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Annals of Oncology : Official Journal... Jul 1997
Comparative Study
Topics: Aminoglutethimide; Anastrozole; Androstenedione; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials, Phase III as Topic; Female; Humans; Letrozole; Nitriles; Triazoles
PubMed: 9296213
DOI: 10.1023/a:1008282315089 -
Cleveland Clinic Journal of Medicine Jul 2002The aromatase inhibitors are established first-line drugs for treating metastatic breast cancer in postmenopausal women, and are gaining acceptance as adjuvant treatment... (Review)
Review
The aromatase inhibitors are established first-line drugs for treating metastatic breast cancer in postmenopausal women, and are gaining acceptance as adjuvant treatment as well.
Topics: Aminoglutethimide; Antineoplastic Agents, Hormonal; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Enzyme Inhibitors; Estrogens; Female; Humans; Neoplasms, Hormone-Dependent; Postmenopause; Tamoxifen
PubMed: 12109640
DOI: 10.3949/ccjm.69.7.561 -
Postgraduate Medical Journal Jul 1970Aminoglutethimide was introduced as an anti-convulsant drug in the U.S.A. in 1960. The occurrence of a number of side-effects, including several endocrine effects such... (Review)
Review
Aminoglutethimide was introduced as an anti-convulsant drug in the U.S.A. in 1960. The occurrence of a number of side-effects, including several endocrine effects such as goitrogenesis, sexual precocity and virilization, led to its withdrawal. Further investigation indicated that the drug inhibited adrenal biosynthesis, particularly of aldosterone, cortisol and androgens, probably by interfering with the conversion of cholesterol to delta-5-pregnenolone. Aminoglutethimide has also been shown to modify the extra-adrenal metabolism of cortisol. The possible clinical applications of these ‘side-effects’ are discussed.
Topics: Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Adrenal Insufficiency; Adrenocortical Hyperfunction; Adult; Aminoglutethimide; Androgens; Aniline Compounds; Animals; Anticonvulsants; Breast Neoplasms; Child; Cholesterol; Cushing Syndrome; Estrogens; Female; Gonads; Humans; Hypothyroidism; Male; Pyridones; Rats
PubMed: 4920933
DOI: 10.1136/pgmj.46.537.409 -
IScience Feb 2024Somatic mutations contribute to cancer development by altering the activity of enhancers. In the study, a total of 135 mutation-driven enhancers, which displayed...
Somatic mutations contribute to cancer development by altering the activity of enhancers. In the study, a total of 135 mutation-driven enhancers, which displayed significant chromatin accessibility changes, were identified as candidate risk factors for breast cancer (BRCA). Furthermore, we identified four mutation-driven enhancers as independent prognostic factors for BRCA subtypes. In Her2 subtype, enhancer G > C mutation was associated with poorer prognosis through influencing its potential target genes FBXW9, TRIR, and WDR83. We identified aminoglutethimide and quinpirole as candidate drugs targeting the mutated enhancer. In normal subtype, enhancer G > A mutation was associated with poorer prognosis through influencing its target genes ALOX15B, LINC00324, and MPDU1. We identified eight candidate drugs such as erastin, colforsin, and STOCK1N-35874 targeting the mutated enhancer. Our findings suggest that somatic mutations contribute to breast cancer subtype progression by altering enhancer activity, which could be potential candidates for cancer therapy.
PubMed: 38303701
DOI: 10.1016/j.isci.2024.108780 -
Journal of Neurochemistry Mar 2004An overactivation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptors has been implicated in the pathophysiology of oligodendrocyte damage...
An overactivation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptors has been implicated in the pathophysiology of oligodendrocyte damage in demyelinating disorders of the CNS. We decided to examine the effect of testosterone on excitotoxic death of oligodendrocytes because a gender difference exists in the incidence and disease course of multiple sclerosis. Short-term pure cultures of oligodendrocytes (4 days in vitro) were exposed to a brief pulse with kainate or AMPA + cyclothiazide for the induction of excitotoxicity. Exposure to testosterone enantate was slightly toxic per se and amplified both AMPA and kainate toxicity. Testosterone treatment induced all gene targets of p53, and amplified the induction of these genes induced by kainate. The effect of testosterone was mediated by the activation of androgen receptors and was resistant to the aromatase inhibitors, dl-aminoglutethimide and 4-hydroxyandrost-4-ene-3,17-dione. Testosterone treatment also potentiated the stimulation of 45Ca2+ influx induced by AMPA + cyclothiazide or kainate without changing the expression of the glutamate receptor (GluR) 1, -2/3, and -4 subunits of AMPA receptors or the GluR6/7 subunits of kainate receptors. We conclude that testosterone amplifies excitotoxic damage of oligodendrocytes acting at an early step of the death cascade triggered by AMPA/kainate receptors.
