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Anastrozole: A New Selective Nonsteroidal Aromatase Inhibitor

Anastrozole: A New Selective Nonsteroidal Aromatase Inhibitor

ABSTRACT: Aromatase (estrogen synthetase) is the enzyme complex responsible for the final step in estrogen synthesis—the conversion of androstenedione and testosterone to estrone and estradiol, respectively. Inhibitors of this enzyme have been shown to be clinically effective in the treatment of advanced breast cancer in postmenopausal women, in whom the major source of estrogen production derives from aromatization of adrenal androgens in peripheral tissues, such as muscle, liver, and fat. The most widely used aromatase inhibitor has been aminoglutethimide; however, it is nonselective and also inhibits adrenocorticosteroid synthesis, necessitating hydrocortisone supplementation. Aminoglutethimide is also associated with frequent and troublesome side effects. Formestane, the first selective aromatase inhibitor to be developed, has an improved safety profile and selectivity, but its use has been limited somewhat by its inconvenient administration via intramuscular injection. In this article, the preclinical and clinical data published to date on the new third-generation aromatase inhibitor anastrozole (Arimidex) are presented in the context of current endocrine therapies. Future applications of aromatase inhibitors, both as monotherapy and in combination with other endocrine therapies, are discussed. The use of aromatase inhibitors in advanced disease, the adjuvant setting, and as possible chemopreventive agents are examined. [ONCOLOGY 11(11): 1697-1703, 1997]


The American Cancer Society estimates that 180,200 women will be diagnosed with breast cancer in 1997, making the breast the leading site of new cancer in women. Breast cancer is also the number two cause of cancer death among Western women.[1]

In 1896, it was established that oophorectomy could result in disease regression in women with metastatic breast cancer.[2] Today, endocrine therapy plays a major role in the treatment of women with hormone-dependent breast cancer.

An important predictor of the likelihood of response to endocrine therapy is estrogen-receptor (ER) and progesterone-receptor (PR) status of the primary tumor. Tumors that are positive for both receptors have a 70% response rate, as compared with an approximate 33% response rate for tumors positive for only one receptor.

Other predictors of response include site of metastases (bone and soft-tissue disease showing a more favorable response than visceral disease), menopausal status (postmenopausal women more responsive than premenopausal women), patient age (response improving with increasing age), disease-free interval (better response associated with prolonged disease-free interval), and prior response to endocrine therapy.[3]

Hormonal therapies for breast cancer include surgical or radiation-induced castration (in premenopausal women with functioning ovaries) or medical treatment with compounds such as antiestrogens, gonadotropin hormone-releasing hormone (GnRH) analogs, progestins, and aromatase inhibitors. All of these agents affect the production or utilization of estrogen or progesterone in premenopausal or postmenopausal women.[4,5]

Current Endocrine Therapies


The most widely used endocrine therapy is tamoxifen (Nolvadex), a nonsteroidal antiestrogen. It is presently indicated for: (1) advanced breast cancer (in both premenopausal and postmenopausal women); (2) coadministration with chemotherapeutic agents; and (3) adjuvant monotherapy.[6] Given as adjuvant therapy, tamoxifen has been shown to prolong survival,[7] extend disease-free survival,[8] and reduce the incidence of new contralateral primary breast tumors.[9]

Although all of its mechanism(s) of action are not completely understood, tamoxifen is known to compete with circulating estrogen to bind to the ER. This binding induces receptor activation, and the complex translocates to the nucleus, where it interacts with specific regions of DNA. As this interaction does not induce gene transcription, cell growth is inhibited.[10,11] Tamoxifen also has partial agonist activity and exerts beneficial estrogenic-like effects on bone and lipids[12]; however, this property may also be associated with detrimental effects. For example, studies have found tamoxifen use to be associated with an increased incidence of endometrial cancer.[13] Moreover, there is evidence from animal models of human breast cancer that the agonist activity of tamoxifen may eventually stimulate breast tumor growth.[14] Thus, new antiestrogens with weak or no agonist activity are in development, which include tamoxifen analogs, such as toremifene (Fareston) and droloxifene, and pure steroidal antiestrogens, such ICI 182,780. The role of these agents in breast cancer is yet to be defined.

Approximately 30% of unselected patients with advanced- or early-stage breast cancer respond to treatment with tamoxifen. Those who do not respond or whose disease progresses after tamoxifen treatment may then be given other hormone therapies, such as progestins or aromatase inhibitors.


