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British Journal of Cancer Oct 1992The influence of the prototype aromatase inhibitor Aminoglutethimide (AG) and its analogue Rogletimide (RG) on peripheral aromatisation were investigated in 13...
The influence of the prototype aromatase inhibitor Aminoglutethimide (AG) and its analogue Rogletimide (RG) on peripheral aromatisation were investigated in 13 postmenopausal women with advanced breast cancer. Seven patients received AG 1,000 mg daily plus Hydrocortisone (HC) cover and six received RG as dose escalation of 200 mg bd, 400 mg bd and 800 mg bd. In vivo aromatase inhibition was investigated using the double bolus injection technique with [4-14C] oestrone ([4-14C]E1) and [6,7-3H] androstenedione ([6,7-3H]4A) followed by a 96 h urine collection. The labelled urinary oestrogens were separated and purified by chromatography and HPLC. Plasma oestradiol (E2) was also measured. AG mean aromatase inhibition was 90.6% +/- 1.8 s.e.m. and E2 suppression 75.7% +/- 7.3 s.e.m. RG mean aromatase inhibition was 50.6% +/- 9.8 s.e.m. at 200 mg bd, 63.5% +/- 5.7 s.e.m. at 400 mg bd and 73.8% +/- 5.8 s.e.m. at 800 mg bd. E2 suppression was 30.7% +/- 9.5 s.e.m., 40.2% +/- 10.3 s.e.m. and 57.6% +/- 9.2 s.e.m. respectively. These results confirm the efficacy of AG as an aromatase inhibitor. RG produced dose dependent E2 suppression and aromatase inhibition, but even at the maximum tolerated dose of 800 mg bd had sub-optimal aromatase inhibition and oestradiol suppression compared with AG.
Topics: Adult; Aged; Aged, 80 and over; Aminoglutethimide; Aromatase Inhibitors; Breast Neoplasms; Drug Administration Schedule; Estrogens; Female; Humans; Hydrocortisone; Middle Aged
PubMed: 1419608
DOI: 10.1038/bjc.1992.339 -
International Journal of Molecular... Sep 2019A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated...
A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated pathways underlying the modulation of reactive microglia. In the present work, the TSPO activation was explored in an in vitro human primary microglia model (immortalized C20 cells) under inflammatory stimulus. Two different approaches were used with the aim to (i) pharmacologically amplify or (ii) silence, by the lentiviral short hairpin RNA, the TSPO physiological function. In the TSPO pharmacological stimulation model, the synthetic steroidogenic selective ligand XBD-173 attenuated the activation of microglia. Indeed, it reduces and increases the release of pro-inflammatory and anti-inflammatory cytokines, respectively. Such ligand-induced effects were abolished when C20 cells were treated with the steroidogenesis inhibitor aminoglutethimide. This suggests a role for neurosteroids in modulating the interleukin production. The highly steroidogenic ligand XBD-173 attenuated the neuroinflammatory response more effectively than the poorly steroidogenic ones, which suggests that the observed modulation on the cytokine release may be influenced by the levels of produced neurosteroids. In the TSPO silencing model, the reduction of TSPO caused a more inflamed phenotype with respect to scrambled cells. Similarly, during the inflammatory response, the TSPO silencing increased and reduced the release of pro-inflammatory and anti-inflammatory cytokines, respectively. In conclusion, the obtained results are in favor of a homeostatic role for TSPO in the context of dynamic balance between anti-inflammatory and pro-inflammatory mediators in the human microglia-mediated inflammatory response. Interestingly, our preliminary results propose that the TSPO expression could be stimulated by NF-κB during activation of the inflammatory response.
Topics: Aminoglutethimide; Anti-Inflammatory Agents; Aromatase Inhibitors; Base Sequence; Cell Line; Cell Survival; Cytokines; Gene Expression; Humans; Inflammation Mediators; Microglia; NF-kappa B; Phenotype; Purines; RNA Interference; Receptors, GABA
PubMed: 31510070
DOI: 10.3390/ijms20184467 -
Oncology (Williston Park, N.Y.) Mar 1998Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately 10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational phase III... (Review)
Review
Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately 10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational phase III trials have compared letrozole (0.5 and 2.5 mg/d) against megestrol acetate and aminoglutethimide, respectively, in patients with locally advanced or metastatic breast cancer. The letrozole vs megestrol acetate trial showed the superiority of letrozole (2.5 mg/d) over megestrol acetate with respect to response rate, response duration, duration of overall clinical benefit (complete response plus partial response plus stable disease > or = 6 months), time to progression, and time to treatment failure. The letrozole-treated patients also showed a nonsignificant trend toward better survival. In the letrozole vs aminoglutethimide trial, letrozole (2.5 mg/d) was significantly superior in terms of duration of overall clinical benefit and survival. There were also strong trends favoring letrozole with regard to objective response rate and duration of response. Unexpectedly, both trials demonstrated a dose-response effect for 2.5 mg of letrozole over 0.5 mg in terms of response and overall survival. This finding raises the possibility that intratumoral aromatase suppression may be more relevant in breast cancer therapy than are plasma estrogen levels.
