Science.gov

Sample records for affects aromatase inhibitor

  1. Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors.

    PubMed

    Kallak, Theodora Kunovac; Baumgart, Juliane; Göransson, Emma; Nilsson, Kerstin; Poromaa, Inger Sundström; Stavreus-Evers, Anneli

    2014-04-01

    Women with breast cancer who are treated with aromatase inhibitors often experience vaginal atrophy symptoms and sexual dysfunction. This work aims to study proliferation and the presence and distribution of steroid hormone receptors in vaginal biopsies in relation to vaginal atrophy and vaginal pH in women with breast cancer who are on adjuvant endocrine treatment and in healthy postmenopausal women. This is a cross-sectional study that compares postmenopausal aromatase inhibitor-treated women with breast cancer (n = 15) with tamoxifen-treated women with breast cancer (n = 16) and age-matched postmenopausal women without treatment (n = 19) or with vaginal estrogen therapy (n = 16). Immunohistochemistry was used to study proliferation and steroid hormone receptor staining intensity. Data was correlated with estrogen and androgen levels, vaginal atrophy scores, and vaginal pH. Aromatase inhibitor-treated women had a lower grade of proliferation, weaker progesterone receptor staining, and stronger androgen receptor staining, which correlated with plasma estrone levels, vaginal atrophy scores, and vaginal pH. Women with aromatase inhibitor-treated breast cancer exhibit reduced proliferation and altered steroid hormone receptor staining intensity in the vagina, which are related to clinical signs of vaginal atrophy. Although these effects are most probably attributable to estrogen suppression, a possible local inhibition of aromatase cannot be ruled out.

  2. Sequencing of aromatase inhibitors

    PubMed Central

    Bertelli, G

    2005-01-01

    Since the development of the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, these agents have been the subject of intensive research to determine their optimal use in advanced breast cancer. Not only have they replaced progestins in second-line therapy and challenged the role of tamoxifen in first-line, but there is also evidence for a lack of cross-resistance between the steroidal and nonsteroidal AIs, meaning that they may be used in sequence to obtain prolonged clinical benefit. Many questions remain, however, as to the best sequence of the two types of AIs and of the other available agents, including tamoxifen and fulvestrant, in different patient groups. PMID:16100523

  3. Aromatase, Aromatase Inhibitors, and Breast Cancer

    PubMed Central

    Chumsri, Saranya; Howes, Timothy; Bao, Ting; Sabnis, Gauri; Brodie, Angela

    2011-01-01

    Estrogens are known to be important in the growth of breast cancers in both pre- and postmenopausal women. As the number of breast cancer patients increases with age, the majority of breast cancer patients are postmenopausal women. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. As aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme are effective targeted therapy for breast cancer. Three aromatase inhibitors (AIs) are now FDA approved and have been shown to be more effective than the antiestrogen tamoxifen and are well tolerated. AIs are now a standard treatment for postmenopausal patients. AIs are effective in adjuvant and first-line metastatic setting. This review describes the development of AIs and their current use in breast cancer. Recent research focuses on elucidating mechanisms of acquired resistance that may develop in some patients with long term AI treatment and also on innate resistance. Preclinical data in resistance models demonstrated that the crosstalk between ER and other signaling pathways particularly MAPK and PI3K/Akt is an important resistant mechanism. Blockade of these other signaling pathways is an attractive strategy to circumvent the resistance to AI therapy in breast cancer. Several clinical trials are ongoing to evaluate the role of these novel targeted therapies to reverse resistance to AIs. PMID:21335088

  4. Aromatase Inhibitors and Other Compounds for Lowering Breast Cancer Risk

    MedlinePlus

    ... Cancer Risk and Prevention Aromatase Inhibitors for Lowering Breast Cancer Risk Aromatase inhibitors (drugs that lower estrogen levels) ... day. Can aromatase inhibitors lower the risk of breast cancer? Aromatase inhibitors are used mainly to treat hormone ...

  5. Natural products as aromatase inhibitors.

    PubMed

    Balunas, Marcy J; Su, Bin; Brueggemeier, Robert W; Kinghorn, A Douglas

    2008-08-01

    With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein.

  6. Substituted androstanes as aromatase inhibitors

    NASA Astrophysics Data System (ADS)

    Levina, Inna S.

    1998-11-01

    The synthesis and structure-activity relationships of inhibitors of steroid aromatase which catalyses the last stage of a multistep biotransformation of cholesterol into estrogens, viz., aromatisation of C19-steroids into C18-phenolic steroids, are discussed. Compounds of the androstane series which are structurally related to the natural substrate, viz., androst-4-ene-3,17-dione, are the subjects of consideration. The review encompasses problems of synthesis of various substituted androstanes and their aromatase-inhibiting activities and structural requirements for selective specific aromatase inhibitors based on in vitro and in vivo structure-activity studies of compounds synthesised, their biological properties and the results of clinical trials. Special attention is paid to practical applications of aromatase inhibitors in the treatment of hormone-dependent mammary and ovarian tumours as well as benign prostatic tumours. In writing this report, the author has used all the information currently available in the chemical, biochemical, endocrinological and medicinal literature as well as in patents. The bibliography includes 173 references.

  7. Natural Products as Aromatase Inhibitors

    PubMed Central

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2010-01-01

    With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein. PMID:18690828

  8. Aromatase Inhibitors and Bone Loss

    PubMed Central

    PEREZ, EDITH A.; M., Serene; Durling, Frances C.; WEILBAECHER, KATHERINE

    2009-01-01

    The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor–positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment–related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < −2.5) and considered on an individual basis for those with osteopenia (T score < −1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor–positive breast cancer. PMID:16986348

  9. Aromatase inhibitors and bone loss.

    PubMed

    Perez, Edith A; Weilbaecher, Katherine

    2006-08-01

    The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.

  10. Aromatase inhibitors: possible future applications.

    PubMed

    Karaer, Oznur; Oruç, Semra; Koyuncu, Faik Mümtaz

    2004-08-01

    In premenopausal women ovaries are the major sites of estrogen production, while in postmenopausal women estrogen is produced by aromatization of ovarian and adrenal androgens in extragonadal sites, mostly in adipose tissue. Aromatase is a cytochrome P450 hemoprotein-containing enzyme complex that catalyzes the rate-limiting step in the conversion of androstenedione and testosterone to estrone and estradiol (E2). Aromatase inhibitors (AIs) have been developed primarily for use in either natural or surgical postmenopausal patients. In premenopausal women, the ovary can overcome the estrogen blockade by reflex increments of luteinizing hormone (LH) and follicle stimulating hormone (FSH), so AIs must be combined with a gonadotropin releasing hormone (GnRH) agonist to prevent the reflex LH and FSH increments. In advanced hormone-dependent breast cancer treatment, AIs have been shown to be superior to tamoxifen. Preliminary evidence also suggests superiority in the adjuvant, neoadjuvant settings and also for breast cancer prevention. AIs have been used in infertility and can increase ovulation rate. Reducing FSH dose, estrogen levels, improving response to FSH, implantation rates, and developing multiple follicles that can be used in in vitro maturation procedures are potential areas that AIs might be used in in assisted reproductive technologies (ART), besides simple ovulation induction. AIs are reported to be successful in treatment of endometriosis, an estrogen-dependent process. The use of AIs in gynecomastia, puberte precox, leiomyoma uteri, some estrogen-dependent cancers (ovarian), endometrial cancer and male infertility are reported; some of the results are promising but more clinical trials are needed. AIs are predicted to become the gold standard in the treatment of estrogen-dependent diseases in reproductive medicine in the near future.

