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

1178 Tamoxifen is a triphenylethylene with the same stilbene
nucleus as DES; compounds of this class display a variety of estrogenic
and anti-estrogenic activities. In general, the trans conformations
have anti-estrogenic activity, whereas the cis conformations
display estrogenic activity. However, the pharmacological activity
of the trans compound depends on the species, target tissue, and gene.
Hepatic metabolism produces primarily N-desmethyltamoxifen,
which has affinity for ER comparable to that of tamoxifen, and lesser
amounts of the highly active 4-hydroxy metabolite, which has a
25-50 times higher affinity for both ERα and ERβ than does tamoxifen
(Kuiper et al., 1997). Tamoxifen is marketed as the pure transisomer.
Toremifene is a triphenylethylene with a chlorine
substitution at the R2 position.
Raloxifene is a polyhydroxylated nonsteroidal compound
with a benzothiophene core. Raloxifene binds with high affinity for
both ERα and ERβ (Kuiper et al., 1997).
Clomiphene citrate is a triphenylethylene; its two isomers,
zuclomiphene (cis-clomiphene) and enclomiphene (trans-clomiphene),
are a weak estrogen agonist and a potent antagonist, respectively.
Clomiphene binds to both ERα and ERβ, but the individual isomers
have not been examined (Kuiper et al., 1997).
Fulvestrant is a 7α-alkylamide derivative of estradiol that
interacts with both ERα and ERβ (Van Den Bemd et al., 1999).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Pharmacological Effects
Tamoxifen exhibits anti-estrogenic, estrogenic, or
mixed activity depending on the species and target gene
measured. In clinical tests or laboratory studies with
human cells, the drug’s activity depends on the tissue
and end point measured. For example, tamoxifen
inhibits the proliferation of cultured human breast
cancer cells and reduces tumor size and number in
women (reviewed in Jaiyesimi et al., 1995), and yet it
stimulates proliferation of endometrial cells and causes
endometrial thickening (Lahti et al., 1993). The drug
has an antiresorptive effect on bone, and in humans it
decreases total cholesterol, LDL, and LPA but does not
increase HDL and triglycerides (Love et al., 1994).
Tamoxifen treatment causes a 2- to 3-fold increase in
the relative risk of deep vein thrombosis and pulmonary
embolism and a roughly 2-fold increase in endometrial
carcinoma (Smith, 2003). Tamoxifen produces hot
flashes and other adverse effects, including cataracts
and nausea. Due to its agonist activity in bone, it does
not increase the incidence of fractures when used in this
setting.
Raloxifene is an estrogen agonist in bone, where
it exerts an antiresorptive effect. It reduces the number
of vertebral fractures by up to 50% in a dose-dependent
manner (Delmas et al., 1997; Ettinger et al., 1999).
The drug also acts as an estrogen agonist in reducing
total cholesterol and LDL, but it does not increase
HDL or normalize plasminogen-activator inhibitor 1 in
postmenopausal women (Walsh et al., 1998). Raloxifene
does not cause proliferation or thickening of the
endometrium. Preclinical studies indicate that raloxifene
has an antiproliferative effect on ER-positive
breast tumors and on proliferation of ER-positive breast
cancer cell lines (Hol et al., 1997) and significantly
reduces the risk of ER-positive but not ER-negative
breast cancer (Cummings et al., 1999). Raloxifene does
not alleviate the vasomotor symptoms associated with
menopause. Adverse effects include hot flashes and leg
cramps and a 3-fold increase in deep vein thrombosis
and pulmonary embolism (Cummings et al., 1999).
Initial animal studies with clomiphene showed slight estrogenic
activity and moderate anti-estrogenic activity, but the most
striking effect was the inhibition of pituitary gonadotropes. In contrast,
the most prominent effect in women was enlargement of the
ovaries and the drug-induced ovulation in many patients with amenorrhea,
polycystic ovarian syndrome, and dysfunctional bleeding
with anovulatory cycles. This is the basis for clomiphene’s major
pharmacological use: to induce ovulation in women with a functional
hypothalamic-hypophyseal-ovarian system and adequate
endogenous estrogen production. In some cases, clomiphene is used
in conjunction with human gonadotropins (Chapter 38) to induce
ovulation.
Fulvestrant and its less potent forerunner ICI 164,384 have
been purely anti-estrogenic in studies to date. In vitro, fulvestrant
was more potent than 4-hydroxytamoxifen (DeFriend et al., 1994) in
inhibiting proliferation of breast cancer cells, and in clinical trials it
is efficacious in treating tamoxifen-resistant breast cancers
(Robertson et al., 2003).
All of these agents bind to the ligand-binding pocket of both
ERα and ERβ and competitively block estradiol binding. However,
the conformation of the ligand-bound ERs is different with different
ligands (Smith and O’Malley, 2004), and this has two important
mechanistic consequences. The distinct ER-ligand conformations
recruit different co-activators and co-repressors onto the promoter
of a target gene by differential protein-protein interactions at the
receptor surface. The tissue-specific actions of SERMs thus can be
explained in part by the distinct conformation of the ER when occupied
by different ligands, in combination with different co-activator
and co-repressor levels in different cell types that together affect the
nature of ER complexes formed in a tissue-selective fashion.
The conformation of ERs, especially in the AF-2 domain,
determines whether a co-activator or a co-repressor will be recruited
to the ER-DNA complex (Smith and O’Malley, 2004). Whereas 17βestradiol
induces a conformation that recruits co-activators to the
receptor, tamoxifen induces a conformation that permits the recruitment
of the co-repressor to both ERα and ERβ. The agonist activity
of tamoxifen seen in tissues such as the endometrium is mediated
by the ligand-independent AF-1 transactivation domain of ER α;
because ERβ does not contain a functional AF-1 domain, tamoxifen
does not activate ERβ (McInerney et al., 1998).
Raloxifene acts as a partial agonist in bone but does not
stimulate endometrial proliferation in postmenopausal women.
Presumably this is due to some combination of differential expression