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

1766 Available Anti-Androgens. Anti-androgens are classified
as steroidal, including cyproterone and megestrol, or nonsteroidal,
including flutamide, bicalutamide (CASODEX,
others), and nilutamide (NILANDRON) (Figure 63–5).
Cyproterone is associated with liver toxicity and has inferior
efficacy compared with other forms of ADT
(Schroder et al., 1999; Thorpe et al., 1996). Cyproterone
is used in the E.U. for treatment of men with metastatic
prostate cancer but is not available in the U.S. Neither
bicalutamide nor flutamide is approved as monotherapy
at any dose for treatment of prostate cancer in the U.S.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Mechanism of Action of Nonsteroidal Anti-Androgens. The nonsteroidal
anti-androgens are taken orally and inhibit ligand binding
and consequent AR translocation from the cytoplasm to the nucleus.
Flutamide. Flutamide has a t 1/2
of 5 hours and therefore is given as a
250-mg dose every 8 hours. Its major metabolite, hydroxyflutamide,
is biologically active; there are at least five other minor metabolites
(Luo et al., 1997). The common side effects include diarrhea, breast
tenderness, and nipple tenderness. Less commonly, nausea, vomiting,
and hepatotoxicity occur (Wysowski and Fourcroy, 1996;
Wysowski et al., 1993).
Bicalutamide. Bicalutamide (CASODEX, others) has a serum t 1/2
of
5-6 days and is taken once daily at a dosage of 50 mg/day when
given with a GnRH agonist. Both enantiomers of bicalutamide
O
F 3 C
O 2 N
F 3 C
C
Cl
O
cyproterone
flutamide
N
O
HO
N
O
Steroidal anti-androgens
OH
O
Non-steroidal anti-androgens
O
S
O
bicalutamide
Figure 63–5. Anti-androgens.
F
F 3 C
O 2 N
megestrol
O
nilutamide
N
OH
N
O
O
undergo glucuronidation to inactive metabolites, and the parent
compounds and metabolites are eliminated in bile and urine. The
elimination t 1/2
of bicalutamide is increased in severe hepatic insufficiency
and is unchanged in renal insufficiency.
Bicalutamide is well tolerated at higher doses with rare additional
side effects. Daily bicalutamide (either low or high dose) is
significantly inferior compared with surgical or medical castration
(Bales and Chodak, 1996; Tyrrell et al., 1998). Although the ease of
administration and favorable toxicity are attractive, concerns about
inferior survival has limited the use of bicalutamide monotherapy.
Nilutamide. Nilutamide (NILADRON) is a second-generation antiandrogen
with an elimination t 1/2
of 45 hours, allowing once-daily
administration at 150 mg/day. Common side effects include mild
nausea, alcohol intolerance (5-20%), and diminished ocular adaptation
to darkness (25-40%); rarely, interstitial pneumonitis occurs
(Decensi et al., 1991; Pfitzenmeyer et al., 1992). It is metabolized to
five known products that are all excreted in the urine. Nilutamide
appears to offer no benefit over the first-generation drugs above and
has the least favorable toxicity profile (Dole and Holdsworth, 1997).
Estrogens. High estrogen levels can reduce testosterone to castrate levels
in 1-2 weeks via negative feedback on the hypothalamic– pituitary
axis. Estrogen also may compete with androgens for steroid hormone
receptors and may thereby exert a cytotoxic effect on prostate cancer
cells (Landström et al., 1994). Numerous estrogenic compounds have
been tested in prostate cancer. Estrogens are associated with increased
myocardial infarctions, strokes, and pulmonary emboli and increased
mortality, as well as impotence, loss of libido, and lethargy. One benefit
is that estrogens prevent bone loss (Scherr et al., 2002).
Most early studies on the use of estrogens used DES and were
conducted between 1960 and 1975 by the Veterans Administration
Cooperative Urological Research Group (VACURG). Two studies
compared orchiectomy to different doses of DES to placebo (Byar,
1973; Byar and Corle, 1988). DES was as effective as orchiectomy for
metastatic prostate cancer but was associated with an increase in cardiovascular
events, including myocardial infarction, cerebrovascular
accident, and pulmonary embolism (Bailar and Byar, 1970; Byar, 1973;
de Voogt et al., 1986; Waymont et al., 1992). Due to its cardiovascular
toxicity and unacceptable mortality at any dose level, DES is not indicated
for prostate cancer treatment and is not available in North
America for that purpose. Other synthetic estrogens have a similar
associated cardiovascular toxicity to that of DES but without the efficacy.
These compounds include conjugated estrogens (PREMARIN, others),
ethinyl estradiol, medroxyprogesterone acetate (PROVERA,
others), and chlorotrianisene (no longer marketed in the U.S.).
Inhibitors of Steroidogenesis. In the castrate state, AR signaling,
despite low steroid levels, supports continued prostate cancer
growth. AR signaling may occur due to androgens produced from
nongonadal sources, AR gene mutations, or AR gene amplification.
Nongonadal sources of androgens include the adrenal glands and the
prostate cancer cells themselves (Figure 63–4). Androstenedione,
produced by the adrenal glands, is converted to testosterone in
peripheral tissues and tumors (Stanbrough et al., 2006). Intratumoral
de novo androgen synthesis also may provide sufficient androgen
for AR-driven cell proliferation (Montgomery et al., 2008).
Ketoconazole is an antifungal agent that interrupts the synthesis
of an essential fungal membrane sterol. In an unrelated action,