  11. Aromatase inhibitors: structural features and biochemical characterization.

    PubMed

    Hong, Yanyan; Chen, Shiuan

    2006-11-01

    Aromatase is the enzyme synthesizing estrogens from androgens. In estrogen-dependent breast tumors, estrogens induce the expression of growth factors responsible for cancer cell proliferation. In situ estrogen synthesis by aromatase "is thought to play a key role in the promotion of breast cancer growth. Aromatase inhibitors (AIs) provide new approaches for the prevention and treatment of breast cancer by inhibiting estrogen biosynthesis. Through reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical techniques, aromatase has been found to be expressed in many endocrine tissues and tumors originating from these tissues. Unexpectedly, this enzyme is now known to also be expressed in liver, lung, and colon cancers. Such findings suggest a potential role for endocrine manipulation of these types of cancer using AIs. Three Food and Drug Administration (FDA)-approved AIs, anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin), effectively challenging tamoxifen, have been used as first-line drugs in the treatment of hormone-dependent breast cancer, and possibly other aromatase-expressing cancers. In addition, natural anti-aromatase chemicals, such as flavones and coumarins, have been identified. Efforts to develop new lines of AIs derived from these phytochemicals have been initiated in several laboratories. Finally, significant progress has been made in the understanding of the structure-function relationship of aromatase. Such information has helped the examination of binding characteristics of AIs, the evaluation of reaction mechanism of aromatase, and the explanation of the molecular basis for a low catalytic activity of the natural variant, M364T.

  12. Understanding the mechanisms of aromatase inhibitor resistance

    PubMed Central

    2012-01-01

    Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment. PMID:22277572

  13. Binding characteristics of aromatase inhibitors and phytoestrogens to human aromatase.

    PubMed

    Chen, S; Kao, Y C; Laughton, C A

    1997-04-01

    We have evaluated the binding characteristics of three steroidal inhibitors [4-hydroxyandrostenedione (4-OHA), 7alpha-(4'-amino)phenylthio-1,4-androstadiene-3,17-dione (7alpha-APTADD), and bridge (2,19-methyleneoxy) androstene-3,17-dione (MDL 101,003)], four nonsteroidal inhibitors [aminoglutethimide (AG), CGS 20267, ICI D1033, and vorozole (R83842)], and two flavone phytoestrogens (chrysin, and 7,8-dihydroxyflavone) to aromatase through a combination of computer modeling and inhibitory profile studies on the wild-type and six aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y). We have generated two aromatase models based on the x-ray structures of cytochrome P450-cam and cytochrome P450bm3, respectively. A major difference between the cytochrome P450cam-based and cytochrome P450bm3-based models is in the predicted lengths of helices F and G. In the cytochrome P450cam-based model, helices F and G lie antiparallel and extend across the active-site face of the molecule from one edge to the center, so that the carboxyl-terminal residues of helix F and the N-terminal residues of helix G make a major contribution to the structure of the active site. In the cytochrome P450bm3-based model, both helices are longer and so extend almost all the way across the active-site face of the molecule. Considering the size of the androgen substrate, we evaluated our results mainly based on the cytochrome P450cam model. The mutations involved in this study are thought to be at or near the proposed active site pocket. The inhibitory profile analysis has produced very interesting results and provided a molecular basis as to how seven aromatase inhibitors with different structures bind to the active site of aromatase. Furthermore, the investigation reveals that phytoestrogens bind to the active site of aromatase in a different orientation from that in the estrogen receptor.

  14. Aromatase inhibitors: past, present and future.

    PubMed

    Séralini, G; Moslemi, S

    2001-06-10

    For the cellular physiology of sex steroid sensitive cells, the androgen/estrogen ratio may be more important than only one hormone action per se, in both sexes. This ratio is controlled in vertebrates by aromatase; its gene expression can be inhibited in different ways, and this is crucial for the treatment of estrogen-dependent diseases such as breast cancer, or gynecomastia in males for instance. To reach this goal, new steroidal and non-steroidal inhibitors are continuously being developed, and some of them are used as first or second line agents. Aromatase inhibition is also an essential tool for studying the role of estrogens in the adult, or during development. Aromatase inhibitors have shown in particular that estrogens are essential also in males for skeletal maturation and bone mineralization, development of masculine dendritic morphology in male brain linked to mating behaviour, and testicular function. Testosterone is often the prohormone converted in situ in active estrogens, at these levels. Several strategies can be used for aromatase inhibition. The first ones employed were blind screening or deductions from in vivo observations, which led for instance to the discovery of the role of aminoglutethimide in aromatase inhibition. Subsequently, in the years 1975-1990, the molecular modeling of compounds to mimic the substrate shape of the enzyme constituted the major idea. Hundreds of chemicals were synthesized by numerous authors, ranging from the well-known and very efficient 4-OHA to complicated imidazole or indane derivatives tested by sophisticated comparative molecular field analyses. Reticulum-bound active aromatase has not as yet been X-ray analyzed. Thus, aromatase inhibitors were also used more recently to probe and understand the active site conformation of the enzyme and its modelization was obtained from comparisons with bacterial-related cytochromes. We developed a mammalian model considerably closer to human aromatase in order to study the

  15. NEW EXPERIMENTAL MODELS FOR AROMATASE INHIBITOR RESISTANCE

    PubMed Central

    Chen, Shiuan; Masri, Selma; Hong, Yanyan; Wang, Xin; Phung, Sheryl; Yuan, Yate-Ching; Wu, Xiwei

    2009-01-01

    Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to tamoxifen, an antagonist of the estrogen receptor (ER), AIs have shown to be better tolerated along with decreased recurrence rates of the disease. Currently, three third-generation AIs are being used: exemestane, letrozole and anastrozole. Our laboratory is attempting to understand several aspects of aromatase inhibitor functionality. In this paper, we first review recent findings from our structure-function studies of aromatase as well as the molecular characterization of the interaction between AIs and aromatase. Based on these studies, we propose new evidence for the interaction of letrozole and exemestane with aromatase. In addition, we will discuss recent results generated from our AI-resistant cell lines. Our laboratory has generated MCF-7aro cells that are resistant to letrozole, anastrozole, exemestane and tamoxifen. Basic functional characterization of aromatase and ERα in these resistant cell lines has been done and microarray analysis has been employed in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. The results generated so far suggest the presence of at least four types of resistant cell lines. Overall, the information presented in this paper supplements our understanding of AI function, and such information can be valuable for the development of treatment strategies against AI resistant breast cancers. PMID:17611102

  16. Molecular basis for the interaction of four different classes of substrates and inhibitors with human aromatase.

    PubMed

    Hong, Yanyan; Cho, Michael; Yuan, Yate-Ching; Chen, Shiuan

    2008-03-01

    Aromatase cytochrome P450 (CYP19) converts androgen to estrogen. In this study, the interactions of four classes of compounds, 17beta-estradiol (the product of aromatase), 17-methyltestosterone (a synthetic androgen), dibenzylfluorescein (a synthetic substrate of aromatase), and coumestrol (a phytoestrogen), with aromatase were investigated through spectral analysis using purified human recombinant aromatase and site-directed mutagenesis studies using CHO cells expressing wild-type human aromatase or five aromatase mutants, E302D, D309A, T310S, S478T and H480Q. Spectral analysis showed that a type I binding spectrum was produced by the binding of 17-methyltestosterone to aromatase and a novel binding spectrum of aromatase was induced by dibenzylfluorescein. Mutagenesis experiments demonstrated that residues S478 and H480 in the beta-4 sheet play an important role in the binding of all four compounds. Computer-assisted docking of these compounds into the three-dimensional model of aromatase revealed that: (1) weak interaction between 17beta-estradiol and the beta-4 sheet of aromatase facilitates the release of 17beta-estradiol from the active site of aromatase; (2) 17-methyl group of 17-methyltestosterone affects its binding to aromatase; (3) dibenzylfluorescein binds to the active site of aromatase with its O-dealkylation site near the heme iron and residue T310; and (4) coumestrol binds to aromatase in a manner such that rings A and C of coumestrol mimic rings A and B of steroid. These structure-function studies help us to evaluate the structural model of aromatase, and to accelerate the structure-based design for new aromatase inhibitors.

