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Journal of Andrology 1991Atamestane is a new, competitive, and irreversible inhibitor of estrogen biosynthesis. Its pharmacologic action has been evaluated in mice, rats, rabbits, dogs, monkeys,... (Review)
Review
Atamestane is a new, competitive, and irreversible inhibitor of estrogen biosynthesis. Its pharmacologic action has been evaluated in mice, rats, rabbits, dogs, monkeys, and humans. In rats, atamestane leads to a decrease of pregnant mare serum gonadotropin-stimulated ovarian estrogen production, and inhibits androstenedione-induced estrogenic effects such as uterine growth and abortion. In all species tested, atamestane lacks other intrinsic hormonal or antihormonal activities, and shows no inhibition of other cytochrome P450-dependent enzymes of adrenal steroidogenesis. However, it inhibits estrogen-related negative feedback. The extent and consequences of the induced counterregulation of the pituitary-hypothalamic axis show major sex- and species-specific differences. Atamestane is highly effective in inhibiting estrogen-induced hyperplastic changes in the fibromuscular stroma of the prostate in androstenedione-treated dogs and monkeys. In male volunteers and patients with benign prostatic hyperplasia (BPH), atamestane induces an expected reduction of serum (and BPH tissue) estrogen concentrations without significant changes in androgen levels. In conclusion, all available results indicate that atamestane is a selective (no inhibition of adrenal function), pure (no endocrine side effects), and highly effective steroidal aromatase inhibitor, with an excellent safety profile. Based on the discussion of its clinical potential, atamestane seems to be a promising compound for the management of BPH.
Topics: Androstenedione; Aromatase Inhibitors; Humans; Male; Prostatic Hyperplasia
PubMed: 1722797
DOI: No ID Found -
Journal of Andrology 1991Today, human benign prostatic hyperplasia (BPH) is considered primarily to be a disease of the stroma, in which estrogens are thought to play a considerable causative or... (Review)
Review
Today, human benign prostatic hyperplasia (BPH) is considered primarily to be a disease of the stroma, in which estrogens are thought to play a considerable causative or permissive role. The growing incidence of BPH with increasing age coincides with a shift in the androgen:estrogen ratio in favor of estrogens, not only in terms of serum hormone values, but also in the prostate itself. Furthermore, evidence has been provided for a preferential accumulation of estrogens in the stroma of human hyperplastic tissue, and the presence of an estrogen receptor satisfying the classical criteria of high affinity and low capacity has been demonstrated. Also, animal studies have emphasized the potential role of estrogens in the pathogenesis of BPH. Experimentally, stimulation of the stroma, particularly of smooth muscle, can be induced by aromatizable substrates, such as androstenedione, in the prostates of beagles and cynomolgus monkeys. These effects can be antagonized by aromatase inhibitors, such as atamestane. In addition, the increase in intraprostatic estrogen concentrations and immunohistochemically detectable estrogen receptor content induced by androstenedione in intact dogs is completely reversed by simultaneous treatment with atamestane. In conclusion, clinical data, as well as that from animal models, emphasize an important role for estrogens in the development of BPH. Estrogen deprivation might, therefore, represent a useful treatment for human BPH.
Topics: Androstenedione; Animals; Aromatase Inhibitors; Disease Models, Animal; Dogs; Macaca fascicularis; Male; Prostatic Hyperplasia
PubMed: 1722796
DOI: No ID Found -
The Journal of Steroid Biochemistry and... Jan 2008Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human...
Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human estrogen receptor (ER) positive breast cancer cells stably transfected with aromatase (Ac-1) are grown in immune-compromised mice. Using this model we have explored a number of therapeutic strategies to maximize the antitumor efficacy of antiestrogens (AEs) and aromatase inhibitors (AIs). This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. In this current study we compared the effect of an AE toremifene and steroidal AI atamestane, alone or in combination, on growth of hormone-dependent human breast cancer. We have also compared toremifene plus atamestane combination with tamoxifen in this study. The growth of Ac-1 cells was inhibited by tamoxifen, toremifene and atamestane in vitro with IC(50) values of 1.8+/-1.3 microM, 1+/-0.3 microM and 60.4+/-17.2 microM, respectively. The combination of toremifene plus atamestane was found to be better than toremifene or atamestane alone in vitro. The effect of this combination was then studied in vivo using Ac-1 xenografts grown in ovariectomized female SCID mice. The mice were injected with toremifene (1000 microg/day), atamestane (1000 microg/day), tamoxifen (100 microg/day), or the combination of toremifene plus atamestane. In this study, our results indicate that the combination of toremifene plus atamestane was as effective as toremifene or tamoxifen alone but may not provide any additional benefit over toremifene alone or tamoxifen alone.
Topics: Androstenedione; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Mice; Mice, SCID; Prognosis; Toremifene; Transfection; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 17942301
DOI: 10.1016/j.jsbmb.2007.04.005 -
Journal of Andrology 1995Prostatic hyperplasia can be induced in both intact and castrated dogs and in intact cynomolgus monkeys by the administration of androgenic steroids. Estrogenic steroids...
