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Oncology (Williston Park, N.Y.) Mar 2003The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormone-responsive metastatic breast cancer. Their... (Review)
Review
The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormone-responsive metastatic breast cancer. Their efficacy and apparent lack of toxicity have led to their evaluation as adjuvant therapy. Although initial results with these agents in early breast cancer are promising, our collective long-term experience documenting tamoxifen's benefits and our uncertainty about the long-term effects of aromatase inhibitors suggest that it is too early to recommend their routine use in the adjuvant setting. However, anastrozole is also a reasonable therapeutic option in the adjuvant setting, particularly in individuals with a contraindication to tamoxifen such as those with thromboembolic disease or those who develop breast cancer while receiving tamoxifen or raloxifene (Evista) therapy. Anastrozole (Arimidex) was recently approved by the Food and Drug Administration for the adjuvant treatment of postmenopausal women with hormone-receptor-positive early breast cancer. Ongoing trials are assessing the potential role of aromatase inhibitors in the adjuvant, neoadjuvant, and preventive settings.
Topics: Aminoglutethimide; Anastrozole; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials as Topic; Female; Humans; Nitriles; Triazoles
PubMed: 12661266
DOI: No ID Found -
Cancer Control : Journal of the Moffitt... 2002A series of in vitro and in vivo studies have been performed to establish the endocrine and clinical endpoints of the type I anti-aromatase agent exemestane in... (Review)
Review
A series of in vitro and in vivo studies have been performed to establish the endocrine and clinical endpoints of the type I anti-aromatase agent exemestane in neoadjuvant therapy. In vitro studies demonstrated a dose-related inhibition of aromatase activity with exemestane, even when activity was measured in a system in which the aromatase enzyme was induced in fibroblasts preincubated with exemestane but assayed in the absence of the drug. In contrast, type II anti-aromatase agents (eg, aminoglutethimide, anastrozole, and letrozole) often caused a paradoxical increase in aromatase activity when measured under similar conditions. In vivo and in situ studies were performed in 12 postmenopausal women with untreated large or locally advanced estrogen receptor-rich tumors. The effect of exemestane 25 mg daily for 3 months on aromatization peripherally and in breast cancer and surrounding normal tissue was determined. Immediately before starting therapy, patients received an 18-hour infusion of radioactively labeled androgen and estrogen, followed by a wedge biopsy. This procedure was repeated after 3 months of treatment with exemestane, and the data were used to calculate peripheral and local aromatization. Changes in tumor volume were based on clinical examination, ultrasound, and mammography. Exemestane treatment was associated with a marked reduction in aromatization peripherally and in nonmalignant breast tissue in every patient and in breast tumor in all but one patient. Median reduction in tumor volume was 85.5% for clinical examination, 82.5% for ultrasound, and 84% for mammography. Eight of 10 patients who would have required mastectomy before treatment were able to undergo breast-conserving surgery after treatment. Clinical benefits were accompanied by a marked reduction in cellular proliferation and progesterone receptor expression. These data support the use of exemestane in neoadjuvant therapy of breast cancer in postmenopausal women.
Topics: Aged; Androstadienes; Androstenedione; Antineoplastic Agents, Hormonal; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Middle Aged; Neoadjuvant Therapy; Postmenopause; Time Factors; Treatment Outcome
PubMed: 11965226
DOI: 10.1177/107327480200902S02 -
Urology Aug 1995A wide range of responses have been reported to second-line hormonal therapies, including corticosteroids and the withdrawal of antiandrogens in patients with... (Review)
Review
OBJECTIVES
A wide range of responses have been reported to second-line hormonal therapies, including corticosteroids and the withdrawal of antiandrogens in patients with hormone-refractory prostate cancers. This suggested the need to classify patients on the basis of hormonal sensitivity. A schema was developed by assessing the differences in entry criteria in relation to outcomes for clinical protocols with hydrocortisone alone or in combination with other agents for patients who had progressed after primary hormone therapy.
METHODS
Published clinical trials of patients who had progressed after primary hormone treatment, which included glucocorticoids, were retrieved from Medline listings. The trials included patients treated with hydrocortisone alone, hydrocortisone and aminoglutethimide, hydrocortisone plus suramin, dexamethasone, and prednisone alone or in combination with chemotherapy.