  17. Presence of aromatase inhibitors in cycads.

    PubMed

    Kowalska, M T; Itzhak, Y; Puett, D

    1995-07-28

    Cycads, the most primitive of the living gymnosperms, have been used and continue to be used for food and medicinal purposes by many cultures, although toxins must be removed before ingestion. In our quest to identify tropical plants that contain inhibitors of the cytochrome P-450 aromatase and thus may be efficacious in treating estrogen-dependent tumors, we have screened extracts from 5 species of cycad folia encompassing 3 genera: Cycas cairnsiana F. Muell., Cycas revoluta Thunb., Cycas rumphii Miq., Dioon spinulosum Dyer and Encephalartos ferox Bertol. All extracts were found to contain inhibitors of the human enzyme.

  18. Aromatase inhibitors: assessment of biochemical efficacy measured by total body aromatase inhibition and tissue estrogen suppression.

    PubMed

    Lønning, Per E; Geisler, Jürgen

    2008-02-01

    The implementation of aromatase inhibitors for treatment of early and metastatic breast cancer has been one of the major improvements in endocrine therapy of breast cancer. Measurement of endocrine effects of aromatase inhibition in vivo has been a major tool in the process of evaluating novel compounds. Biochemical efficacy of aromatase inhibitors in vivo may be determined from their effects on "total body aromatization" as well changes in plasma and tissue estrogen levels. Due to high sensitivity, tracer methods allowing calculation of whole body aromatase inhibition are still considered the gold standard. The method developed by our group in collaboration with the Royal Marsden Hospital and the results of this joint program are summarized and discussed. These studies allowed classification of the different aromatase inhibitors and their optimal dosage, selecting the best compounds for clinical evaluation. In vivo total body aromatase assessment is a work-consuming method, allowing such studies to be conducted in a limited number of patients only. In contrast, plasma estrogen measurement is a cruder but simpler method, allowing screening of larger groups of patients. As plasma estrogens arise through passive diffusion of estrogens synthesized in different body compartments, plasma estrogens, as well as total body aromatase assessment, present a rough estimate of total body tissue estrogen production, and changes associated with treatment with aromatase inhibitors reflect the effects on tissue estrogen production in general. However, plasma estrogen levels do not correlate to breast cancer tissue estrogen levels. This is due to the endocrine autonomy of breast cancer tissue with significant local estrogen production in some tumors. Thus, direct measurement of intratumor estrogens is demanded to evaluate the effects of aromatase inhibitors in malignant target tissues. Our group has developed a highly sensitive HPLC-RIA for the simultaneous measurement of estrone

  19. Lead optimization of 4-imidazolylflavans: new promising aromatase inhibitors.

    PubMed

    Yahiaoui, Samir; Pouget, Christelle; Buxeraud, Jacques; Chulia, Albert José; Fagnère, Catherine

    2011-06-01

    Our previous studies have shown that several 7-substituted-4-imidazolylflavans are potent inhibitors of aromatase. These compounds were designed considering the anti-aromatase effect of some natural flavonoids and the importance of an azole ring for synthetic inhibitors such as letrozole or anastrozole towards binding to the heme iron of aromatase. In this study, we report the optimization of these lead compounds by the modulation of flavan A ring. The resulting 7,8-benzo-4-imidazolylflavans were tested in order to assess their ability to inhibit aromatase. Biological data concerning enantiomers obtained from the chiral separation of the racemate compound 4-imidazolyl-7-methoxyflavan are also presented.

  20. Vaginal Gene Expression During Treatment With Aromatase Inhibitors.

    PubMed

    Kallak, Theodora Kunovac; Baumgart, Juliane; Nilsson, Kerstin; Åkerud, Helena; Poromaa, Inger Sundström; Stavreus-Evers, Anneli

    2015-12-01

    Aromatase inhibitor (AI) treatment suppresses estrogen biosynthesis and causes genitourinary symptoms of menopause such as vaginal symptoms, ultimately affecting the quality of life for many postmenopausal women with breast cancer. Thus, the aim of this study was to examine vaginal gene expression in women during treatment with AIs compared with estrogen-treated women. The secondary aim was to study the presence and localization of vaginal aromatase. Vaginal biopsies were collected from postmenopausal women treated with AIs and from age-matched control women treated with vaginal estrogen therapy. Differential gene expression was studied with the Affymetrix Gene Chip Gene 1.0 ST Array (Affymetrix Inc, Santa Clara, CA) system, Ingenuity pathway analysis, quantitative real-time polymerase chain reaction, and immunohistochemistry. The expression of 279 genes differed between the 2 groups; AI-treated women had low expression of genes involved in cell differentiation, proliferation, and cell adhesion. Some differentially expressed genes were found to interact indirectly with the estrogen receptor alpha. In addition, aromatase protein staining was evident in the basal and the intermediate vaginal epithelium layers, and also in stromal cells with a slightly stronger staining intensity found in AI-treated women. In this study, we demonstrated that genes involved in cell differentiation, proliferation, and cell adhesion are differentially expressed in AI-treated women. The expression of vaginal aromatase suggests that this could be the result of local and systemic inhibition of aromatase. Our results emphasize the role of estrogen for vaginal cell differentiation and proliferation and future drug candidates should be aimed at improving cell differentiation and proliferation. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Bone scan alterations in aromatase inhibitor-treated patients.

    PubMed

    De Geeter, Frank; Van den Bruel, Annick; De Cuypere, Eveline; Langlois, Michel

    2015-01-01

    We report bone scan changes in 3 patients receiving aromatase inhibitors as adjuvant treatment for postmenopausal hormone receptor-positive breast cancer. Compared with bone scans before treatment, repeated scans after at least 10 months of aromatase inhibitor treatment showed increased activity in the peripheral skeleton and the skull. In 2 patients, these alterations could be correlated with increased markers of bone turnover. They probably result from high bone turnover induced by estrogen depletion caused by aromatase inhibitors. This effect should be taken into account in the differential diagnosis of a bone scan pattern suggestive of hyperparathyroidism, which was ruled out.

  2. Effectively nursing patients receiving aromatase inhibitor therapy.

    PubMed

    Wengström, Y

    2008-06-01

    Inhibiting estrogen production is a common means of preventing breast cancer recurrence. The aromatase inhibitors (AIs) are becoming the preferred treatment over tamoxifen as adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer. Like all adjuvant therapies, AIs have adverse events (AEs) associated with their use, many of which resemble symptoms common to menopause. Because of the greater efficacy of AIs in preventing breast cancer recurrence over tamoxifen, these AEs may be considered tolerable by many patients and often can be effectively managed and/or prevented. Educating patients about anticipated AEs may help them understand, accept, and cope with these AEs. This article reviews the AEs associated with different adjuvant AI treatments and highlights some strategies to manage them effectively. It also highlights the importance of patient education regarding AI therapy and involvement in treatment decisions, which may lead to better long-term adherence and ultimately to better outcomes.

  3. The Use of Aromatase Inhibitors for Ovulation Induction and Superovulation

    PubMed Central

    Pavone, Mary Ellen

    2013-01-01

    Context: Anovulation is likely responsible for 20% of female infertility. Although clomiphene citrate remains the first-line therapy for ovulation induction in anovulatory patients who are not estrogen-deficient and to treat unexplained infertility, there remains a discrepancy between ovulation and conception rates with its use, attributed to its antiestrogenic effects on cervical mucus and the endometrium. Alternative agents, including aromatase inhibitors, have been used that have not been associated with these side effects. Evidence Acquisition: A literature search was conducted to specifically explore the use of aromatase inhibitors for ovulation induction and superovulation. Evidence Synthesis: Recent studies have found that aromatase inhibitors may be safe and useful agents for ovulation induction in patients with polycystic ovarian syndrome as well a treatment option for superovulation in patients with either unexplained infertility or endometriosis. Conclusions: Aromatase inhibitors may be an effective alternative treatment to clomiphene citrate for both ovulation induction and superovulation. PMID:23585659

  4. Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression.