The most common progestational agents used in the treatment of advanced breast cancer are megestrol acetate (Megace) and medroxyprogesterone acetate. Due to the significant side effects associated with these agents, such as weight gain and fluid retention, they are generally used as second- or third-line therapy. Response rates in unselected patients with advanced disease are in the range of 30%.[15,16] However, high- vs low-dose studies have suggested that superior responses may be achieved with higher doses.[17,18]

The mechanism of action of progestins is not well understood but may involve a direct action on the cell mediated through the progesterone receptor, as well as an indirect effect mediated through the hypothalamus/pituitary/ovarian and pituitary/adrenal axes. It has been suggested that megestrol and medroxyprogesterone may have different modes of action; however, randomized studies need to be performed to address this issue.

GnRH Analogs

Gonadotropin hormone-releasing analogs, such as leuprolide acetate (Lupron) and goserelin acetate (Zoladex), are used for the treatment of advanced breast cancer patients with intact ovarian function, ie, premenopausal and perimenopausal women. Objective disease response rates of approximately 40% have been reported in patients with advanced disease.[4] These compounds bind to luteinizing hormone-releasing hormone (LHRH) receptors in the pituitary and subsequently cause a decrease in estrogen to castrate levels. Gonadotropin hormone-releasing analogs are administered monthly by injection.

Aromatase Inhibitors

Aromatase inhibitors reduce the synthesis of estrogens by inhibiting the aromatase enzyme complex. As monotherapy, these agents are useful in postmenopausal women, in whom estrogens are produced predominantly by the aromatization of adrenal androgens (androstenedione, testosterone) in peripheral tissues, such as fat, muscle, and skin. By reducing the levels of estrogens in these tissues, aromatase inhibitors decrease ER binding, which, in turn, inhibits estrogen-induced cellular effects.

The most extensively studied first-generation aromatase inhibitor is aminoglutethimide. This compound inhibits the conversion of cholesterol to pregnenolone by blocking the enzyme 20,22-desmolase (cytochrome P450, side-chain cleavage [cyt P450scc]). However, because this inhibition occurs early in the steroid biosynthesis pathway, hydrocortisone supplementation is necessary to avoid adrenal insufficiency (Figure 1). Thus, this agent is neither a selective nor a powerful inhibitor of aromatase. Reported objective response rates in patients with advanced breast cancer range from 28% to 43%.[19-22]

Aminoglutethimide is associated with various side effects, including lethargy, ataxia,[23] rash, nausea, and anorexia,[24] as well as some potentially serious, but rare, effects, such as hypothyroidism,[25] prolonged thrombocytopenia,[26] agranulocytosis, pancytopenia,[27] and systemic lupus erythematosus.[28] In approximately 10% of patients, aminoglutethimide treatment must be discontinued due to toxicity. Research has therefore focused on synthesizing more specific and potent inhibitors of aromatase.

Formestane (4-hydroxyandrostenedione), commercially available in Europe, is a highly specific, selective aromatase inhibitor. It produces an objective response rate of 24% to 35% in the first-line treatment of advanced breast cancer.[29] Its use is limited somewhat by its parenteral formulation and associated injection site reactions.[30]


Preclinical Pharmacology

Anastrozole (Arimidex), a potent nonsteroidal aromatase inhibitor, is the first selective, orally administered aromatase inhibitor to be approved in the United States for use in the treatment of advanced breast cancer in postmenopausal women. It has high potency, inhibiting human placental aromatase in vitro with an IC50 (concentration that inhibits enzyme activity by 50%) of 14.6 nM.[31] In mature female rats, 0.1 mg/kg of anastrozole blocks ovulation, and twice-daily administration of

³ 0.1 mg/kg of anastrozole to male pigtailed monkeys inhibits peripheral aromatase and reduces circulating estradiol by 50% to 60%.[32]

The selectivity of this compound was assessed by investigating its effects on the enzymes associated with steroid hormone metabolism (Table 1). These data show that anastrozole is highly selective for aromatase, as inhibition of other enzymes occurs at much higher doses than are required to inhibit aromatase.[32]

In various isolated animal tissues in vivo, anastrozole, at concentrations up to 10-5 M, had little or no effect on muscarinic acetylcholine receptors, histamine (H1 or H2) receptors, serotonin (HT1 or HT2) receptors, or alpha-1-, alpha-2-, beta-1-, or beta-2-adrenoreceptors. At doses of 10 mg/kg, anastrozole had no central nervous system effects in mice or rats, no local anesthetic activity, no effect on pain perception, no effect on gastrointestinal motility in mice, and no effect on cardiovascular function, renal function, gastric acid secretion, clotting mechanisms, or inflamma- tory responses in rats.[33]


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