RESULTS
The definitions used for refractory disease ranged from none, to "progression", to "unsuccessful second medical or surgical castration. "None of the trials included a definition for hormone-refractory disease based on objective criteria. Details were lacking on most trials with respect to the response to and specific types of hormonal therapies. Furthermore, few trials controlled for the potential contribution of the "flutamide withdrawal syndrome" on outcome.
CONCLUSIONS
The term "hormone-refractory" prostate cancer has evolved to include patients with a spectrum of diseases. As utilized in clinical trials of second-line hormonal therapies, patients who have received one and as many as six different treatments have been included in the same study. A new classification of patients based on hormonal sensitivity is proposed to recognize that androgen-independent proliferation, progression of disease despite castrate levels of testosterone, does not necessarily mean that a tumor is refractory to hormonal manipulations. Future trials in hormonally relapsed patients must include more details of the hormonal therapies utilized.
Topics: Aminoglutethimide; Clinical Trials as Topic; Cortisone; Dexamethasone; Drug Therapy, Combination; Humans; Hydrocortisone; Male; Medroxyprogesterone; Mitoxantrone; Neoplasm Recurrence, Local; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Suramin; Treatment Outcome
PubMed: 7624983
DOI: 10.1016/s0090-4295(99)80182-4 -
The Journal of Endocrinology Feb 2007The objective of this study was to determine the effects of manipulating glucocorticoid negative feedback on acute ACTH and corticosterone responses to...
The objective of this study was to determine the effects of manipulating glucocorticoid negative feedback on acute ACTH and corticosterone responses to corticotropin-releasing hormone (CRH) injection in 7-day-old rats exposed to normoxia or hypoxia from birth. Chemical adrenalectomy was achieved with aminoglutethimide, and glucocorticoids were replaced with a low dose of dexamethasone. Hypoxia per se increased basal plasma corticosterone and attenuated the plasma ACTH response to CRH. Aminoglutethimide per se decreased plasma corticosterone and strongly increased basal plasma ACTH and anterior pituitary POMC gene expression. Dexamethasone partially attenuated elevations in basal plasma ACTH due to aminoglutethimide in both normoxic and hypoxic pups, but inhibited anterior pituitary POMC expression and CRH-induced plasma ACTH only in hypoxic pups. Despite this inhibition, hypoxic pups treated with both dexamethasone and aminoglutethimide still exhibited a significant CRH-induced increment in plasma ACTH, which was lacking in hypoxic pups not treated with either dexamethasone or aminoglutethimide. We conclude that ACTH responses to acute stimuli in hypoxic neonatal rats are prevented by ACTH-independent increases in corticosterone, rather than by intrinsic hypothalamic-pituitary hypoactivity.
Topics: Adrenergic Agents; Adrenocorticotropic Hormone; Aminoglutethimide; Animals; Animals, Newborn; Corticosterone; Corticotropin-Releasing Hormone; Dexamethasone; Feedback, Physiological; Glucocorticoids; Hypoxia; Pituitary Gland, Anterior; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Stimulation, Chemical
PubMed: 17283245
DOI: 10.1677/JOE-06-0103 -
The Journal of Biological Chemistry Jul 2022Neurosteroids, modulators of neuronal and glial cell functions, are synthesized in the nervous system from cholesterol. In peripheral steroidogenic tissues, cholesterol...
Neurosteroids, modulators of neuronal and glial cell functions, are synthesized in the nervous system from cholesterol. In peripheral steroidogenic tissues, cholesterol is converted to the major steroid precursor pregnenolone by the CYP11A1 enzyme. Although pregnenolone is one of the most abundant neurosteroids in the brain, expression of CYP11A1 is difficult to detect. We found that human glial cells produced pregnenolone, detectable by mass spectrometry and ELISA, despite the absence of observable immunoreactive CYP11A1 protein. Unlike testicular and adrenal cortical cells, pregnenolone production in glial cells was not inhibited by CYP11A1 inhibitors DL-aminoglutethimide and ketoconazole. Furthermore, addition of hydroxycholesterols increased pregnenolone synthesis, suggesting desmolase activity that was not blocked by DL-aminoglutethimide or ketoconazole. We explored three different possibilities for an alternative pathway for glial cell pregnenolone synthesis: (1) regulation by reactive oxygen species, (2) metabolism via a different CYP11A1 isoform, and (3) metabolism via another CYP450 enzyme. First, we found oxidants and antioxidants had no significant effects on pregnenolone synthesis, suggesting it is not regulated by reactive oxygen species. Second, overexpression of CYP11A1 isoform b did not alter synthesis, indicating use of another CYP11A1 isoform is unlikely. Finally, we show nitric oxide and iron chelators deferoxamine and deferiprone significantly inhibited pregnenolone production, indicating involvement of another CYP450 enzyme. Ultimately, knockdown of endoplasmic reticulum cofactor NADPH-cytochrome P450 reductase had no effect, while knockdown of mitochondrial CYP450 cofactor ferredoxin reductase inhibited pregnenolone production. These data suggest that pregnenolone is synthesized by a mitochondrial cytochrome P450 enzyme other than CYP11A1 in human glial cells.