    PubMed

    Kijima, Ikuko; Phung, Sheryl; Hur, Gene; Kwok, Sum-Ling; Chen, Shiuan

    2006-06-01

    Aromatase is the enzyme that converts androgen to estrogen. It is expressed at higher levels in breast cancer tissues than normal breast tissues. Grape seed extract (GSE) contains high levels of procyanidin dimers that have been shown in our laboratory to be potent inhibitors of aromatase. In this study, GSE was found to inhibit aromatase activity in a dose-dependent manner and reduce androgen-dependent tumor growth in an aromatase-transfected MCF-7 (MCF-7aro) breast cancer xenograft model, agreeing with our previous findings. We have also examined the effect of GSE on aromatase expression. Reverse transcription-PCR experiments showed that treatment with 60 mug/mL of GSE suppressed the levels of exon I.3-, exon PII-, and exon I.6-containing aromatase mRNAs in MCF-7 and SK-BR-3 cells. The levels of exon I.1-containing mRNA, however, did not change with GSE treatment. Transient transfection experiments with luciferase-aromatase promoter I.3/II or I.4 reporter vectors showed the suppression of the promoter activity in a dose-dependent manner. The GSE treatment also led to the down-regulation of two transcription factors, cyclic AMP-responsive element binding protein-1 (CREB-1) and glucocorticoid receptor (GR). CREB-1 and GR are known to up-regulate aromatase gene expression through promoters I.3/II and I.4, respectively. We believe that these results are exciting in that they show GSE to be potentially useful in the prevention/treatment of hormone-dependent breast cancer through the inhibition of aromatase activity as well as its expression.

  5. Aromatase inhibitors in stimulated IVF cycles

    PubMed Central

    2011-01-01

    Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels PMID:21693033

  6. Aromatase inhibitors from Urtica dioica roots.

    PubMed

    Gansser, D; Spiteller, G

    1995-04-01

    Methanolic extracts of stinging nettle (Urtica dioica L.) roots were investigated for aromatase inhibition. Enzyme inhibition was detected only after appropriate chromatographic separation. Inhibitory effects on aromatase could be demonstrated in vitro for a variety of compounds belonging to different classes. The following compounds developed weak to moderate activity: secoisolariciresinol, oleanolic and ursolic acid, (9Z,11E)-13-hydroxy-9,11-octadecadienoic acid, and 14-octacosanol (5). Inhibitory effects on aromatase have been known to date neither for pentacyclic triterpenes nor for secondary fatty alcohols. The potential physiological significance of the above findings is discussed. Compound 5 is a previously unknown constituent of plants.

  7. Two aromatase inhibitors inhibit the ability of a third to promote mating in male rats.

    PubMed

    Yahr, Pauline

    2015-09-01

    Aromatase, the enzyme that aromatizes androstenedione (A) to estrone and testosterone (T) to estradiol (E), affects androgen control of male sex behavior in many vertebrates. In male monkeys, rats and quail, E mimics the ability of T to promote mating, and aromatase inhibitors block mating induced by T but not E. Aromatase inhibitors include androgens with different A-rings than T and A, e.g., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g., fadrozole, and androgens α-halogenated at carbon 6, e.g., 6α-bromoA, 6α-fluoroA and 6α-fluoroT. 6α-FluoroT is the only 6α-halogenated androgen studied in regard to mating. It promotes mating in male rats and quail and was studied, before it was known to inhibit aromatase, because it cannot be aromatized yet has the same A-ring as T. 6α-FluoroT might promote mating by binding estrogen receptors (ER) directly, i.e., unassisted, or by metabolism to an androgen that binds ER. Since neither process would require aromatase, this study tested both hypotheses by determining how mating induced in castrated male rats by 6α-fluoroT is affected by ATD and fadrozole. Both aromatase inhibitors inhibited the effects of 6α-fluoroT on mating. Thus, 6α-fluoroT does not promote mating by direct ER binding or metabolism to another androgen. Since aromatase underlies a process in which 6α-fluoroT, unlike most nonaromatizable androgens, mimics T effects on male sex behavior, the process must involve a feature that 6α-fluoroT shares with T but not other nonaromatizable androgens. A-ring structure is a candidate. A hypothesis is also offered for how aromatase may participate without aromatizing the androgen.

  8. Fetal safety profile of aromatase inhibitors: Animal data.

    PubMed

    Tiboni, Gian Mario; Ponzano, Adalisa

    2016-12-01

    Aromatase inhibitors (AIs) are a class of drugs that act by blocking the production of estrogens from androgens. The current review concentrates on the prenatal developmental toxicity of AIs in experimental models. Available data indicate that AIs may affect pregnancy at human therapeutic or lower doses. The window of vulnerability to AIs is not limited to organogenesis, but also includes the preimplantation stage and fetal periods. Decreased embryo/fetal survival was the prominent treatment-related effect. Morphological anomalies noted in fetuses exposed to AIs included skeletal anomalies, abnormal head morphology, increased ano-genital distance in female fetuses, and minor urinary tract system anomalies. Placental enlargement was consistently reported in rats and non-human primates after maternal treatment with several AIs. In conclusion, data from basic scientific research suggest that low intensity exposure to AIs applied during a wide gestational window can profoundly affect prenatal development.

  9. Effectiveness of aromatase inhibitors in the treatment of advanced endometrial adenocarcinoma.

    PubMed

    Bogliolo, Stefano; Gardella, Barbara; Dominoni, Mattia; Musacchi, Valentina; Cassani, Chiara; Zanellini, Francesca; De Silvestri, Annalisa; Gaggero, Chiara Roberta; Babilonti, Luciana; Spinillo, Arsenio

    2016-04-01

    Type I endometrial cancer is a common tumor of the female genital tract. Since in post-menopausal women aromatase enzyme can stimulate the endometrial tissue neoplastic growth, the use of aromatase inhibitors may have a therapeutic effect, especially in patients not eligible for surgery. A systematic review has been performed, with a very specific scope, i.e., the use of aromatase inhibitors in the treatment of advanced or recurrent endometrial cancer, as a single agent or in combination with others drugs. On the basis of the 117 records retrieved from the bibliographic search, the rationale for the use of aromatase inhibitors in endometrial cancer therapy is discussed. Six papers fall within the scope of our systematic review and their results are thoroughly analyzed. Moreover, we report our experience on the clinical effectiveness of anastrozole in the post-chemotherapy treatment of a patient affected by advanced-stage endometrial cancer. In general, aromatase inhibitors seem to have limited clinical benefit in the treatment of advanced and recurrent endometrial cancer, although further clinical trials are necessary to investigate more in depth their role. In our case, we experienced a positive feedback in terms of control of an advanced-stage disease.

  10. Bicalutamide and Third-Generation Aromatase Inhibitors in Testotoxicosis

    PubMed Central

    Lenz, Anne M.; Shulman, Dorothy; Eugster, Erica A.; Rahhal, Samar; Fuqua, John S.; Pescovitz, Ora H.; Lewis, Katherine A.

    2014-01-01

    Testotoxicosis, a form of gonadotropin-independent precocious puberty, results from an activating mutation of the luteinizing hormone receptor expressed in testicular Leydig cells. Affected males experience early testosterone secretion, virilization, advancing bone age, and resultant short stature. Recently, the use of combination therapy with a potent antiandrogen agent (bicalutamide) and a third-generation aromatase inhibitor (anastrozole or letrozole) was reported to yield encouraging short-term results. We present here the results of longer-term treatment (4.5 and 5 years) with this combination therapy in 2 boys who demonstrated that it is well tolerated, slows bone-age advancement in the face of continued linear growth, and prevents progression of virilization. PMID:20713483

  11. A yeast screen system for aromatase inhibitors and ligands for androgen receptor: yeast cells transformed with aromatase and androgen receptor.

