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

factor V Leiden mutation and tamoxifen-induced thromboembolism
has been found (Abramson, 2006).
Like estrogen, tamoxifen is a hepatic carcinogen in animals,
although increases in primary hepatocellular carcinoma have not
been reported in patients on the drug. Tamoxifen causes retinal
deposits, decreased visual acuity, and cataracts in occasional
patients, although the frequency of these changes is more common
in patients on high doses of drug.
In addition to its ability to prevent recurrence or the development
of primary breast cancer, tamoxifen has other end-organ
benefits related to its partial estrogenic action. For example, it may
slow the development of osteoporosis in postmenopausal women.
Like certain estrogens, tamoxifen lowers total serum cholesterol,
low-density-lipoprotein cholesterol, and lipoproteins and raises
apolipoprotein A-I levels, potentially decreasing the risk of myocardial
infarction.
Tamoxifen Resistance. Despite its benefits, initial or acquired resistance
to tamoxifen frequently occurs (Moy and Goss, 2006).
Polymorphisms in CYP2D6 that reduce its activity lead to lower
plasma levels of 4-OH tamoxifen, a potent metabolite, and are associated
with higher risks of disease relapse and a lower incidence of hot
flashes (Goetz et al., 2005). CYP2D6 is responsible for the activation
of tamoxifen to its active metabolite endoxifen (Figure 63–1). Crosstalk
between the ER and HER2/neu pathway also has been implicated
in tamoxifen resistance. The paired box 2 gene product (PAX2) has
been identified as a crucial mediator of ER repression of ErbB2 by
tamoxifen (Hurtado et al., 2008). Interactions between PAX2 and the
ER co-activator AIB-1/SRC-3 determine tamoxifen response in breast
cancer cells.
Toremifene. Toremifene (FARESTON) is a triphenylethylene
derivative of tamoxifen and has a similar pharmacological
profile (Figure 63–2). Toremifene is indicated
for the treatment of breast cancer in women with
tumors that are ER + or of unknown receptor status.
In preclinical models, toremifene has activity against breast
cancer cells in vitro and in vivo similar to that of tamoxifen. Unlike
tamoxifen, however, toremifene is not hepatocarcinogenic in experimental
animals. Two adjuvant studies have compared efficacy of
these two agents and, in particular, long-term tolerability and
safety, in early-stage breast cancer. There were no significant differences
in efficacy or tolerability after a median follow-up of 4.4
years, and the number of subsequent second cancers was similar
(Howell et al., 2004a). However, in vitro in a low-estrogen environment,
toremifene has less estrogen agonist effect than tamoxifen.
This may make toremifene more effective in combination with an
AI than tamoxifen, and this possibility is the subject of ongoing
clinical trials.
Selective Estrogen Receptor
Downregulators
SERDs, also termed “pure anti-estrogens,” include
fulvestrant and a host of agents in experimental trials
(RU 58668, SR 16234, ZD 164384, and ZK 191703).
Cl
HO
O
Toremifene
CH 3 OH
(CH 2 ) 6
O S
CF 2
Fulvestrant
CF 3
N CH 3
CH 3
Figure 63–2. Chemical structures of toremifene and fulvestrant.
SERDs, unlike SERMs, are devoid of any estrogen
agonist activity.
Fulvestrant. Fulvestrant (FASLODEX) is the first agent
approved by the U.S. Food and Drug Administration
(FDA) in the class of ER downregulators (Figure 63–2).
This new class of hormone antagonists was hypothesized
to have an improved safety profile, faster onset,
and longer duration of action than the SERMs due to
their pure ER antagonist activity (Robertson, 2002).
Fulvestrant is approved for postmenopausal women
with hormone receptor–positive metastatic breast cancer
that has progressed on tamoxifen.
Mechanism of Action. Fulvestrant is a steroidal anti-estrogen that binds
to the ER with an affinity >100 times that of tamoxifen. The drug
inhibits the binding of estrogen but also alters the receptor structure
such that the receptor is targeted for proteasomal degradation; fulvestrant
also may inhibit receptor dimerization. Unlike tamoxifen, which
stabilizes or even increases ER expression, fulvestrant reduces the
number of ER molecules in cells, both in vitro and in vivo; as a consequence
of this ER downregulation, the drug abolishes ER-mediated
transcription of estrogen-dependent genes (Howell et al., 2004b).
Absorption, Fate, and Excretion. Maximum plasma concentrations
are reached ~7 days after intramuscular administration of fulvestrant
and are maintained over 1 month. The plasma t 1/2
is ~40 days.
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CHAPTER 63
NATURAL PRODUCTS IN CANCER CHEMOTHERAPY: HORMONES AND RELATED AGENTS