Topics: Aminoglutethimide; Cholesterol; Cholesterol Side-Chain Cleavage Enzyme; Humans; Ketoconazole; Neuroglia; Neurosteroids; Pregnenolone; Reactive Oxygen Species
PubMed: 35688208
DOI: 10.1016/j.jbc.2022.102110 -
The Journal of Allergy and Clinical... Nov 2013Cytochrome P450, family 11, subfamily A, polypeptide 1 (Cyp11a1), a cytochrome P450 enzyme, is the first and rate-limiting enzyme in the steroidogenic pathway,...
BACKGROUND
Cytochrome P450, family 11, subfamily A, polypeptide 1 (Cyp11a1), a cytochrome P450 enzyme, is the first and rate-limiting enzyme in the steroidogenic pathway, converting cholesterol to pregnenolone. Cyp11a1 expression is increased in activated T cells.
OBJECTIVES
We sought to determine the role of Cyp11a1 activation in the development of peanut allergy and TH cell functional differentiation.
METHODS
A Cyp11a1 inhibitor, aminoglutethimide (AMG), was administered to peanut-sensitized and challenged mice. Clinical symptoms, intestinal inflammation, and Cyp11a1 levels were assessed. The effects of Cyp11a1 inhibition on T(H)1, T(H)2, and T(H)17 differentiation were determined. Cyp11a1 gene silencing was performed with Cyp11a1-targeted short hairpin RNA.
RESULTS
Peanut sensitization and challenge resulted in diarrhea, inflammation, and increased levels of Cyp11a1, IL13, and IL17A mRNA in the small intestine. Inhibition of Cyp11a1 with AMG prevented allergic diarrhea and inflammation. Levels of pregnenolone in serum were reduced in parallel. AMG treatment decreased IL13 and IL17A mRNA expression in the small intestine without affecting Cyp11a1 mRNA or protein levels. In vitro the inhibitor decreased IL13 and IL17A mRNA and protein levels in differentiated T(H)2 and T(H)17 CD4 T cells, respectively, without affecting GATA3, retinoic acid-related orphan receptor γt (RORγt), or T(H)1 cells and IFNG and T-bet expression. Short hairpin RNA-mediated silencing of Cyp11a1 in polarized T(H)2 CD4 T cells significantly decreased pregnenolone and IL13 mRNA and protein levels.
CONCLUSION
Cyp11a1 plays an important role in the development of peanut allergy, regulating peanut-induced allergic responses through effects on steroidogenesis, an essential pathway in T(H)2 differentiation. Cyp11a1 thus serves as a novel target in the regulation and treatment of peanut allergy.
Topics: Anaphylaxis; Animals; Cell Differentiation; Cell Lineage; Cholesterol Side-Chain Cleavage Enzyme; Cytokines; Disease Models, Animal; Enzyme Activation; Female; Gene Expression Regulation; Gene Silencing; Intestines; Mice; Peanut Hypersensitivity; RNA Interference; RNA, Messenger; T-Lymphocytes, Helper-Inducer; Th17 Cells; Th2 Cells; Transcription Factors
PubMed: 23870673
DOI: 10.1016/j.jaci.2013.05.027 -
Chemical Research in Toxicology Jul 2007Aminoglutethimide (AG) is a first-generation aromatase inhibitor used for estrogen-dependent breast cancer. Unfortunately, its use has also been associated with...
