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

Mechanism of Action. In contrast to the reversible competitive
inhibitors of aromatase (anastrozole and letrozole), exemestane
irreversibly inactivates the enzyme and is referred to as a “suicide
substrate.” Doses of 25 mg/day inhibit aromatase activity by 98%
and lower plasma estrone and estradiol levels by ~90% in postmenopausal
women.
Absorption, Fate, and Excretion. Exemestane is rapidly absorbed from
the GI tract, reaching maximum plasma levels after 2 hours. Its
absorption is increased by 40% after a high-fat meal. Exemestane is
highly protein bound in plasma and has a terminal t 1/2
of ~24 hours. It
is extensively metabolized in the liver to inactive metabolites. A key
metabolite, 17-hydroxyexemestane, which is formed by reduction of
the 17-oxo group via 17-β-hydroxysteroid dehydrogenase, has weak
androgenic activity, which also could contribute to antitumor activity.
The elimination t 1/2
of the parent drug is 24 hours. Although significant
quantities of active metabolites are excreted in the urine, no dosage
adjustments are recommended in patients with renal dysfunction.
Therapeutic Uses. Exemestane (AROMASIN), 25 mg administered orally
once daily, is approved for disease progression in postmenopausal
women who completed 2-3 years of adjuvant tamoxifen based on
results from a randomized clinical trial in women with ER + breast
cancer. Women who had completed 2-3 years of adjuvant tamoxifen
were randomized to complete a total of 5 years of adjuvant treatment
with tamoxifen or exemestane (Coombes et al., 2004). The
unadjusted hazard ratio in the exemestane group versus the tamoxifen
group was 0.68, representing a 32% reduction in risk and corresponding
to an absolute benefit in terms of disease-free survival of
4.7% at 3 years after randomization. Overall survival was not significantly
different in the two groups.
In advanced breast cancer, exemestane improves time to disease
progression compared with tamoxifen as first-line treatment
(Paridaens et al., 2008). Exemestane also has been evaluated in a phase
III trial against megestrol in women with disease progressing on prior
anti-estrogen therapy. Patients receiving exemestane had a similar
response rate but improved time to disease progression and time to
treatment failure and had a longer duration of survival compared with
those taking megestrol acetate. Responses to treatment also have been
shown in women with disease progressing on prior nonsteroidal AIs.
Clinical Toxicity. Exemestane generally is well tolerated.
Discontinuations due to toxicity are uncommon (2.8%). Hot flashes,
nausea, fatigue, increased sweating, peripheral edema, and increased
appetite have been reported. In the trial comparing exemestane to
tamoxifen in early-stage breast cancer, exemestane caused more
frequent arthralgia and diarrhea but less frequent vaginal bleeding
and muscle cramps. Visual disturbances and clinical fractures were
more common with exemestane (Coombes et al., 2004).
Whether exemestane negatively affects long-term bone
metabolism remains to be determined. The drug has less androgenic
activity than formestane but otherwise has a similar toxicity profile.
HORMONE THERAPY IN PROSTATE
CANCER
Androgens stimulate the growth of normal and cancerous
prostate cells. The critical role of androgens for
prostate cancer growth was established in 1941 and led
to the awarding of a Nobel Prize in 1966 to Dr. Charles
Huggins (Huggins and Hodges, 1941; Huggins et al.,
1941). These findings established androgen deprivation
therapy as the mainstay of treatment for patients with
advanced prostate cancer.
Localized prostate cancer frequently is curable
with surgery or radiation therapy. However, when distant
metastases are present, hormone therapy is the primary
treatment. Standard approaches either reduce the concentration
of endogenous androgens or inhibit their effects.
Androgen deprivation therapy (ADT) is the standard
first-line treatment (Sharifi et al., 2005). ADT is accomplished
via surgical castration (bilateral orchiectomy) or
medical castration (using gonadotropin-releasing hormone
[GnRH] agonists or antagonists). Other hormone
therapy approaches are used in second-line
treatment and include anti-androgens, estrogens, and
inhibitors of steroidogenesis (see the discussion later
in this section).
ADT is considered palliative, not curative, treatment
(Walsh et al., 2001). ADT can alleviate cancerrelated
symptoms, produce objective responses, and
normalize serum prostate-specific antigen (PSA) in
>90% of patients. ADT provides important quality-oflife
benefits, including reduction of bone pain and
reduction of rates of pathological fracture, spinal cord
compression, and ureteral obstruction (Huggins et al.,
1941). It also prolongs survival (Sharifi et al., 2005).
The duration of response to ADT for patients with metastatic
disease is variable but typically lasts 14-20 months (Crawford
et al., 1989; Eisenberger et al., 1998). Disease progression despite ADT
signifies a castration-resistant state. However, many men respond to
secondary hormonal manipulations. Despite castrate levels of testosterone,
low-level androgen (DHEA) synthesis from the adrenal
glands may permit the continued androgen-driven growth of prostate
cancer cells. Therefore, anti-androgens (which competitively bind
the androgen receptor [AR]), inhibitors of steroidogenesis (such as
ketoconazole), and estrogens frequently are employed as secondary
hormone therapies. Unlike the nearly universal response to ADT,
only the minority of patients experience symptomatic relief or tumor
regression when treated with secondary hormone therapies. When
patients become refractory to further hormonal therapies, their disease
is considered androgen independent. In these patients, the next
treatment option usually is cytotoxic chemotherapy; docetaxel has a
proven survival benefit, with average overall survival of 18 months
(Petrylak et al., 2004; Tannock et al., 2004).
Common side effects of androgen deprivation include vasomotor
flashing, loss of libido, impotence, gynecomastia, fatigue, anemia,
weight gain, decreased insulin sensitivity, altered lipid profiles,
osteoporosis and fractures, and loss of muscle mass (Saylor and
Smith, 2009). The spectrum of side effects of GnRH agonists is distinct
from the metabolic syndrome (Smith, 2008). ADT is associated
with an increased risk of diabetes and coronary heart disease
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CHAPTER 63
NATURAL PRODUCTS IN CANCER CHEMOTHERAPY: HORMONES AND RELATED AGENTS