bleomycinic Acid: OH
O H
OH
OH
O
+ CH 3
Bleomycin A 2 : NHCH 2 CH 2 CH 2 S
OH
CH 3
O
OH
NH
Bleomycin B
NH 2 : NHCH
O
2 CH 2 CH 2 CH 2 NHC
2
NH 2
Figure 61–14. Chemical structures of bleomycin A 2
and B 2
.
produce oxygen radicals (Burger, 1998). Metallobleomycin
complexes can be activated by reaction with the flavin enzyme,
NADPH-cytochrome P450 reductase. Bleomycin binds to DNA,
and the activated complex generates free radicals that are responsible
for abstraction of a proton at the 3′ position of the deoxyribose
backbone of the DNA chain, opening the deoxyribose ring and generating
a strand break in DNA. The process for repair of this break
is poorly understood, but an excess of breaks generates apoptosis.
Bleomycin is degraded by a specific hydrolase found in various
normal tissues, including liver. Hydrolase activity is low in skin and
lung, perhaps contributing to the serious toxicity at those sites. Some
bleomycin-resistant cells contain high levels of hydrolase activity (Sebti
et al., 1991). In other cell lines, resistance has been attributed to
decreased uptake, repair of strand breaks, or drug inactivation by thiols
or thiol-rich proteins. A polymorphism of the hydrolase gene, SNP
A1450G, has been identified in 10% of patients with testicular cancer,
and the G/G genotype is associated with a 20% decreased survival in
patients treated with bleomycin combination therapy, suggesting that
this single nucleotide polymorphism is associated with increased
hydrolase activity (de Haas et al., 2008).
Absorption, Fate, and Excretion. Bleomycin is administered intravenously,
intramuscularly, or subcutaneously or instilled into the
bladder for local treatment of bladder cancer. After intravenous infusion,
relatively high drug concentrations are detected in the skin and
lungs of experimental animals, and these organs become major sites
of toxicity. Having a high molecular mass, bleomycin crosses the
blood-brain barrier poorly.
After intravenous administration of a bolus dose of 15 mg/m 2 ,
peak concentrations of 1-5 mg/mL are achieved in plasma. The halftime
for elimination is ~3 hours. About two-thirds of the drug are
excreted intact in the urine. Concentrations in plasma are greatly elevated
if usual doses are given to patients with renal impairment and
if such patients are at high risk of developing pulmonary toxicity.
Doses of bleomycin should be reduced in the presence of a CrCl <60
mL/min (Dalgleish et al., 1984).
Therapeutic Uses. The recommended dose of bleomycin (BLENOX-
ANE, others) is 10-20 units/m 2 given weekly or twice weekly by the
intravenous, intramuscular, or subcutaneous route. A test dose of ≤2
units before the first two doses is recommended for lymphoma
patients. A variety of regimens are employed clinically, with
bleomycin doses expressed in units. In treating testicular cancer, a
standard total dose of 30 mg is given weekly for 3 consecutive
weeks, and for three to four cycles of treatment. Total courses
exceeding 250 mg should be given with caution, and usually only in
high-risk testicular cancer treatment, because of a marked increase
in the risk of pulmonary toxicity above this total dose. Bleomycin
also may be instilled into the pleural cavity in doses of 5-60 mg
(depending on the technique) to ablate the pleural space in patients
with malignant effusions.
Bleomycin is highly effective against germ cell tumors of the
testis and ovary. In testicular cancer, it is curative when used with cisplatin
and vinblastine or cisplatin and etoposide. It is a component
of the standard curative ABVD regimen (doxorubicin [adriamycin],
bleomycin, vinblastine, and dacarbazine) for Hodgkin’s lymphoma.
Clinical Toxicities. Because bleomycin causes little myelosuppression,
it has significant advantages in combination with other cytotoxic
drugs. However, it does cause a constellation of cutaneous
toxicities, including hyperpigmentation, hyperkeratosis, erythema,
and even ulceration. Rarely, patients with severe skin toxicity may
experience Raynaud’s phenomenon. Skin changes may begin with
tenderness and swelling of the distal digits and progress to erythematous,
ulcerating lesions over the elbows, knuckles, and other
pressure areas. Healing of these lesions often leaves a residual
hyperpigmentation, and lesions may recur when patients are treated
with other antineoplastic drugs. Rarely, bleomycin causes a flagellate
dermatitis consisting of bands of pruritic erythema on the arms,
back, scalp, and hands. This rash responds readily to topical corticosteroids.
The most serious adverse reaction to bleomycin is pulmonary
toxicity, which begins with a dry cough, fine rales, and diffuse
1717
CHAPTER 61
CYTOTOXIC AGENTS