Topics: Animals; Benzothiadiazines; Calcium; Cells, Cultured; Drug Synergism; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Gene Expression; Kainic Acid; L-Lactate Dehydrogenase; Neurotoxins; Oligodendroglia; Quinoxalines; Rats; Receptors, AMPA; Receptors, Androgen; Receptors, Kainic Acid; Testosterone; Time Factors; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 15009673
DOI: 10.1046/j.1471-4159.2004.02284.x -
Oncology (Williston Park, N.Y.) Aug 2001Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide... (Review)
Review
Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials as Topic; Enzyme Inhibitors; Female; Humans; Letrozole; Neoplasms, Hormone-Dependent; Nitriles; Triazoles
PubMed: 11548977
DOI: No ID Found -
ACS Omega Jun 2022[This corrects the article DOI: 10.1021/acsomega.2c00011.].
Correction to "Synthesis and Characterization of an Inclusion Complex of dl-Aminoglutethimide with β-Cyclodextrin and Its Innovative Application in a Biological System: Computational and Experimental Investigations".
[This corrects the article DOI: 10.1021/acsomega.2c00011.].
PubMed: 35755346
DOI: 10.1021/acsomega.2c03057 -
Reproductive Biology and Endocrinology... Feb 2006The objective of this study was to investigate whether the steroid hormone(s) secreted from cumulus-oocyte complexes (COCs) is a prerequisite for bovine oocyte...
BACKGROUND
The objective of this study was to investigate whether the steroid hormone(s) secreted from cumulus-oocyte complexes (COCs) is a prerequisite for bovine oocyte maturation and cumulus expansion using aminoglutethimide (AGT), a P450 cholesterol side-chain cleavage inhibitor.
METHODS
In experiment 1, COCs were cultured in maturation medium with various concentrations of AGT for 22 h to determine the effective concentration of AGT to inhibit steroid hormone secretion, meiotic maturation and cumulus expansion. In experiment 2, COCs were cultured in conditioned medium (CM) and TCM-199 medium with or without 10 mM AGT to check whether steroid hormones secreted from COCs were responsible for oocyte maturation and cumulus expansion. Experiments 3 and 4 were carried out to determine whether exogenous progesterone or estradiol-17beta was able to overcome the inhibitory effects of AGT on oocytes maturation and cumulus expansion. COCs cultured in 10 mM AGT-containing medium supplemented with various concentrations of progesterone or estradiol-17beta for 22 h were examined for oocyte maturation and cumulus expansion.
RESULTS
Experiment 1 showed that a concentration of 10 mM AGT in medium was sufficient to block steroid hormone secretion, oocyte maturation and cumulus expansion, and that these inhibitory effects were fully reversible. In experiment 2, the addition of 10 mM AGT to CM did not significantly prevent oocyte maturation and cumulus expansion, implying that CM contains the steroid hormone(s) secreted from COCs, which are closely associated with oocyte maturation and cumulus expansion. The results in experiments 3 and 4 demonstrated that the addition of any concentration of progesterone or estradiol-17beta in the medium did not reduce the inhibitory effects of AGT on oocyte maturation and cumulus expansion.
CONCLUSION
Our results indicate that bovine oocytes surrounded by cumulus cells are prevented from maturation and cumulus expansion through the inhibition of steroid secretion due to AGT, and that these inhibitory effects of AGT on oocyte maturation and cumulus expansions can not be overcome by the addition of either progesterone or estradiol-17beta in the medium. These observations suggest that some steroid hormone(s) other than P4 and E2 secreted from bovine COCs is essential for their meiotic maturation and cumulus expansion.
Topics: Aminoglutethimide; Animals; Aromatase Inhibitors; Cattle; Estradiol; Female; Gonadal Steroid Hormones; Oocytes; Progesterone
PubMed: 16457731
DOI: 10.1186/1477-7827-4-4 -
Neuropharmacology Jun 2022Binge drinking is a harmful pattern of alcohol use that is associated with a number of serious health problems. Of particular interest are the rapid alterations in...
