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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Given orally, its use has not been taken up worldwide on the grounds that it is not as effective as tamoxifen in the clinic. For example, one randomized clinical trial carried out in the early 1990s compared fadrozole (2 mg daily) versus tamoxifen (20 mg daily) in 80 previously untreated postmenopausal patients with metastatic breast cancer. Although there were no statistically significant differences in objective response rates, time to treatment failure (TTF) or survival, there were more complete responses with tamoxifen, for which the duration of objective responses was significantly longer. Toxicity between the two treatment arms was similar and consisted of mild to moderate hot flashes (37%), headaches (6.5%), and mild fatigue (2.6%). These results meant that any further use of fadrozole would be confined to second-line therapy.
Hormonal and Nonhormonal Mechanisms of Sexual Differentiation of the Zebra Finch Brain: Embracing the Null Hypothesis
Published in Akira Matsumoto, Sexual Differentiation of the Brain, 2017
More convincing were experiments using fadrozole, a potent inhibitor of estrogen synthesis. Fadrozole inhibited aromatase activity by 75 to 100% in vivo and in vitro, measured in both young and adult zebra finches.64 Thus, there was no doubt about the effectiveness of this drug. However, when fadrozole or the similar aromatase inhibitor vorozole was given to males for several weeks after hatching, the brain developed to be as masculine that of control males.65–67 Males treated before hatching with fadrozole, on Days 3, 5, or 8 of embryonic life, also have a masculine neural circuit and song.68–72 These studies suggest that high levels of estrogen synthesis during development are not necessary for masculine neural development. Two studies suggest that inhibition of steroid synthesis has some demasculinizing effect. Merten and Stocker-Buschina73 found some demasculinization in two song nuclei caused by posthatching treatment with fadrozole, although the fadrozole-treated males sang and appeared to have neurons that were closer in phenotype to male that to female neurons. Posthatching treatment with the steroid synthesis inhibitor MK434 also is reported to have modest demasculinizing effects on portions of the song system,74 suggesting a role for steroids in masculine neural development. However, no study using steroid synthesis inhibitors or steroid receptor blockers has substantially prevented masculine song system development in males, despite numerous attempts with drugs administered both before and after hatching.
Role of Aromatase Inhibitors (AIs) and Selective Estrogen Receptor Modulators (SERMs) in the Treatment of Uterine Leiomyoma
Published in John C. Petrozza, Uterine Fibroids, 2020
Hilário et al. treated 20 premenopausal patients using anastrazole 1 mg/day for 12 weeks, resulting in a decrease of 9.2% of uterine volume and 32% reduction in symptoms (menstrual duration and dysmenorrhea). They also reported no alterations in gonadotropin measurements, and group concluded that the use of anastrazole was effective; however, it was inferior to GnRH analogues [12]. In another study, Parsanezhad et al. randomized 70 premenopausal women who had a single fibroid 5 cm or greater to treatment with either letrozole 2.5 mg a day or the gonadotropin release-hormone analogue (GnRHa) triptorelin (3.75 mg/month) for 12 weeks. They observed a statistically significant reduction in leiomyoma size in the letrozole group compared with the triptorelin (46% vs. 33%). In addition, serum E2 levels were significantly reduced in the triptorelin arm compared with letrozole; they concluded that there was rapid onset of action of the aromatase inhibitor with the avoidance of the initial flare associated with GnRH analogues [13]. In another study, Gurates et al. treated 16 premenopausal women with uterine leiomyoma measuring 2 cm or greater using a higher dose of letrozole (5 mg daily) for 3 months, resulting in a 47% reduction in uterine leiomyoma size compared with baseline and a mean volume reduction of uterine size of 22% [14]. In this particular study, the mean FSH and LH levels were noted to be statistically higher as the treatment advanced with a significant decrease in serum E2 levels [14]. In addition, there was a significant reduction in blood loss after 3 months of treatment, with no apparent effect on lumbar bone density measurements compared to baseline [14]. Shozu et al. presented a case report in a perimenopausal woman with large uterine fibroids and urinary retention where they used fadrozole 2 mg daily for 8 weeks followed by 1 mg for 4 weeks, resulting in a significant improvement of symptoms and a volume reduction of 71% at 12 weeks [15].
Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Michele De Luca, Maria Antonietta Occhiuzzi, Bruno Rizzuti, Giuseppina Ioele, Gaetano Ragno, Antonio Garofalo, Fedora Grande
The emergence and progression of hormone-responsive breast cancer largely depend on the endocrine oestrogenic activity. The treatment of this form of cancer is currently pursued following two main approaches. The first one, more effective during pre-menopausal events when the gonads are the primary producers of oestrogen, is based on the use of antagonists targeting oestrogen receptors. In this case, tamoxifen is the most prescribed drug1. A second approach is preferred in post-menopause, when the production of oestrogen is limited to extra-glandular tissues and consists in the administration of aromatase inhibitors. This enzyme, belonging to the CYP450 superfamily, is expressed in several tissues including gonads, placenta, brain, bone, and adipose tissue. Aromatase acts as a monooxygenase, catalysing the conversion of androgen to oestrogen; thus, its inhibition results in a near complete oestrogen deprivation. Several compounds have been proposed as aromatase inhibitors, leading to a first, second, and third generation of specific agents, the latter being the most prescribed nowadays. Fadrozole and vorozole, which show a non-steroidal structure, were once commonly prescribed but are no longer utilised today, whereas the use of the irreversible steroid inhibitor exemestane is limited to patients pre-treated with tamoxifen in adjuvant therapy2,3.
Drug design strategies for Cushing’s syndrome
Published in Expert Opinion on Drug Discovery, 2019
S. A. Usanov, A. V. Kliuchenovich, N. V. Strushkevich
In contrast to all the aforementioned drugs, LCI699 (osilodrostat) (Figure 2, 3) was designed as a first-in-class aldosterone synthase (CYP11B2) inhibitor by Novartis. LCI699 was developed based on FAD289, a R-enantiomer of fadrozole (Figure 2, 2), initially used for the treatment of breast cancer through the inhibition of CYP19 (aromatase) [21]. LCI699 was shown to decrease plasma and urine aldosterone concentrations by up to 70–80% in healthy volunteers and in patients with primary aldosteronism [22]. However, at doses >3mg per day, it also inhibits cortisol synthesis. Due to the inhibition of CYP11B1, LCI699 was repurposed for treatment of Cushing’s syndrome [23,24]. It is currently in Phase II clinical development (NCT02180217).
Successes and failures of uterine leiomyoma drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Mohamed Ali, Zunir Tayyeb Chaudhry, Ayman Al-Hendy
Uterine fibroids are known to express high levels of aromatase enzyme and therefore can generate higher amount of local estrogen relative to normal myometrium [26]. Aromatase inhibitors, including letrozole, anastrozole, and fadrozole can inhibit in situ aromatase action and may be used for treatment of UFs. This has been successfully shown in post-menopausal women with fibroids as they lack ovarian estrogen production. Yet, in premenopausal UFs, local aromatization inhibition is overtaken by ovarian robust estrogen production, and the systemic estrogen level remains normal. Eventually, this may reduce the efficacy of aromatase inhibitors in premenopausal women but may also contribute to their favorable side-effect profile over GnRH agonists that cause a flare-up effect owing to receptor stimulation and hyperestrogenesim, followed by receptor down regulation and consequent hypoestrogenism-related side effects. Unfortunately, long-term use of aromatase inhibitors may be associated with bone loss and increased fracture risk that may necessitate concomitant ‘add-back’ therapy [27].