In vitro and in vivo studies demonstrating potent and selective estrogen inhibition with the nonsteroidal aromatase inhibitor CGS 16949A

Steele, Ronald E.; Mellor, Lynn B.; Sawyer, Wilbur K.; Wasvary, Jong M.; Browne, Leslie J.

doi:10.1016/0039-128x(83)90068-5

Cited by 204 publications

(65 citation statements)

References 22 publications

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“…1). 33,35 It has been reported to inhibit other enzymes but only at concentrations 4-5 orders of magnitude greater than those needed to inhibit CYP19, which are higher concentrations than those used in this study. 6,30 In our study, the sensitivity analysis shows that E2 is sensitive to the uptake and inhibition of FAD (k 15 , k 16 ), while T is not sensitive to either the uptake or inhibition of FAD (k 15 , k 16 , k 17 ).…”

Section: Discussionmentioning

confidence: 67%

Mechanistic Computational Model of Ovarian Steroidogenesis to Predict Biochemical Responses to Endocrine Active Compounds

et al. 2007

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Abstract-Sex steroids, which have an important role in a wide range of physiological and pathological processes, are synthesized primarily in the gonads and adrenal glands through a series of enzyme-mediated reactions. The activity of steroidogenic enzymes can be altered by a variety of endocrine active compounds (EAC), some of which are therapeutics and others that are environmental contaminants. A steady-state computational model of the intraovarian metabolic network was developed to predict the synthesis and secretion of testosterone (T) and estradiol (E2), and their responses to EAC. Model predictions were compared to data from an in vitro steroidogenesis assay with ovary explants from a small fish model, the fathead minnow. Model parameters were estimated using an iterative optimization algorithm. Model-predicted concentrations of T and E2 closely correspond to the time-course data from baseline (control) experiments, and dose-response data from experiments with the EAC, fadrozole (FAD). A sensitivity analysis of the model parameters identified specific transport and metabolic processes that most influence the concentrations of T and E2, which included uptake of cholesterol into the ovary, secretion of androstenedione (AD) from the ovary, and conversions of AD to T, and AD to estrone (E1). The sensitivity analysis also indicated the E1 pathway as the preferred pathway for E2 synthesis, as compared to the T pathway. Our study demonstrates the feasibility of using the steroidogenesis model to predict T and E2 concentrations, in vitro, while reducing model complexity with a steady-state assumption. This capability could be useful for pharmaceutical development and environmental health assessments with EAC.

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Section: Discussionmentioning

confidence: 67%

Mechanistic Computational Model of Ovarian Steroidogenesis to Predict Biochemical Responses to Endocrine Active Compounds

et al. 2007

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“…First, the capacities of aromatase inhibitors to increase aromatase protein in cells may reflect their binding affinities (Ki-values) for aromatase. The K-values of 4-OHA and atamestane are reported to be about 250 nm (Henderson et al, 1986), whereas those of fadrozole and vorozole are 1.6 (Steele et al, 1987) and 0.7 nM (Vanden Bossche et al, 1990) respectively. Judging from this difference, non-steroidal inhibitors would be expected to be more tightly associated with the aromatase molecules in stable complexes that may be more resistant to proteolytic cleavage.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of aromatase prevent degradation of the enzyme in cultured human tumour cells