Aminoglutethimide (AG) is a first-generation aromatase inhibitor used for estrogen-dependent breast cancer. Unfortunately, its use has also been associated with agranulocytosis. We have investigated the metabolism of AG by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that AG oxidation by MPO/H2O2 would produce an AG cation radical that, in the absence of a biochemical reductant, would lead to the oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms only by the reaction of DMPO with a protein free radical. We found that AG metabolism by MPO/H2O2 induced the formation of DMPO-MPO, which was inhibited by MPO inhibitors and ascorbate. Glutethimide, a congener of AG that lacks the aromatic amine, did not cause DMPO-MPO formation, indicating the necessity of oxidation of the aniline moiety in AG. When analyzed by electron spin resonance spectroscopy, we detected a phenyl radical adduct, derived from AG, which may be involved in the free radical formation on MPO. Furthermore, we also found protein-DMPO adducts in MPO-containing, intact human promyelocytic leukemia cells (HL-60). MPO was affinity-purified from HL-60 cells treated with AG/H2O2 and was found to contain DMPO. These findings were also supported by the detection of protein free radicals with electron spin resonance in the cellular cytosolic lysate. The formation of an MPO protein free radical is believed to be mediated by one of two free radical drug metabolites of AG, one of which was characterized by spin trapping with 2-methyl-2-nitrosopropane. These results are the first demonstration of MPO free-radical detection by the anti-DMPO antibody that results from drug oxidation. We propose that drug-dependent free radical formation on MPO may play a role in the origin of agranulocytosis.
Topics: Adenosine Triphosphate; Agranulocytosis; Aminoglutethimide; Aniline Compounds; Aromatase Inhibitors; Ascorbic Acid; Blotting, Western; Chromatography, Affinity; Cyclic N-Oxides; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Enzyme-Linked Immunosorbent Assay; Free Radicals; Glucose; Glutethimide; HL-60 Cells; Humans; Hydrogen Peroxide; Nitrogen Oxides; Nitroso Compounds; Peroxidase; Spectrophotometry
PubMed: 17602675
DOI: 10.1021/tx6003562 -
American Journal of Physiology.... Jul 2008During cholestatic liver diseases, cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides by paracrine and autocrine...
During cholestatic liver diseases, cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides by paracrine and autocrine mechanisms. We examined whether the neuroendocrine hormone progesterone is produced by and targeted to cholangiocytes, thereby regulating biliary proliferation during cholestasis. Nuclear (PR-A and PR-B) and membrane (PRGMC1, PRGMC2, and mPRalpha) progesterone receptor expression was evaluated in liver sections and cholangiocytes from normal and bile duct ligation (BDL) rats, and NRC cells (normal rat cholangiocyte line). In vivo, normal rats were chronically treated with progesterone for 1 wk, or immediately after BDL, rats were treated with a neutralizing progesterone antibody for 1 wk. Cholangiocyte growth was measured by evaluating the number of bile ducts in liver sections. The expression of the progesterone synthesis pathway was evaluated in liver sections, cholangiocytes and NRC. Progesterone secretion was evaluated in supernatants from normal and BDL cholangiocytes and NRC. In vitro, NRC were stimulated with progesterone and cholangiocyte supernatants in the presence or absence of antiprogesterone antibody. Aminoglutethimide was used to block progesterone synthesis. Cholangiocytes and NRC express the PR-B nuclear receptor and PRGMC1, PRGMC2, and mPRalpha. In vivo, progesterone increased the number of bile ducts of normal rats, whereas antiprogesterone antibody inhibited cholangiocyte growth stimulated by BDL. Normal and BDL cholangiocytes expressed the biosynthetic pathway for and secrete progesterone. In vitro, 1) progesterone increased NRC proliferation; 2) cholangiocyte supernatants increased NRC proliferation, which was partially inhibited by preincubation with antiprogesterone; and 3) inhibition of progesterone steroidogenesis prevented NRC proliferation. In conclusion, progesterone may be an important autocrine/paracrine regulator of cholangiocyte proliferation.
Topics: 3-Hydroxysteroid Dehydrogenases; Animals; Autocrine Communication; Bile Ducts; Cell Proliferation; Cytochrome P-450 Enzyme System; Female; Gene Expression Regulation; Male; Paracrine Communication; Phosphoproteins; Progesterone; Rats; Rats, Inbred F344; Receptors, Progesterone; Sex Characteristics
PubMed: 18511743
DOI: 10.1152/ajpgi.00536.2007 -
The Journal of Clinical Investigation Jul 1978An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive...