    PubMed

    Mak, P; Cruz, F D; Chen, S

    1999-11-01

    Endocrine disruptors are hormone mimics that modify hormonal action in humans and animals. It is thought that some endocrine disruptors modify estrogen and androgen action in humans and animals by suppressing aromatase activity. Aromatase cytochrome P450 is the key enzyme that converts C19 androgens to aromatic C18 estrogenic steroids. We have developed a novel aromatase inhibitor screening method that allows us to identify antiaromatase activity of various environmental chemicals. The screen was developed by coexpressing the human aromatase and the mouse androgen receptor in yeast cells, which carry the androgen-responsive ss-galactosidase reporter plasmid. Functional expression of aromatase in yeast has been demonstrated using the [3H]-water release assay with intact cells as well as with yeast microsomes. The aromatase activity could be blocked by known aromatase inhibitors such as aminoglutethimide (AG). Yeast-produced androgen receptors were able to transactivate a yeast basal promoter linked to an androgen-responsive element in response to androgens. The resultant triple yeast transformant responded to the treatment of testosterone, androstenedione, or 5 alpha-dihydrotestosterone (5 alpha-DHT). In the absence of the aromatase inhibitor AG, transcriptional activation was observed only for the nonaromatizable androgen 5 alpha-DHT. However, the two aromatizable androgens (testosterone and androstenedione) induced the reporter activity in the presence of AG. Using this yeast-based assay, we confirmed that two flavones, chrysin and alpha-naphtholflavone, are inhibitors of aromatase. Thus, this yeast system allows us to develop a high-throughput screening method, without using radioactive substrate, to identify aromatase inhibitors as well as new ligands (nonaromatizable androgen mimics) for the androgen receptors. In addition, this screening method also allows us to distinguish nonandrogenic aromatase inhibitors from inhibitors with androgenic activity. This yeast

  12. The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum

    PubMed Central

    Lønning, P. E.

    2011-01-01

    The strategy of using estrogen suppression to treat breast cancer led to the development of aromatase inhibitors, including the third-generation nonsteroidal compounds anastrozole and letrozole, and the steroidal compound exemestane. Aromatase inhibitors potently inhibit aromatase activity and also suppress estrogen levels in plasma and tissue. In clinical studies in postmenopausal women with breast cancer, third-generation aromatase inhibitors were shown superior to tamoxifen for the treatment of metastatic disease. Studies of adjuvant therapy with aromatase inhibitors include (i) head-to-head studies of 5 years of the aromatase inhibitor versus 5 years of tamoxifen monotherapy; (ii) sequential therapy of 2–3 years of tamoxifen followed by an aromatase inhibitor (or the opposite sequence) versus 5 years of tamoxifen monotherapy; (iii) extended therapy with an aromatase inhibitor after 5 years of tamoxifen; and (iv) sequential therapy with an aromatase inhibitor versus aromatase inhibitor monotherapy. Recent results from the Arimidex, Tamoxifen, Alone or in Combination and Breast International Group 1–98 trials advocate using an aromatase inhibitor upfront. This article examines the clinical data with aromatase inhibitors, following a brief summary of their pharmacology. PMID:20616198

  13. Aromatase Inhibitor Associated Musculoskeletal Symptoms are associated with Reduced Physical Activity among Breast Cancer Survivors

    PubMed Central

    Brown, Justin C.; Mao, Jun J.; Stricker, Carrie; Hwang, Wei-Ting; Tan, Kay-See; Schmitz, Kathryn H.

    2014-01-01

    Background Physical activity has numerous health benefits for breast cancer survivors. Recent data suggest that some breast cancer survivors treated with aromatase inhibitors may experience aromatase inhibitor associated musculoskeletal symptoms. It is unknown whether aromatase inhibitor associated musculoskeletal symptoms are associated with reduced physical activity and what other risk factors are associated with such physical activity reductions. Methods We conducted a cross-sectional study at a large university-based breast cancer clinic among breast cancer survivors prescribed an aromatase inhibitor. At routine follow-up, we surveyed participants about aromatase inhibitor associated musculoskeletal symptoms, as well as pre-aromatase inhibitor, and current, physical activity levels. Results Among 300 participants, 90 (30%) reported a reduction of physical activity since the initiation of aromatase inhibitor therapy. Those with aromatase inhibitor associated musculoskeletal symptoms were more likely to report decreased physical activity (62% versus 38%, p=0.001) compared to those without aromatase inhibitor associated musculoskeletal symptoms. In multivariate analyses, aromatase inhibitor associated musculoskeletal symptoms [odds ratio (OR) =2.29 (95% confidence interval (CI): 1.36–3.86)], and body mass index [OR=1.06 (95% CI: 1.02–1.12)] were associated with reductions in physical activity. In subgroup analysis among breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms, self-reported lower extremity joint pain [OR=1.23 (95% CI: 1.00–1.50)] and impaired lower extremity physical function [OR=1.07 (95% CI: 1.01–1.14)] were associated with reductions in physical activity. Conclusion Breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms were more likely to report reductions in physical activity since initiating aromatase inhibitor therapy compared to those without aromatase inhibitor associated

  14. Aromatase inhibitor therapy and hair loss among breast cancer survivors.

    PubMed

    Gallicchio, Lisa; Calhoun, Carla; Helzlsouer, Kathy J

    2013-11-01

    The objective of this study was to examine the associations between aromatase inhibitor therapy and hair loss or hair thinning among female breast cancer survivors. Data were analyzed from 851 female breast cancer survivors who responded to a hospital registry-based survey. Data on hair loss, hair thinning, demographic characteristics, and health habits were based on self-report; data on aromatase inhibitor therapy were collected on the survey and verified using medical record review. Logistic regression was used to estimate the odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between aromatase inhibitor therapy and the hair outcome variables adjusted for potential confounders, including age and chemotherapy treatment. The results showed that 22.4 % of the breast cancer survivors reported hair loss and 31.8 % reported hair thinning. In the confounder-adjusted analyses, breast cancer survivors who were within 2 years of starting aromatase inhibitor treatment at the time of survey completion were approximately two and a half times more likely to report reporting hair loss (OR 2.55; 95 % CI 1.19-5.45) or hair thinning (OR 2.33; 95 % CI 1.10-4.93) within the past 4 weeks compared to those who were never treated with an aromatase inhibitor. Current aromatase inhibitor use for two or more years at the time of the survey and prior use were significantly associated with hair thinning (current users, ≥2 years: OR 1.86; prior users: OR 1.62), but not hair loss. Findings from this study suggest that aromatase inhibitor use is associated with an increased risk of hair loss and hair thinning independent of chemotherapy and age; these side effects are likely due to the substantial decrease in estrogen concentrations resulting from treatment with this drug. Future research should focus on examining these associations in a prospective manner using more detailed and objective measures of hair loss and thinning.

  15. Clinical utilities of aromatase inhibitors in breast cancer

    PubMed Central

    Chumsri, Saranya

    2015-01-01

    Aromatase is an enzyme that converts testosterones to estrogens. Inhibition of this enzyme has been shown to have several clinical utilities in breast cancer. Currently, there are three aromatase inhibitors (AIs) in clinical use, namely anastrozole, letrozole, and exemestane. AIs have been used in various clinical settings for breast cancer, ranging from chemoprevention in breast cancer to treating breast cancer in both early stage in the adjuvant setting and metastatic disease. This article reviews mechanism of action, AI classification, and clinical utilities of AIs in various clinical settings in the context of breast cancer. PMID:26005359

  16. Molecular modeling evaluation of non-steroidal aromatase inhibitors.

    PubMed

    Narayana, Bheemanapalli Lakshmi; Pran Kishore, Deb; Balakumar, Chadrasekaran; Rao, Kaki Venkata; Kaur, Rajwinder; Rao, Akkinepally Raghuram; Murthy, Javali Narashima; Ravikumar, Muttineni

    2012-05-01

    A recent discovery of aromatase crystal structure triggered the efforts to design novel aromatase inhibitors for breast cancer therapy. While correlating docking scores with inhibitory potencies of known ligands, feeble robustness of scoring functions toward prediction was observed. This prompted us to develop new prediction models using stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LIGANDFIT, and GLIDE). Quantitative structure-activity relationships were developed between the aromatase inhibitory activity (pIC(50) ) of flavonoid derivatives (n=39) and docking scores and docking descriptors. QSAR models have been validated internally [using leave-one-out cross-validated r(2)(cv) (LOO-Q2))] and externally to ensure the predictive capacity of the models. Model 2 [M2] developed using consensus of docking scores of scoring functions viz. ASP, potential of mean force and DOCK Score (r(2)(cv)=0.850, r(2) = 0.870, r(2)(pred) = 0.633, RMSE = 0.363 μm, r(2)(m(test)) =0.831, r(2)(m(overall)) =0.832) was found to be better in predicting aromatase inhibitory potency (pIC(50) ) compared to the Model 1 [M1] based on docking descriptors (r(2)(cv)= 0.848, r(2) = 0.825, r(2)(pred) =0.788, RMSE=0.421μm, r(2)(m(test)) =0.808, r(2)(m(overall)) =0.821). It has been observed that the natural flavonoids and their derivatives were less potent compared to these scaffolds with imidazolylmethyl substitution owing to the interaction of nitrogen atom of the imidazole ring toward the heme (Fe(3+) ) of the aromatase. Results confirm the potential of our methodology for the design of new potent non-steroidal aromatase inhibitors.