Topics: Aminoglutethimide; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Letrozole; Megestrol Acetate; Nitriles; Treatment Outcome; Triazoles
PubMed: 9556791
DOI: No ID Found -
British Journal of Cancer Jul 1989Plasma level, plasma clearance, production rate and interconversions of oestrone and oestrone sulphate were measured in six breast cancer patients receiving...
Plasma level, plasma clearance, production rate and interconversions of oestrone and oestrone sulphate were measured in six breast cancer patients receiving aminoglutethimide therapy. Three additional patients had the production rate of oestrone sulphate investigated. Plasma oestrone and oestrone sulphate levels were reduced by a mean of 46% (P less than 0.05) and 71% (P less than 0.005) respectively. These alterations were due to a combined action of aminoglutethimide inhibiting oestrogen production but also increasing oestrogen metabolism. While oestrone and oestrone sulphate production rate was reduced by a mean of 31% (P less than 0.05) and 41% (P less than 0.005) respectively, the plasma clearance rate of oestrone was found to be increased by a mean of 30% (P less than 0.05), and the plasma clearance rate of oestrone sulphate was increased by a mean of 112% during aminoglutethimide treatment. The fraction of oestrone sulphate converted into plasma oestrone was reduced by 52% (P less than 0.05), the transfer of circulating oestrone into sulphate was non-significantly reduced by a mean of 16%. The findings in this investigation show that aminoglutethimide treatment influences oestrogen disposition by mechanisms unrelated to aromatase inhibition. The possibility that such effects might be partly responsible for the mechanism of action of aminoglutethimide in advanced breast cancer should be considered.
Topics: Aged; Aminoglutethimide; Breast Neoplasms; Estrogens, Conjugated (USP); Estrone; Female; Humans; Middle Aged
PubMed: 2553085
DOI: 10.1038/bjc.1989.231 -
The Biochemical Journal Feb 19731. Experimental evidence is presented for a role of progesterone and 20alpha-hydroxypregn-4-en-3-one as inhibitors of cholesterol ester synthetase in the acute depletion...
1. Experimental evidence is presented for a role of progesterone and 20alpha-hydroxypregn-4-en-3-one as inhibitors of cholesterol ester synthetase in the acute depletion of ovarian cholesterol ester after trophic stimulation. 2. Luteinizing hormone in vitro decreased by 84% the rate of esterification of cholesterol with added [(14)C]oleate by slices of rabbit ovarian interstitial tissue; this effect was mimicked by cyclic AMP (adenosine 3':5'-cyclic monophosphate) in vitro, and occurred without large changes in precursor pool sizes or membrane permeability. 3. Cyclic AMP was shown to have no direct effect on cholesterol ester synthetase or cholesterol esterase in cell-free extracts of rabbit ovarian interstitial tissue, but decreased the activity of cholesterol ester synthetase (not that of cholesterol esterase) in extracts prepared from slices previously incubated with it. 4. The inhibitory effect of cyclic AMP on esterification of cholesterol with added [(14)C]-oleate was prevented by both cycloheximide and aminoglutethimide phosphate (which also inhibited steroid synthesis in response to cyclic AMP). 5. Cyclic AMP raised the intracellular concentrations of progesterone and 20alpha-hydroxypregn-4-en-3-one in incubated slices by factors of 2.8 and 3.9 respectively. 6. Cycloheximide and aminoglutethimide phosphate administered in vivo blocked cholesterol ester depletion in response to luteinizing hormone in rats; in these ovaries cycloheximide and aminoglutethimide phosphate decreased the concentrations of progesterone and 20alpha-hydroxypregn-4-en-3-one and luteinizing hormone raised them. 7. Progesterone and 20alpha-hydroxypregn-4-en-3-one added to cell-free extracts of rabbit ovarian interstitial tissue in vitro (at concentrations comparable with those found in incubated slices) inhibited cholesterol ester synthetase by up to 85%. 8. The results are discussed with reference to the acute control of cholesterol ester concentrations in the ovary and adrenal cortex.
Topics: Acetyltransferases; Aminoglutethimide; Animals; Carbon Isotopes; Cholesterol; Cyclic AMP; Cycloheximide; Esterases; Esters; Extracellular Space; Female; In Vitro Techniques; Luteinizing Hormone; Oleic Acids; Ovary; Progesterone; Rabbits; Sorbitol; Tritium
PubMed: 4353446
DOI: 10.1042/bj1320313 -
International Journal of Molecular... Jun 2016The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high...
The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being.
Topics: Astrocytes; Cell Line; Cell Proliferation; Humans; Indoles; Neurogenesis; Oxidation-Reduction; Pregnenolone
PubMed: 27367681
DOI: 10.3390/ijms17071028 -
International Journal of Molecular... Sep 2022With the aim of searching for phytochemicals with aromatase inhibitory activity, five new prenylcoumarins, mammeasins K (), L (), M (), N (), and O (), were isolated...
Phytochemicals with Chemopreventive Activity Obtained from the Thai Medicinal Plant (Miq.) T. Anders.: Isolation and Structure Determination of New Prenylcoumarins with Inhibitory Activity against Aromatase.