Harada

Hatano²

1998

Br J Cancer

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Summary 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 using cultured JEG-3 and HepG2 cells. Immunocytochemical studies demonstrated increased quantities of immunoreactive aromatase in both cell types as a result of these treatments. To clarify this effect in detail, quantitation of aromatase protein in JEG-3 cells was performed after various treatments using an enzyme-linked immunosorbent assay. Time-dependent increase was observed with all the aromatase inhibitors except 4-hydroxyandrostenedione. The three non-steroidal agents caused an approximately fourfold elevation in the cells 24 h after the treatment compared with untreated controls. The inhibitors also appeared to block the rapid degradation observed in JEG-3 cells after induction with forskolin. However, aromatase mRNA levels in JEG-3 cells remained unchanged. Furthermore, the increase in aromatase protein in JEG-3 cells due to the inhibitor action was not blocked by treatment with cycloheximide, an inhibitor of protein synthesis. These results thus suggest that aromatase inhibitors increase aromatase protein through stabilization and reduced protein turnover as a side-effect of their binding.Keywords: aromatase inhibitors; oestrogen synthetase; suicide substrate; choriocarcinoma cell; hepatoma cell Aromatase catalyses a rate-limiting step of aromatization of androgens in oestrogen biosynthesis and is known to play an important role through oestrogen production in various physiological functions. This enzyme has been shown to be present in breast (AbulHajj et al, 1979;Santner et al, 1984;Miller and O'Neill, 1987) and endometrial cancer tissues (Noble et al, 1996) as well as various gonadal and extragonadal tissues. In the case of breast cancer, aromatase protein and mRNA were reported to be localized in adipose stromal cells proximal to tumours (Bulun et al, 1993;Santen et al, 1994;Sasano et al, 1994;Harada et al, 1995) and intratumoral stromal cells (Esteban et al, 1992;Lu et al, 1996). Oestrogens are known to function as mitogenic factors in certain tissues, suggesting that local production of oestrogens by aromatase may play an essential role in the pathogenesis of oestrogen-dependent breast and endometrial cancers, maintaining proliferation in a paracrine or autocrine fashion. Therefore, one approach to therapy is to reduce or eliminate continuous stimulation by circulating and locally produced oestrogens, and a number of aromatase inhibitors capable of causing cancer regression in patients have been introduced for such endocrine therapy (Brodie, 1994).Aminoglutethimide is an agent initially finding clinical application as a possible therapeutic aromatase inhibitor for breast cancer patients (Santen and Misbin, 1981). However, it also inhibits cholesterol side-chain cleavage reaction by P-450scc, resulting in a deficiency of glucocorticoids and mineralocorticoids as well as sex steroids....

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“…In rats and humans, antioestrogens have been shown to exhibit oestrogen-like effects on lipid metabolism (Lmener and Jordan, 1990), a predominantly liver-mediated response. The dichotomy of the arcinogenic response of the liver to fadrozole hydrochloride, a slctive aromataw inhibitor devoid of oestrogenic activity (Steele et al, 1987), as compared with tamoxifen, an antioestrogen with weak oestrogenic activity (Lener and Jordan, 1990), may be related to expression of oestrogenic activity in the liver of the rat by tamoxifen. It will be of interest to see if other steroidal and non-steroidal aromatase inhibitors also reduce the incidence of liver tumours in rats.…”

Section: Resdsmentioning

confidence: 99%

“…Removal of the oestrogen source causes regression of existing tumours and prevets the occurrence of further mammany tumours (Rogers, 1983). The oestrogen source may be removed surgically by ovariectomy (Rogers, 1983), or pharmacologically by an aromatase inhibitor that prevents the conversion of aromatisable androgens to oestrogens (Steele et al, 1987;Schieweck et al, 1988). Fadrozole hydrochloride,[4][5]6,7, benzonitrile monohydrochloride (CGS 16949A), is a potent and selective non-steroidal inhibitor of aromatase.…”

mentioning

confidence: 99%

Prevention of spontaneous tumours in female rats by fadrozole hydrochloride, an aromatase inhibitor

Gunson¹,

Steele²,

Chau³

1995

Br J Cancer

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(Banting et al., 1989). Such drugs are usually tested in rats with chemically induced mammary tumours; these are generally both oestrogen and prolactin dependent in female rats (Rogers, 1983). Removal of the oestrogen source causes regression of existing tumours and prevets the occurrence of further mammany tumours (Rogers, 1983 (Mantel, 1963; Peto, 1974; Dinse, 1985). ResdsFadrozole hydrochloride had no adverse effect on the survival of treated female rats, and there were very few palpable masses in treated females. The total number of rats with any benign and/or malignant neoplasms is shown in Table I.

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In vitro and in vivo studies demonstrating potent and selective estrogen inhibition with the nonsteroidal aromatase inhibitor CGS 16949A

Cited by 204 publications

References 22 publications

Mechanistic Computational Model of Ovarian Steroidogenesis to Predict Biochemical Responses to Endocrine Active Compounds

Mechanistic Computational Model of Ovarian Steroidogenesis to Predict Biochemical Responses to Endocrine Active Compounds

Inhibitors of aromatase prevent degradation of the enzyme in cultured human tumour cells

Prevention of spontaneous tumours in female rats by fadrozole hydrochloride, an aromatase inhibitor

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