  17. Mechanisms of Aromatase Inhibitor-induced Musculoskeletal Symptoms

    DTIC Science & Technology

    2012-07-01

    the blood, there are neurosteroids metabolized by cytochrome P450s within first and second-order sensory neurons. These neurosteroids have been...aromatase inhibitor (AI) therapies in breast cancer is limited in many patients because they induce musculoskeletal pain; however, the effects of...AIs) are the current standard of care for endocrine treatment of breast cancer in post-menopausal women. Yet the use of AIs is limited in many

  18. New 7,8-benzoflavanones as potent aromatase inhibitors: synthesis and biological evaluation.

    PubMed

    Yahiaoui, Samir; Fagnere, Catherine; Pouget, Christelle; Buxeraud, Jacques; Chulia, Albert-José

    2008-02-01

    Some natural compounds such as flavonoids are known to possess a moderate inhibitory activity against aromatase, this enzyme being an interesting target for hormone-dependent breast cancer treatment. It has been demonstrated that the modulation of flavonoid skeleton could increase anti-aromatase effect. Therefore, new 7,8-benzoflavanones were synthesized and tested for their activity toward aromatase inhibition. It was observed that the introduction of a benzo ring at position C-7 and C-8 on flavanone skeleton led to new potent aromatase inhibitors, the resulting 7,8-benzoflavanones being until nine times more potent than aminogluthetimide (the first aromatase inhibitor used clinically).

  19. A yeast screen system for aromatase inhibitors and ligands for androgen receptor: yeast cells transformed with aromatase and androgen receptor.

    PubMed Central

    Mak, P; Cruz, F D; Chen, S

    1999-01-01

    Endocrine disruptors are hormone mimics that modify hormonal action in humans and animals. It is thought that some endocrine disruptors modify estrogen and androgen action in humans and animals by suppressing aromatase activity. Aromatase cytochrome P450 is the key enzyme that converts C19 androgens to aromatic C18 estrogenic steroids. We have developed a novel aromatase inhibitor screening method that allows us to identify antiaromatase activity of various environmental chemicals. The screen was developed by coexpressing the human aromatase and the mouse androgen receptor in yeast cells, which carry the androgen-responsive ss-galactosidase reporter plasmid. Functional expression of aromatase in yeast has been demonstrated using the [3H]-water release assay with intact cells as well as with yeast microsomes. The aromatase activity could be blocked by known aromatase inhibitors such as aminoglutethimide (AG). Yeast-produced androgen receptors were able to transactivate a yeast basal promoter linked to an androgen-responsive element in response to androgens. The resultant triple yeast transformant responded to the treatment of testosterone, androstenedione, or 5 alpha-dihydrotestosterone (5 alpha-DHT). In the absence of the aromatase inhibitor AG, transcriptional activation was observed only for the nonaromatizable androgen 5 alpha-DHT. However, the two aromatizable androgens (testosterone and androstenedione) induced the reporter activity in the presence of AG. Using this yeast-based assay, we confirmed that two flavones, chrysin and alpha-naphtholflavone, are inhibitors of aromatase. Thus, this yeast system allows us to develop a high-throughput screening method, without using radioactive substrate, to identify aromatase inhibitors as well as new ligands (nonaromatizable androgen mimics) for the androgen receptors. In addition, this screening method also allows us to distinguish nonandrogenic aromatase inhibitors from inhibitors with androgenic activity. This yeast

  20. [Progress in study of the structure, catalytic mechanism and inhibitors of aromatase].

    PubMed

    Fu, Jing; Shen, Zhong-Hua; Cheng, Fei-Xiong; Liu, Gui-Xia; Li, Wei-Hua; Tang, Yun

    2012-01-01

    Aromatase is a key enzyme responsible for in vivo estrogen biosynthesis. Inhibition of the activity of the aromatase has become an alterative way for treatment of breast cancer. In this review, the structure and catalytic mechanism of the aromatase is briefly introduced followed by thorough review of the progress in the study of the steroidal and non-steroidal aromatase inhibitors. This review is focused on the natural compounds that exhibit the aromatase inhibition, which include flavonoids, xanthones, coumarins, and sesquiterpenes. The structure-activity relationship of these compounds is also discussed.

  1. TRPA1 Mediates Aromatase Inhibitor-Evoked Pain by the Aromatase Substrate Androstenedione.

    PubMed

    De Logu, Francesco; Tonello, Raquel; Materazzi, Serena; Nassini, Romina; Fusi, Camilla; Coppi, Elisabetta; Li Puma, Simone; Marone, Ilaria M; Sadofsky, Laura R; Morice, Alyn H; Susini, Tommaso; Terreni, Alessandro; Moneti, Gloriano; Di Tommaso, Mariarosaria; Geppetti, Pierangelo; Benemei, Silvia

    2016-12-01

    Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024-35. ©2016 AACR.

  2. Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha-demethylase and aromatase.

    PubMed

    Zarn, Jürg A; Brüschweiler, Beat J; Schlatter, Josef R

    2003-03-01

    Azole compounds play a key role as antifungals in agriculture and in human mycoses and as non-steroidal antiestrogens in the treatment of estrogen-responsive breast tumors in postmenopausal women. This broad use of azoles is based on their inhibition of certain pathways of steroidogenesis by high-affinity binding to the enzymes sterol 14-alpha-demethylase and aromatase. Sterol 14-alpha-demethylase is crucial for the production of meiosis-activating sterols, which recently were shown to modulate germ cell development in both sexes of mammals. Aromatase is responsible for the physiologic balance of androgens and estrogens. At high doses, azole fungicides and other azole compounds affect reproductive organs, fertility, and development in several species. These effects may be explained by inhibition of sterol 14-alpha-demethylase and/or aromatase. In fact, several azole compounds were shown to inhibit these enzymes in vitro, and there is also strong evidence for inhibiting activity in vivo. Furthermore, the specificity of the enzyme inhibition of several of these compounds is poor, both with respect to fungal versus nonfungal sterol 14-alpha-demethylases and versus other P450 enzymes including aromatase. To our knowledge, this is the first review on sterol 14-alpha-demethylase and aromatase as common targets of azole compounds and the consequence for steroidogenesis. We conclude that many azole compounds developed as inhibitors of fungal sterol 14-alpha-demethylase are inhibitors also of mammalian sterol 14-alpha-demethylase and mammalian aromatase with unknown potencies. For human health risk assessment, data on comparative potencies of azole fungicides to fungal and human enzymes are needed.

  3. Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha-demethylase and aromatase.