Prostatic hyperplasia can be induced in both intact and castrated dogs and in intact cynomolgus monkeys by the administration of androgenic steroids. Estrogenic steroids potentiate this effect in dogs. These changes also can be induced by androstenedione, which increases androgen and estrogen levels. Atamestane (ATA; 1-methyl-3,17-dione-androsta-1,4-diene), a potent aromatase inhibitor, inhibits some of the androstendione-induced effects; however, the nonsteroidal aromatase inhibitor, CGS-16949A, has been reported to decrease serum estradiol levels in adult rats but to have no effect on androgen-dependent organ weights. To examine the mechanisms by which ATA affects the rat prostate, in vivo and in vitro studies were conducted using adult rat ventral prostate (VP). Intact Sprague-Dawley rats were injected daily for 14 days with sesame seed oil, ATA (70 mg/kg/day), finasteride (FIN; 5 mg/kg/day), a 5 alpha-reductase inhibitor, or the combination of FIN plus ATA. A fifth group was castrated (CASTR) on day 1. The mean +/- standard error VP weight of the controls was 350 +/- 19 mg. It was reduced 17% (P < 0.05) by ATA, 29% (P < 0.001) by FIN, 48% (P < 0.001) by FIN plus ATA, and 86% (P < 0.001) by CASTR. The DNA/VP was reduced 22% (not significant) by ATA, 18% by FIN (not significant), 35% (P < 0.01) by FIN plus ATA, and 60% (P < 0.001) by CASTR. More significant changes were observed in RNA and protein. The mRNA for prostatein C3 was reduced by each of the treatments, but only CASTR increased the mRNA for TRPM-2, a marker of apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Androgen Antagonists; Androgen-Binding Protein; Androstenedione; Animals; Aromatase Inhibitors; Binding, Competitive; Castration; DNA; Enzyme Inhibitors; Finasteride; Male; Organ Size; Prostate; Prostatein; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Secretoglobins; Uteroglobin
PubMed: 7559139
DOI: No ID Found -
Journal of Advanced Research Jul 2020Seven new derivatives, 6-hydroxy-1-methyl-3-oxo-5-androst-1-en-17-yl acetate (), 6,17-dihydroxy-1-methyl-3-oxo-5-androst-1-en (),...
Seven new derivatives, 6-hydroxy-1-methyl-3-oxo-5-androst-1-en-17-yl acetate (), 6,17-dihydroxy-1-methyl-3-oxo-5-androst-1-en (), 7-hydroxy-1-methyl-3-oxo-5-androst-1-en-17-yl acetate (), 15,20-dihydroxy-1-methyl-3-oxo-5-androst-1-en-17-yl acetate (), 15-hydroxy-1-methyl-3-oxo-5-androst-1-en-17-yl acetate (), 12,17-dihydroxy-1-methyl-3-oxoandrosta-1,4-dien (), and 71517-trihydroxy-1-methyl-3-oxo-5-androst-1-en (), along with six known metabolites, 17-hydroxy-1-methyl-3-oxoandrosta-1,4-dien (), 17-hydroxy-1-methyl-3-oxo-5-androst-1-en (), 17-hydroxy-1-methyl-3-oxo-5-androst-1-en (), 1-methyl-5-androst-1-en-3,17-dione (10), 1-methyl-3-oxoandrosta-1,4-dien-3,17-dione (), and 17-hydroxy-1-methyl-5-androstan-3-one () of metenolone acetate (), were synthesized through whole-cell biocatalysis with , , , and . Atamestane (), an aromatase inhibitor, was synthesized for the first time -mediated transformation of as the major product. Hydroxylation, dehydrogenation, and reduction were occurred during biocatalysis. Study indicated that was able to catalyze dehydrogenation reactions selectively. Structures of compounds - were determined through NMR, HRFAB-MS, and IR spectroscopic data. Compounds - were identified as non-cytotoxic against BJ human fibroblast cell line (ATCC CRL-2522). Metabolite (81.0 ± 2.5%) showed a potent activity against TNF- production, as compared to the substrate (62.5 ± 4.4%). Metabolites (73.4 ± 0.6%), (69.7 ± 1.4%), (73.2 ± 0.3%), (60.1 ± 3.3%), and (71.0 ± 7.2%), also showed a good inhibition of TNF-α production. Compounds (IC = 4.4 ± 0.01 µg/mL), and (IC = 10.2 ± 0.01 µg/mL) showed a significant activity against T-cell proliferation. Identification of selective inhibitors of TNF-α production, and T-cell proliferation is a step forward towards the development of anti-inflammatory drugs.
PubMed: 32195009
DOI: 10.1016/j.jare.2020.02.009 -
British Journal of Cancer Feb 1998The effects of two steroidal (4-hydroxyandrostenedione and atamestane) and three non-steroidal (fadrozole, vorozole and pentrozole) aromatase inhibitors on the levels of...
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.
Topics: Androstenedione; Aromatase; Aromatase Inhibitors; Carcinoma, Hepatocellular; Choriocarcinoma; Colforsin; Cycloheximide; Enzyme-Linked Immunosorbent Assay; Fadrozole; Humans; Liver Neoplasms; Neoplasm Proteins; Protein Synthesis Inhibitors; RNA, Messenger; Triazoles; Tumor Cells, Cultured
PubMed: 9484813
DOI: 10.1038/bjc.1998.92