Binge drinking is a harmful pattern of alcohol use that is associated with a number of serious health problems. Of particular interest are the rapid alterations in neuroimmune gene expression and the concurrent activation of the hypothalamic-pituitary-adrenal (HPA) axis activation associated with high intensity drinking. Using a rat model of acute binge-like ethanol exposure, the present studies were designed to assess the role of corticosterone (CORT) in ethanol-induced neuroimmune gene expression changes, particularly those associated with the NFκB signaling pathway, including rapid induction of IL-6 and IκBα, and suppression of IL-1β and TNFα gene expression evident after administration of moderate to high doses of ethanol (1.5-3.5 g/kg ip) during intoxication (3 h post-injection). Experiment 1 tested whether inhibition of CORT synthesis with metyrapone and aminoglutethimide (100 mg/kg each, sc) would block ethanol-induced changes in neuroimmune gene expression. Results indicated that rapid alterations in IκBα, IL-1β, and TNFα expression were completely blocked by pretreatment with the glucocorticoid synthesis inhibitors, an effect that was reinstated by co-administration of exogenous CORT (3.75 mg/kg) in Experiment 2. Experiment 3 assessed whether these rapid alterations in neuroimmune gene expression would be evident when rats were challenged with a subthreshold dose of ethanol (1.5 g/kg) in combination with 2.5 mg/kg CORT, which showed limited evidence for additive effects of low-dose CORT combined with a moderate dose of ethanol. Acute inhibition of mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) receptors, alone (Experiment 4) or combined (Experiment 5) had no effect on ethanol-induced changes in neuroimmune gene expression, presumably due to poor CNS penetrance of these drugs. Finally, Experiments 6 and 7 showed that dexamethasone (subcutaneous; a GR agonist) recapitulated effects of ethanol. Overall, we conclude that ethanol-induced CORT synthesis and release is responsible for suppression of IL-1β, TNFα, and induction of IκBα in the hippocampus through GR signaling. Interventions designed to curb these changes may reduce drinking, and subdue detrimental neuroimmune activation induced by ethanol.
Topics: Alcoholic Intoxication; Animals; Corticosterone; Hypothalamo-Hypophyseal System; Male; NF-kappa B; Pituitary-Adrenal System; Rats; Receptors, Glucocorticoid; Signal Transduction
PubMed: 35341791
DOI: 10.1016/j.neuropharm.2022.109044 -
The Journal of Clinical Investigation Mar 1980We evaluated the comparative effects of aminoglutethimide (AG) on androgen and estrogen levels estrone ([E1], estradiol [E2], plasma dehydroepiandrosterone-sulfate... (Comparative Study)
Comparative Study Review
We evaluated the comparative effects of aminoglutethimide (AG) on androgen and estrogen levels estrone ([E1], estradiol [E2], plasma dehydroepiandrosterone-sulfate [DHEA-S], testosterone [T], dihydrotestosterone [DHT], delta 4-androstenedione [delta 4-A]), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin in postmenopausal patients with breast cancer randomly allocated to either AG treatment or bilateral surgical adrenalectomy as a control group. In response to either treatment, the plasma levels of E1 fell 62-75% (P less than 0.001) and urine E1 85.7-88.7% (P less than 0.001) in all study days over a 12-wk period. Similarly, the concentrations of E2 in plasma and urine fell 40-72% without statistically significant differences between the two treatment modalities. The relatively weak androgen, DHEA-S, was reduced by 92% (877.3 +/- 184.6 to 71.8 +/- 14.5 ng/ml) at 12 wk in women treated with AG, but suppressed nearly 99% (1,151 +/- 262 to 5.8 +/- 3.3 ng/ml) in adrenalectomized women. At all time points after treatment, the DHEA-S levels were significantly higher in patients receiving AG. Plasma concentrations of the potent androgens, T and DHT, were also relatively preserved during AG treatment. T levels were never significantly reduced by AG, and DHT concentrations were decreased only at the 4th wk to a maximum of 20%. delta 4-A levels fell 56% in response to this drug only on the 12th wk of therapy (basal, 0.79 +/- 0.09 ng/ml; 12 wk, 0.35 +/- 0.07 ng/ml). In marked contrast, all androgens fell significantly at each time period in response to surgical adrenalectomy, with an 81% maximum suppression of T, 73% of DHT, and 97% of delta 4-A. In response to estrogen suppression, plasma levels of FSH, LH, and prolactin did not change significantly throughout the treatment period in either therapy group. To examine possible contributions of the postmenopausal ovary to hormone levels during therapy, data from surgically castrate and spontaneously menopausal women were evaluated separately. No significant differences between the two groups were observed for E1, E2, T, DHT, DHEA-S, delta 4-A, LH, FSH, and prolactin. We conclude that equivalent and highly significant estrogen suppression occurs with either AG or surgical adrenalectomy although androgen secretion is preserved during AG treatment but not after surgical adrenalectomy. The combined effects of estrogen deprivation associated with androgen preservation might be significant in the therapeutic action of AG in hormone-responsive neoplasms.
Topics: Adrenalectomy; Aged; Aminoglutethimide; Androgens; Breast Neoplasms; Castration; Estrogens; Female; Gonadotropins, Pituitary; Humans; Menopause; Middle Aged; Neoplasms, Hormone-Dependent
PubMed: 6986409
DOI: 10.1172/JCI109705