With the aim of searching for phytochemicals with aromatase inhibitory activity, five new prenylcoumarins, mammeasins K (), L (), M (), N (), and O (), were isolated from the methanolic extract of (Miq.) T. Anders. flowers (fam. Calophyllaceae), originating in Thailand. The stereostructures of - were elucidated based on their spectroscopic properties. Among the new compounds, (IC = 7.6 µM) and (9.1 µM) possessed relatively strong inhibitory activity against aromatase, which is a target of drugs already used in clinical practice for the treatment and prevention of estrogen-dependent breast cancer. The analysis through Lineweaver-Burk plots showed that they competitively inhibit aromatase (, i = 3.4 µM and , 2.3 µM). Additionally, the most potent coumarin constituent, mammea B/AB cyclo D (, i = 0.84 µM), had a competitive inhibitory activity equivalent to that of aminoglutethimide (0.84 µM), an aromatase inhibitor used in therapeutics.
Topics: Aminoglutethimide; Aromatase; Aromatase Inhibitors; Coumarins; Estrogens; Mammea; Phytochemicals; Plant Extracts; Plants, Medicinal; Thailand
PubMed: 36232534
DOI: 10.3390/ijms231911233 -
Journal of Oncology 2012Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol,...
Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone "RU-486"). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ "PPAR-γ" ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.
PubMed: 22934113
DOI: 10.1155/2012/685213 -
Physiological Research Jul 2020Glucocorticoids (GCS) are known to modulate cardiovascular response during stress conditions. The present study was aimed to test the hypothesis that permissive and/or...
Glucocorticoids (GCS) are known to modulate cardiovascular response during stress conditions. The present study was aimed to test the hypothesis that permissive and/or stimulating effect of GCs is essential for the maintenance of peripheral vascular resistance and for the adequate response of cardiovascular system to stressor exposure. The effects of acute pharmacological adrenalectomy (PhADX) on humoral and cardiovascular parameters were studied in adult Wistar rats under the basal conditions and during the acute restraint stress. Acute PhADX was performed by the administration of metyrapone and aminoglutethimide (100 mg/kg s.c. of each drug) resulting in a suppression of endogenous glucocorticoid synthesis. Blood pressure (BP), heart rate (HR) and core body temperature were measured using radiotelemetry. BP responses to administration of vasoactive agents were determined in pentobarbital-anesthetized animals. PhADX considerably attenuated stress-induced increase of BP, HR and core body temperature. PhADX did not abolish BP and HR lowering effects of ganglionic blocker pentolinium indicating preserved sympathetic function in PhADX rats. BP response to exogenous norepinephrine administration was attenuated in PhADX rats, suggesting reduced sensitivity of cardiovascular system. Suppression of corticosterone synthesis by PhADX increased basal plasma levels of ACTH, aldosterone and plasma renin activity in unstressed animals but there was no further increase of these hormones following stressor exposure. In conclusion, PhADX attenuated stress-induced rise of blood pressure, heart rate and core body temperature indicating an important permissive and/or stimulating role of glucocorticoids in the maintenance of the adequate response of cardiovascular system and thermoregulation to several stimuli including acute exposure to stressor.
Topics: Adrenalectomy; Aminoglutethimide; Animals; Antimetabolites; Aromatase Inhibitors; Blood Pressure; Disease Models, Animal; Glucocorticoids; Heart Rate; Male; Metyrapone; Rats; Rats, Wistar; Restraint, Physical; Vascular Resistance
PubMed: 32469228
DOI: 10.33549/physiolres.934432 -
PloS One 2020Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic...
Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic mice. We determined if levels of CYP11A1 in peripheral blood T cells from peanut-allergic (PA) children compared to non-allergic controls were increased and if levels correlated to IL-13 production and oral challenge outcomes to peanut. CYP11A1 mRNA and protein levels were significantly increased in activated CD4+ T cells from PA patients. In parallel, IL-13 production was significantly increased; IFNγ levels were not different between groups. There were significant correlations between expression levels of CYP11A1 mRNA and levels of IL13 mRNA and protein, levels of serum IgE anti-Ara h 2 and to outcomes of peanut challenge. The importance of CYP11A1 on cytokine production was tested using a CYP11A1 CRISPR/Cas9 KO plasmid or an inhibitor of enzymatic CYP11A1 activity. Inhibition of CYP11A1 activation in patient cells treated with the inhibitor, aminoglutethimide, or CD4+ T cell line transfected with the CYP11A1 KO plasmid resulted in reduced IL-13 production. These data suggest that the CYP11A1-CD4+Tcell-IL-13 axis in activated CD4+ T cells from PA children is associated with development of PA reactions. CYP11A1 may represent a novel target for therapeutic intervention in PA children.
Topics: Adolescent; Aminoglutethimide; Cell Line; Child; Child, Preschool; Cholesterol Side-Chain Cleavage Enzyme; Enzyme Activation; Female; Gene Knockout Techniques; Humans; Interleukin-13; Lymphocyte Activation; Male; Peanut Hypersensitivity; RNA, Messenger; Th2 Cells; Transfection; Young Adult
PubMed: 32497050
DOI: 10.1371/journal.pone.0233563