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

Aromatase activity is the product of the CYP19
gene. CYP19 is highly expressed in human placenta
and in granulosa cells of ovarian follicles, where its
expression depends on cyclical gonadotropin stimulation.
Aromatase also is present, at lower levels, in several
nonglandular tissues, including subcutaneous fat,
liver, muscle, brain, and normal breast and in breastcancer
tissue. The aromatase enzyme is responsible for
the conversion of adrenal androgens and gonadal
androstenedione and testosterone to the estrogens,
estrone (E1) and estradiol (E2), respectively (Figure 63–4).
In postmenopausal women, this conversion is the primary
source of circulating estrogens, while estrogen
production in premenopausal women primarily is from
the ovaries.
In postmenopausal women, AIs can suppress
most peripheral aromatase activity, leading to profound
estrogen deprivation. This strategy of estrogen deprivation
of ER + breast cancer cells stands in contrast to the
ER antagonist activity that SERMs and SERDs exert.
Based on their sequence of development, AIs are
classified as first, second, or third generation. In addition,
they are further classified as type 1 (steroidal) or
Cholesterol
Pregnenolone
3β
Progesterone
21
Deoxycorticosterone
11β
Corticosterone
abiraterone
17α
17α
ketoconazole
17-hydroxypregnenolone
3β
17-hydroxyprogesterone
21
11-deoxycortisol
11β
Cortisol
type 2 (nonsteroidal) AIs according to their structure
and mechanism of action. Type 1 inhibitors are
steroidal analogs of androstenedione (Figure 63–3).
Androstenedione analogs bind covalently to the same
site on the aromatase molecule, but unlike androstenedione,
they bind irreversibly because of their conversion
to reactive intermediates by aromatase. Thus,
they commonly are known as aromatase inactivators.
Type 2 inhibitors are nonsteroidal and bind reversibly
to the heme group of the enzyme.
Third-Generation Aromatase Inhibitors
The third-generation inhibitors, developed in the 1990s,
include the type 1 steroidal agent exemestane and the
type 2 nonsteroidal imidazoles anastrozole and letrozole.
Currently, third-generation AIs are used as part of the
standard of care for treatment of early-stage and
advanced breast cancer in postmenopausal women.
Anastrozole. Anastrozole is a potent and selective triazole
AI.
Mechanism of Action. Anastrozole, like letrozole, binds competitively
and specifically to the heme of the CYP19. Anastrozole, 1 mg or 10 mg,
abiraterone
17, 20
17, 20
17, 20
abiraterone
Dehydroepiandrosterone
(DHEA)
3β
Androstenedione
5αR
DHEA
sulfate
A
17βR
Estrone
Testosterone
A
17βR
Dihydrotestosterone
Estradiol
1761
CHAPTER 63
NATURAL PRODUCTS IN CANCER CHEMOTHERAPY: HORMONES AND RELATED AGENTS
18
Aldosterone
Figure 63–4. Steroid synthesis pathways. The enclosed area contains the pathways used by the adrenal glands and gonads. Enzymes are
labeled in green, inhibitors in red. 11β: 11β-hydroxylase; 17,20: C-17,20-lyase (also CYP17); 17α: 17α-hydroxylase (CYP17); 17βR:
17β-reductase; 18: aldosterone synthase; 21: 21-hydroxylase; 3β: 3β-hydroxysteroid dehydrogenase; 5αR: 5α-reductase; A: aromatase.