    PubMed Central

    Zarn, Jürg A; Brüschweiler, Beat J; Schlatter, Josef R

    2003-01-01

    Azole compounds play a key role as antifungals in agriculture and in human mycoses and as non-steroidal antiestrogens in the treatment of estrogen-responsive breast tumors in postmenopausal women. This broad use of azoles is based on their inhibition of certain pathways of steroidogenesis by high-affinity binding to the enzymes sterol 14-alpha-demethylase and aromatase. Sterol 14-alpha-demethylase is crucial for the production of meiosis-activating sterols, which recently were shown to modulate germ cell development in both sexes of mammals. Aromatase is responsible for the physiologic balance of androgens and estrogens. At high doses, azole fungicides and other azole compounds affect reproductive organs, fertility, and development in several species. These effects may be explained by inhibition of sterol 14-alpha-demethylase and/or aromatase. In fact, several azole compounds were shown to inhibit these enzymes in vitro, and there is also strong evidence for inhibiting activity in vivo. Furthermore, the specificity of the enzyme inhibition of several of these compounds is poor, both with respect to fungal versus nonfungal sterol 14-alpha-demethylases and versus other P450 enzymes including aromatase. To our knowledge, this is the first review on sterol 14-alpha-demethylase and aromatase as common targets of azole compounds and the consequence for steroidogenesis. We conclude that many azole compounds developed as inhibitors of fungal sterol 14-alpha-demethylase are inhibitors also of mammalian sterol 14-alpha-demethylase and mammalian aromatase with unknown potencies. For human health risk assessment, data on comparative potencies of azole fungicides to fungal and human enzymes are needed. PMID:12611652

  4. Impact of nonsteroidal aromatase inhibitors on steroid profile in a Chinese population

    PubMed Central

    Xing, Yanyi; Liu, Xin; Yan, Mengmeng; Chen, Tianqi; Lu, Fei; Xu, Bing; Gong, Yan; Chu, Fuhao; Lei, Haimin

    2017-01-01

    Abstract 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. PMID:28700478

  5. Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer.

    PubMed

    Ahmad, Irshad; Shagufta

    2015-09-18

    Aromatase, a cytochrome P450 enzyme complex present in breast tissues, plays a significant role in the biosynthesis of important endogenous estrogens from androgens. The source of estrogen production in breast cancer tissues is intra-tumoral aromatase, and inhibition of aromatase may inhibit the growth stimulation effect of estrogens in breast cancer tissues. Consequently, aromatase is considered a useful therapeutic target in the treatment and prevention of estrogen-dependent breast cancer. Recently, different natural products and synthetic compounds have been rapidly developed, studied, and evaluated for aromatase inhibitory activity. Aromatase inhibitors are classified into two categories on the basis of their chemical structures, i.e., steroidal and nonsteroidal aromatase inhibitors. This review highlights the synthetic steroidal and nonsteroidal aromatase inhibitors reported in the literature in the last few years and will aid medicinal chemists in the design and synthesis of novel and pharmacologically-potent aromatase inhibitors for the treatment of breast cancer.

  6. Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer.

    PubMed

    Yadav, Mange Ram; Barmade, Mahesh A; Tamboli, Riyaj S; Murumkar, Prashant R

    2015-11-13

    Breast cancer, an emerging disease among the women population, occurs due to overexpression of estrogens. The enzyme aromatase plays a key rate limiting role in the biosynthesis of estrogens. Certain clinical advantages of the use of exemestane, a steroidal aromatase inhibitor over non-steroidal aromatase inhibitors have drawn the attention of researchers for the development of novel steroidal aromatase inhibitors.The current review is a humble attempt to compile the reports by various researchers till date on the synthesis of steroidal aromatase inhibitors. It has been tried to encompass the structural modifications carried out by various researchers in the steroid ring system by taking up the functional group modifications on rings A, B, ring A/B junction, ring-D, ring modifications, bridged derivatives and heterocyclic ring-fused derivatives in a systematic way.

  7. [Growth inhibition of MCF-7 human breast cancer cells by aromatase inhibitors].

    PubMed

    Fukuoka, M; Kitawaki, J; Yamamoto, T; Okada, H

    1991-12-01

    MCF-7 cell line is a model for estrogen-dependent tumors that have both aromatase activity and estrogen receptor. We studied the contribution of aromatase to cell growth and DNA synthesis by means of aromatase inhibitors. MCF-7 cells were cultured in phenol red-free medium containing 10% charcoal-treated fetal bovine serum and test reagents for 96 hours and pulse-labeled with [3H]thymidine for 1 hour. Physiological concentrations of estradiol, estrone, testosterone(T) and androstenedione(delta 4A) increased [3H] thymidine incorporation. Stimulation by T or dihydrotestosterone (DHT) was reduced by tamoxifen, but not by androgen receptor blocker cyproterone acetate, suggesting that T and DHT stimulated cellular proliferation via estrogen receptor but not via androgen receptor. Stimulation by T or delta 4A was reduced by aromatase inhibitors (aminoglutethimide and 14 alpha-hydroxy-4-androstene-3,6,17-trione), but stimulation by nonaromatizable DHT was not reduced by aromatase inhibitors. These results have suggested that estrogens which are biosynthesized from androgens by the intracellular aromatase play a significant role in growth stimulation of MCF-7 cells and that aromatase inhibitors block this pathway. These methods are useful in assessing the ability of aromatase inhibitors to suppress cell growth.

  8. Long-term complete remission of metastatic breast cancer, induced by a steroidal aromatase inhibitor after failure of a non-steroidal aromatase inhibitor

    PubMed Central

    Shioi, Yoshihiro; Kashiwaba, Masahiro; Inaba, Toru; Komatsu, Hideaki; Sugai, Tamotsu; Wakabayashi, Go

    2014-01-01

    Patient: Female, 56 Final Diagnosis: Breast cancer Symptoms: Solid mass in the right breast Medication: Exemestane Clinical Procedure: — Specialty: Oncology Objective: Unusual clinical course Background: The efficacy of third-generation aromatase inhibitors for hormone receptor-positive postmenopausal metastatic breast cancer is well established. Although several clinical trials have reported incomplete cross-resistance between different aromatase inhibitors, few cases of complete responses of recurrent metastatic breast cancer occurring after substituting a second aromatase inhibitor have been reported. We here present a rare case of non-steroidal aromatase inhibitor-tolerant metastatic breast cancer with long-term complete remission following substitution of a steroidal aromatase inhibitor. Case Report: We present the case of a 56-year-old Japanese woman who underwent right breast-conserving surgery for breast cancer, TNM staging T1, N0, M0, Stage I. She received adjuvant chemotherapy with 6 cycles of FEC100 and radiation therapy, and then began hormonal therapy with anastrozole. Twelve months postoperatively, computed tomography (CT) revealed multiple lung metastases. Exemestane was substituted for anastrozole. After 3 months of exemestane, CT showed that all lung metastases had completely resolved. Her complete response was maintained for 5 years: she died during a tsunami 6 years after the initial surgery. Conclusions: Substitution of a steroidal for a non-steroidal aromatase inhibitor produced a sustained complete remission in a patient with hormonal receptor-positive postmenopausal recurrent breast cancer. Achieving complete response after switching from a non-steroidal to a steroidal aromatase inhibitor in a hormonal receptor-positive postmenopausal recurrent breast cancer contributed to a higher quality of life for the patient. Further investigation is needed to identify the predictors of long-term remission following such a switch. PMID:24587856

  9. Nelumal A, the active principle of Ligularia nelumbifolia, is a novel aromatase inhibitor.

    PubMed

    Epifano, Francesco; Genovese, Salvatore; Fiorito, Serena; Nde, Chantal Magne; Clyne, Colin

    2014-06-01

    Nelumal A, the active principle of Ligularia nelumbifolia was preliminarily tested as an aromatase inhibitors in HEK293 cells transfected with aromatase cDNA and using anastrazole as the reference drug. This screening revealed that it showed an appreciable level of inhibition. Subsequent experiments aimed to evaluate the aromatase activity and expression in KGN cells confirmed that the title natural product, after an incubation of 48 h, compared favourably with anastrazole (1 microM) in the concentration range 10-30 microM. Moreover, nelumal A (30 microM) abolished the aromatase mRNA expression in the same cell line.

  10. Mechanism-based Categorization of Aromatase Inhibitors: A Potential Discovery and Screening Tool

    EPA Science Inventory

    Cytochrome P450 aromatase is a key steroidogenic enzyme that converts androgens to estrogens in vertebrates. There is much interest in aromatase inhibitors (AIs) because a number of environmental contaminants can act as AIs, thereby disrupting endocrine function in humans and wil...

