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in drug combinations that will be mentioned throughout this review. Aromatase inhibitors Human aromatase belongs to the cytochrome P450 family and is the product of the CYP19A1 gene on chromosome 15. Aromatase is the only known enzyme in
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The effects of two steroidal (4-hydroxyandrostenedione and atamestane) and three non-steroidal (fadrozole, vorozole, and pentrozole) aromatase inhibitors on the levels of aromatase mRNA and protein were examined in vitro and in vivo. Immunocytochemistry revealed increased quantities of immunoreactive aromatase in human choriocarcinoma-derived JEG-3 cells in response to pretreatment with the non-steroidal inhibitors. To elucidate this effect in detail, aromatase protein in JEG-3 cells after treatment with various inhibitors was quantified using an enzyme-linked immunosorbent assay (ELISA). A time-dependent increase in aromatase protein in the cells was observed with all the aromatase inhibitors except 4-hydroxyandrostenedione, whereas aromatase mRNA levels in the cells remained unchanged during the inhibitor treatment. The three non-steroidal agents caused an approximately fourfold increase in aromatase protein in the cells 24 h after the treatment, as compared with untreated controls. The increase in aromatase protein in the cells was not blocked by treatment with cycloheximide, an inhibitor of protein synthesis. The inhibitors also appeared to block the rapid degradation observed in JEG-3 cells after induction by forskolin. In vivo, daily injection of the inhibitors into adult female mice caused increases in levels of both aromatase mRNA and protein in the ovary. The increase in aromatase mRNA in this in vivo study could be explained by an increase in gonadotropin concentrations in response to decreased plasma concentrations of estrogens. In conclusion, we suggest that aromatase inhibitors increase aromatase protein through stabilization and reduced protein turnover.
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was only with the discovery aromatase inhibitors (AIs) that a real step forward was made possible ( Santen et al . 1974 ), as until then no SERMS had provided superior activity when compared with tamoxifen. Therefore, the first report of the results
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KU Leuven, University Hospitals Leuven, University Hospitals Leuven, Department of Oncology, Leuven, Belgium
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KU Leuven, University Hospitals Leuven, University Hospitals Leuven, Department of Oncology, Leuven, Belgium
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KU Leuven, University Hospitals Leuven, University Hospitals Leuven, Department of Oncology, Leuven, Belgium
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–To offer more? (aTTom) trial presented at the 2013 ASCO meeting ( Gray et al . 2013 ). Another important type of anti-estrogen therapy is treatment with aromatase inhibitors (AIs). This hormone therapy is typically administered in postmenopausal breast
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has been established as an important target for the anti-estrogen therapy in the hormone-dependent breast carcinoma in postmenopausal patients. Third-generation aromatase inhibitors are currently available, and these inhibitors are classified into two
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The development of aromatase inhibitors for breast cancer therapy is a result of successful translational research exploring the biochemical effects of different compounds in vivo. Studies assessing plasma oestrogen levels as well as in vivo aromatase inhibition have revealed a consistent difference with respect to biochemical efficacy between the third generation compounds (anastrozole, letrozole and exemestane) and the previous, first and second generation drugs, corresponding to the improved clinical effects of these compounds as outlined in large phase III studies. Thus, endocrine evaluation has been found to be a valid surrogate parameter for clinical efficacy. Moreover, the results from these studies have added important biological information to our understanding of endocrine regulation of breast cancer. Based on the clinical results so far, aromatase inhibitors are believed to play a key role in future adjuvant therapy of postmenopausal breast cancer patients and potentially also for breast cancer prevention. Interesting findings such as the lack of cross-resistance between steroidal and non-steroidal compounds should be further explored, as this may add additional information to our understanding of breast cancer biology.
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Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.
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findings may also explain why the aromatase inhibitor (AI) anastrozole was less effective in obese women as compared to women of normal weight ( Sestak et al . 2010 ). Moreover, breast cancer patients treated with hormone depletion therapy such as AIs gain
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Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung City, Taiwan, Republic of China
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Introduction Approximately 70% breast cancers are estrogen receptor positive (ER+), and endocrine therapy is the main treatment for ER+ breast cancer patients. Selective ER modulators (e.g. tamoxifen) and aromatase inhibitors (AIs) constitute
