Disease relevance of FADROZOLE

• Preliminary study of the treatment of advanced breast cancer in postmenopausal women with the aromatase inhibitor CGS 16949A [1].
• CGS 16949A was ineffective against transplantable hormone-independent tumors such as R-3230AC mammary carcinoma, 11095 prostate carcinoma, leukemia L1210, and B16 melanoma [2].
• CGS-16949A might, therefore, be a drug that can be used in the treatment of primary hyperaldosteronism [3].
• Aldosterone release by the dispersed adenoma cells obtained from a patient with primary aldosteronism was also significantly suppressed by CGS-16949A [3].
• To evaluate the role of aromatase inhibitors in the treatment of benign prostatic hyperplasia (BPH), the effects of a potent, oral, nonsteroidal aromatase inhibitor [4-(5,6,7,8-tetrahydroimidazo[1,5a]pyridin-5yl)benzonitrile; CGS-16949A, CIBA-GEIGY] on canine BPH have been studied [4].

High impact information on FADROZOLE

• When ovariectomized mice with MCF-7Ca tumors supplemented with androstenedione were treated with aromatase inhibitors 4-hydroxyandrostenedione (1 mg/mouse/day, s.c.) or CGS 16949A (0.5 mg/mouse/day, s.c.), or with the antiestrogen tamoxifen (10 micrograms/mouse/day, s.c.), tumor growth was significantly inhibited [5].
• CGS 16949A, a new nonsteroidal aromatase inhibitor: effects on hormone-dependent and -independent tumors in vivo [2].
• CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations [6].
• Use of gas liquid chromatography-mass spectrometry techniques revealed similar patterns of reduction in catechol estrogens, estriol, and total urinary estrogens, suggesting that CGS 16949A does not alter the pathways of estrogen metabolism [7].
• Aldosterone release was suppressed 50% by 10(-9) M CGS-16949A, while the IC50 for cortisol in the same cells was 10(-7) M [3].

Chemical compound and disease context of FADROZOLE

• A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion [6].
• We evaluated an imidazole, cytochrome P450-related inhibitor, CGS 16949A, in postmenopausal patients with metastatic breast cancer [8].
• BACKGROUND: In a phase III randomized trial, we compared the effectiveness and tolerability of fadrozole (CGS 16949A), a non-steroidal aromatase inhibitor, to tamoxifen as first-line endocrine therapy in postmenopausal women with advanced breast cancer [9].
• In order to determine the effects of different inhibitors on aromatase in the whole cell, we have utilized the human choriocarcinoma cell line, JEG-3 in culture to compare and study three classes of aromatase inhibitors, 4-hydroxyandrostenedione, fadrozole (CGS 16949A), and aminoglutethimide [10].
• Fourteen-day oral combination dose toxicity study of CGS 16949 A (aromatase inhibitor) with 5-fluorouracil or tamoxifen in rats [11].

Biological context of FADROZOLE

• The IC50 values of YM511 for cell growth and DNA synthesis were 0.13 nM and 0.18 nM, respectively, demonstrating that YM511 was about 3-5 times more potent than CGS 16949A and had no anti-estrogenic or cytotoxic activity [12].
• Cell proliferation stimulated by IL-1beta was reduced by the addition of the Arom inhibitor fadrozole-HCL (CGS-16949A) [13].
• Aromatase activity could be inhibited by administering CGS 16949A (50 micrograms/day/rat) via a mini osmotic Alzet pump (model 2002) for 3 days during pseudopregnancy [14].
• The new nonsteroidal aromatase inhibitor, Fadrozole (CGS 16949A, CIBA-Geigy Corp.), was tested for its ability (i) to inhibit the conversion of testosterone (T) to estradiol (E2) in brain and (ii) to suppress male sexual activity [15].
• (iii) Transfection of aromatase into MCF7 cells led to their growth being stimulated by low doses of androgens and this was inhibited by the aromatase inhibitor CGS 16949A [16].

Anatomical context of FADROZOLE

• Under the effects of Fadrozole (CGS 16949A), a nonsteroidal aromatase inhibitor, the right gonad generally becomes a testis, and the left gonad a testis or an ovotestis [17].
• To prove the hypothesis that E regulates BDNF expression in vivo, fetuses and newborns were treated with the aromatase antagonist CGS 16949A [18].
• CGS 16949A exposure reduced midbrain BDNF mRNA/protein levels [18].
• CGS 16949A inhibited the conversion of [4-14C]androstenedione (A) to [4-14C]estrone by human placental microsomes in a competitive manner (Ki = 1.6 nM) [19].
• The effects of the aromatase inhibitor fadrozole hydrochloride on fetuses and uteri in late pregnant rats [20].

Associations of FADROZOLE with other chemical compounds

• Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis [6].
• We concluded that 1) the new nonsteroidal aromatase inhibitor CGS 16949A is an inhibitor of 11 beta-hydroxylase which is equipotent to metyrapone [3].
• The effect of aromatase inhibitors, 4-hydroxyandrostenedione, CGS 16949A and aminoglutethimide on the inhibition of estrogen 2-hydroxylase activity in rat liver microsomes in vitro and on its induction in vivo has been examined [21].
• Thus compared to each other, CGS 16949A and CGS 20267 are both highly potent in inhibiting estrogen biosynthesis in vitro and in vivo [22].
• In vitro potency and selectivity of the non-steroidal androgen aromatase inhibitor CGS 16949A compared to steroidal inhibitors in the brain [23].

Gene context of FADROZOLE

• PURPOSE: The study investigated the therapeutic effects of fadrozole (CGS 16949A), a new aromatase inhibitor, in women who had received prior treatment for metastatic breast cancer [24].
• The specific involvement of estrogen in the stimulation of this protein was established by demonstrating a reduction in the level of this protein by the addition of CGS 16949 A, an inhibitor of aromatase, a key enzyme in the biosynthesis of estradiol 17-beta and ICI 182,780, an estrogen receptor antagonist [25].
• In vitro investigations with dispersed normal and hyperplastic human adrenocortical cells showed that CGS-16949A at 10(-7)-10(-6) M is a potent 11 beta-hydroxylase inhibitor, which inhibits ACTH-stimulated cortisol release to a similar extent as an equimolar concentration of metyrapone (IC50 for both compounds, 10(-7)-5 X 10(-7) M) [3].
• The gonads of X. laevis were successfully maintained for 14 days in vitro in a medium containing 20 microg/ml aromatase inhibitor (CGS 16949A) [26].
• The results suggest the mechanisms of CGS 16949A action not to be influenced by the presence or absence of ER, but to be due to its potent aromatase inhibition of the conversion of androgens to estrogens [27].

Analytical, diagnostic and therapeutic context of FADROZOLE

• We evaluated the effects of CGS 16949A, a nonsteroidal inhibitor of aromatase activity, in 12 postmenopausal women with breast cancer by measuring plasma and/or urinary androgens and estrogens after oral administration of CGS 16949A at doses ranging from 0.6-16 mg daily; each dose was given for 2 weeks [7].
• The enantiomers of the potent nonsteroidal inhibitor of aromatase fadrozole hydrochloride 3 have been separated and their absolute configuration determined by X-ray crystallography [28].
• CGS 16949A, a newer agent, is also in Phase III clinical trials [29].
• CGS 16949A was neither androgenic nor estrogenic in rats using standard bioassays [19].
• Using high pressure liquid chromatography and employing estradiol as a substrate, the IC50 values were 2.2, 98, 110 and 908 microM for the reference compound ketoconazole and the aromatase inhibitors, 4-hydroxyandrostenedione, CGS 16949A and aminoglutethimide, respectively [21].

References