An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive action of the drug was compared with its effects on adrenal steroid production. In all patients aldosterone concentrations in plasma and urine were within normal limits before the study. Mean arterial pressure was reduced from a pretreatment value of 117+/-2 (mean+/-SE) mm Hg to 108+/-3 mm Hg after 4 days of aminoglutethimide therapy and further to 99+/-3 mm Hg when drug administration was stopped (usually 21 days). Body weight was also reduced from 81.6+/-7.2 kg in the control period to 80.6+/-7.0 kg after 4 days of drug treatment and to 80.1+/-6.7 kg at the termination of therapy. Plasma renin activity was not significantly increased after 4 days of treatment but had risen to the normal range by the termination of aminoglutethimide therapy. Mean plasma concentrations of deoxycorticosterone and cortisol were unchanged during aminoglutethimide treatment whereas those of 18-hydroxydeoxycorticosterone, progesterone, 17alpha-hydroxyprogesterone, and 11-deoxycortisol were increased as compared to pretreatment values. In contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of control values. Excretion rates of 16beta-hydroxydehydroepiandrosterone, 16-oxo-androstenediol, 17-hydroxycorticosteroids and 17-ketosteroids, and the secretion rate of 16beta-hydroxydehydroepiandrosterone were not significantly altered by aminoglutethimide treatment whereas the excretion rate of aldosterone was reduced from 3.62+/-0.5 (mean+/-SE) in the control period to 0.9+/-0.2 mug/24 h after 4 days and to 1.1+/-0.3 mug/24 h at the termination of aminoglutethimide treatment. The gradual lowering of blood pressure and body weight during aminoglutethimide therapy is consistent with the view that the antihypertensive effect of the drug is mediated through a reduction in the patients' extracellular fluid volume, probably secondary to the persistent decrease in aldosterone production. The observation that chronic administration of aminoglutethimide lowered blood pressure in these patients and elevated their plasma renin activity to the normal range without decreasing production of the adrenal steroids, deoxycorticosterone, 18-hydroxydeoxycorticosterone, and 16beta-hydroxydehydroepiandrosterone, makes it unlikely that these steroids are responsible either for the decreased renin or the elevated blood pressure in patients with low renin essential hypertension.
Topics: 18-Hydroxydesoxycorticosterone; Adrenal Cortex Hormones; Aminoglutethimide; Blood Pressure; Dehydroepiandrosterone; Female; Humans; Hypertension; Male; Renin; Steroids
PubMed: 149141
DOI: 10.1172/JCI109101 -
Medicine Jul 2017Steroid profiling was introduced to determine the endogenous steroid misuse in sports. Thus, screening for the exogenous use of these prohibited substances can be... (Randomized Controlled Trial)
Randomized Controlled Trial
Steroid profiling was introduced to determine the endogenous steroid misuse in sports. Thus, screening for the exogenous use of these prohibited substances can be established by monitoring a range of endogenous steroids, which constitute the steroid profile and evaluate their concentrations and ratios against reference values. The steroid profiling is currently based on population statistics. As large interindividual variations exist, athlete biological passport (ABP) analysis is ongoing. This study aimed to identify new biomarker(s) for aromatase inhibitor detection in sports using statistical analysis and adapt the model into ABP analysis.Forty-one Chinese nonathlete volunteers (21 males and 20 females) were administered 3 nonsteroidal aromatase inhibitors (aminoglutethimide, letrozole, and anastrozole) independently. Statistical analysis was performed on 16 steroid profile parameters.After administration, the concentrations of endogenous androgen biomarkers including testosterone (T), epitestosterone, androsterone (AN), etiocholanolone (ETIO), 5α-diol, 5β-diol, and dehydroepiandrosterone were increased, while the level of estrogen was decreased. These biomarkers returned to the baselines levels within 1 month. In females, the concentrations of endogenous biomarkers were affected by nonsteroidal aromatase inhibitors, without a common trend. Three new endogenous biomarkers (AN/estrone, ETIO/estrone, and T/estrone) elevated significantly after treatment. The 3 new models were more sensitive than the World Anti-Doping Agency ratio biomarkers. They were also effective in exponentially weighted moving average chart analysis.Verification experiment demonstrated that the biomarker T/estrone was valid in judging the steroidal aromatase inhibitor abuse. The screening of these new endogenous biomarkers can provide additional parameters to support ABP monitoring and specific information regarding the administered steroids.
Topics: Aminoglutethimide; Anastrozole; Aromatase Inhibitors; Biomarkers, Pharmacological; Doping in Sports; Female; Hormones; Humans; Letrozole; Male; Models, Biological; Nitriles; Single-Blind Method; Steroids; Substance-Related Disorders; Triazoles; Young Adult
PubMed: 28700478
DOI: 10.1097/MD.0000000000007411