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

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SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
hormone-dependent breast cancer and in the management
of endometrial carcinoma previously treated by
surgery and radiotherapy. In addition, progestins
stimulate appetite and restore a sense of well-being
in cachectic patients with advanced stages of cancer
and acquired immunodeficiency syndrome (AIDS).
Although progesterone itself is poorly absorbed when
given orally and must be used with an oil carrier
when given intramuscularly, there are synthetic progesterone
preparations.
Medroxyprogesterone (DEPO-PROVERA, others) can be
administered intramuscularly in doses of 400-1000 mg weekly. An
alternative and more commonly used oral agent is megestrol
acetate (MEGACE, others; 40-320 mg daily in divided doses).
Hydroxyprogesterone (not available in the U.S.) usually is administered
intramuscularly in doses of 1000 mg one or more times weekly.
Beneficial effects have been observed in approximately one-third of
patients with endometrial cancer. The response of breast cancer to
megestrol is predicted by both the presence of estrogen receptors
(ERs) and the evidence of response to a prior hormonal treatment.
The effect of progestin therapy in breast cancer appears to be dose
dependent, with some patients demonstrating second responses following
escalation of megestrol to 1600 mg/day. Clinical use of progestins
in breast cancer has been largely superseded by the advent of
tamoxifen and the aromatase inhibitors (AIs). Responses to progestational
agents also have been reported in metastatic carcinomas of
the prostate and kidney.
ESTROGENS AND ANDROGENS
Discussions of the pharmacology of the estrogens and
androgens appear in Chapters 40, 41, and 66. These
agents are of value in certain neoplastic diseases,
notably those of the prostate and mammary gland,
because these organs are dependent on hormones for
their growth, function, and morphological integrity.
Carcinomas arising from these organs often retain the
hormonal responsiveness of their normal counterpart
tissues. By changing the hormonal environment of such
tumors, it is possible to alter the course of the neoplastic
process.
Estrogens and Androgens in the Treatment
of Mammary Carcinoma
High doses of estrogen have long been recognized as
effective treatment of breast cancer. However, serious
side effects such as thromboembolism prompted the
development of alternate strategies. Paradoxically,
anti-estrogens also are effective, as seen by remission
of disease achieved with oophorectomy. Thus, because
of equivalent efficacy and more favorable side effects,
anti-estrogens such as tamoxifen and the AIs have
replaced estrogens or androgens for breast cancer. The
presence of the ERs and progesterone receptors (PRs)
on tumor tissue serves as a biomarker for response to
hormonal therapy in breast cancer and identifies the
subset of patients with a ≥60% likelihood of responding.
The response rate to anti-estrogen treatment is somewhat
lower in the subset of patients with tumors that
are ER+ or PR+ but also positive for human epidermal
growth factor receptors HER1/neu amplification. In
contrast, ER-negative and PR-negative carcinomas do
not respond to hormonal therapy.
Responses to hormonal therapy may not be apparent clinically
or by imaging for 8-12 weeks. If the disease responds or remains stable
on a given treatment, the medication typically should be continued
until the disease progresses or unwanted toxicities develop. The
duration of an induced remission in patients with metastatic disease
averages 6-12 months but sometimes can last for many years.
Anti-Estrogen Therapy
Anti-estrogen approaches for the therapy of hormone
receptor–positive breast cancer include the use of selective
estrogen-receptor modulators (SERMs), selective
estrogen-receptor downregulators (SERDs), and AIs
(Table 63–1).
Selective Estrogen-Receptor Modulators. SERMs bind to
the ER and exert either estrogenic or anti-estrogenic
effects, depending on the specific organ. Tamoxifen citrate
is the most widely studied anti-estrogenic treatment
in breast cancer. The recent decline in breast cancer
mortality in Western countries is believed to be partly
due to the common use of tamoxifen, especially in the
adjuvant setting. However, in addition to its estrogen
antagonist effects in breast cancer, tamoxifen also
exerts estrogenic agonist effects on non-breast tissues,
thus influencing the overall therapeutic index of the drug.
Therefore, several novel anti-estrogen compounds that
offer the potential for enhanced efficacy and reduced toxicity
compared with tamoxifen have been developed.
These novel anti-estrogens can be divided into tamoxifen
analogs [e.g., toremifene (FARESTON), droloxifene,
idoxifene], “fixed ring” compounds [e.g., raloxifene
(EVISTA), lasofoxifene, arzoxifene, miproxifene, levormeloxifene,
EM652], and the SERDs [e.g., fulvestrant
(FASLODEX), SR 16234, and ZK 191703, the latter also
termed “pure anti-estrogens”] (Howell et al., 2004a).
Tamoxifen. Tamoxifen was first synthesized in 1966 and
initially developed as an oral contraceptive but instead
was found to induce ovulation and proved to have antiproliferative
effects on estrogen-dependent breast cancer
cell lines. For >3 decades, tamoxifen has been studied