  11. Mechanism-based Categorization of Aromatase Inhibitors: A Potential Discovery and Screening Tool

    EPA Science Inventory

    Cytochrome P450 aromatase is a key steroidogenic enzyme that converts androgens to estrogens in vertebrates. There is much interest in aromatase inhibitors (AIs) because a number of environmental contaminants can act as AIs, thereby disrupting endocrine function in humans and wil...

  12. Successful use of aromatase inhibitor letrozole in NOA with an elevated FSH level: a case report.

    PubMed

    Zhao, D; Pan, L; Zhang, F; Pan, F; Ma, J; Zhang, X; Liu, Y

    2014-05-01

    Aromatase inhibitors inhibit the conversion of testosterone to oestrogens and could reduce serum oestradiol concentrations. Letrozole is one of aromatase inhibitors frequently used in treatment of men with oligospermia. We present the case of an infertile man with small testes and an elevated FSH level, which was diagnosed as NOA, hypospermatogenesis proven by testicular biopsy. After taking letrozole for 3 months, semen analyses by computer-aided sperm analysis present that this man had normal spermatogenesis. This is the first case report of the activation of spermatogenesis, in man who was NOA with elevated FSH level, resulting from the use of the one of aromatase inhibitors.

  13. Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors.

    PubMed

    Mohammed, Hamdoon A; Ba, Lalla A; Burkholz, Torsten; Schumann, Elena; Diesel, Britta; Zapp, Josef; Kiemer, Alexandra K; Ries, Christina; Hartmann, Rolf W; Hosny, Mohammed; Jacob, Claus

    2011-01-01

    Flavones such as chrysin show structural similarities to androgens, the substrates of human aromatase, which converts androgens to estrogens. Aromatase is a key target in the treatment of hormone-dependent tumors, including breast cancer. Flavone-based aromatase inhibitors are of growing interest, and chrysin in particular provides a (natural) lead structure. This paper reports multicomponent synthesis as a means for facile modification of the chrysin core structure in order to add functional elements. A Mannich-type reaction was used to synthesize a range of mono- and disubstituted chrysin derivatives, some of which are more effective aromatase inhibitors than the benchmark compound, aminoglutethimide. Similarly, the reaction of chrysin with various isonitriles and acetylene dicarboxylates results in a new class of flavone derivatives, tricyclic pyrano-flavones which also inhibit human aromatase. Multicomponent reactions involving flavones therefore enable the synthesis of a variety of derivatives, some of which may be useful as anticancer agents.

  14. Design, synthesis, and 3D QSAR of novel potent and selective aromatase inhibitors.

    PubMed

    Leonetti, Francesco; Favia, Angelo; Rao, Angela; Aliano, Rosaria; Paluszcak, Anja; Hartmann, Rolf W; Carotti, Angelo

    2004-12-30

    The design, synthesis, and biological evaluation of a series of new aromatase inhibitors bearing an imidazole or triazole ring linked to a fluorene (A), indenodiazine (B), or coumarin scaffold (C) are reported. Properly substituted coumarin derivatives displayed the highest aromatase inhibitory potency and selectivity over 17-alpha-hydroxylase/17-20 lyase. The modeling of the aromatase inhibition data by Comparative Molecular Field Analysis (CoMFA/GOLPE 3D QSAR approach) led to the development of a PLS model with good fitting and predictive powers (n = 22, ONC = 3, r(2) = 0.949, s = 0.216, and q(2) = 0.715). The relationship between aromatase inhibition and the steric and electrostatic fields generated by the examined azole inhibitors enables a clear understanding of the nature and spatial location of the main interactions modulating the aromatase inhibitory potency.

  15. Use of Network Inference to Unravel the Mechanisms of Action and Specificity of Aromatase Inhibitors

    EPA Science Inventory

    The vertebrate hypothalamus-pituitary-gonadal (HPG) axis is controlled through various feedback mechanisms in order to maintain a dynamic homeostasis during changing environmental conditions, including exposure to chemical stressors. In this study, three aromatase inhibitors, fad...

  16. Clinical review: The use of aromatase inhibitors for ovulation induction and superovulation.

    PubMed

    Pavone, Mary Ellen; Bulun, Serdar E

    2013-05-01

    Anovulation is likely responsible for 20% of female infertility. Although clomiphene citrate remains the first-line therapy for ovulation induction in anovulatory patients who are not estrogen-deficient and to treat unexplained infertility, there remains a discrepancy between ovulation and conception rates with its use, attributed to its antiestrogenic effects on cervical mucus and the endometrium. Alternative agents, including aromatase inhibitors, have been used that have not been associated with these side effects. A literature search was conducted to specifically explore the use of aromatase inhibitors for ovulation induction and superovulation. Recent studies have found that aromatase inhibitors may be safe and useful agents for ovulation induction in patients with polycystic ovarian syndrome as well a treatment option for superovulation in patients with either unexplained infertility or endometriosis. Aromatase inhibitors may be an effective alternative treatment to clomiphene citrate for both ovulation induction and superovulation.

  17. Use of Network Inference to Unravel the Mechanisms of Action and Specificity of Aromatase Inhibitors

    EPA Science Inventory

    The vertebrate hypothalamus-pituitary-gonadal (HPG) axis is controlled through various feedback mechanisms in order to maintain a dynamic homeostasis during changing environmental conditions, including exposure to chemical stressors. In this study, three aromatase inhibitors, fad...

  18. The case for aromatase inhibitors use in oncofertility patients. Should aromatase inhibitors be combined with gonadotropin treatment in breast cancer patients undergoing ovarian stimulation for fertility preservation prior to chemotherapy? A debate.

    PubMed

    Fatum, Muhammad; McVeigh, Enda; Child, Tim

    2013-12-01

    Breast cancer is one of the hormone-dependent cancers that may be adversely affected by elevated oestrogen or progesterone concentrations, particularly the endocrine active (hormone receptor positive) breast cancers. Treatment for breast cancer patients aimed at fertility preservation, includes ovarian hyperstimulation, the harvest of oocytes, and subsequent cryopreservation of oocytes or embryos. Classically, gonadotrophins have been used effectively for ovulation induction, a treatment often accompanied by high blood oestrogen concentrations produced by the hyperstimulated granulosa cells. Despite the uncertainty which surrounds this issue and the lack of clear-cut clinical evidence, it is still of major concern that these ensuing high hormone levels might be associated with a high risk of recurrence of the cancer. A growing number of clinical studies have strongly suggested the benefits of using aromatase inhibitors in infertility treatment, both as single agents or as adjuncts to FSH-containing ovulation induction regimes in reproductive medicine. Combining gonadotrophins with aromatase inhibitors would augment the stimulation effect, with a reduced increase in serum concentrations of estradiol. We propose to open a debate over the use of aromatase inhibitors in combination with FSH in ovulation induction treatment of breast cancer oncofertility patients. As the safety of aromatase inhibitors such as letrozole has recently been demonstrated in several studies, and there is growing concern over the possible detrimental effects of high estradiol levels on breast cancer cells (at least in mouse models), the co-administration of letrozole in these patients would reduce both the high supraphysiologic serum levels of estradiol and the intratumoral in situ production of oestrogen. However, since it is unlikely that a well-founded evidence-based justification of this treatment will be formulated in the near future, based on well-designed prospective randomised

  19. Bilateral de quervain syndrome after aromatase inhibitor administration: a case report and review of the literature.

    PubMed

    Papadimitriou, Konstantinos; Kountourakis, Panteleimon; Morakis, Emmanouil; Vassiliou, Vassilios; Barbounis, Vasileios; Ardavanis, Alexandros

    2012-01-01

    Aromatase inhibitors are widely used as one of the main treatment options of both early and advanced hormone receptor-positive breast cancer in postmenopausal women. Unfortunately, musculoskeletal symptoms are often presented in patients treated with aromatase inhibitors (AIs), and, although the pathogenesis is unknown, postulated mechanisms have been described. Herein, to our knowledge, we present the first report of bilateral De Quervain syndrome related with AIs therapy with a review of the relevant literature.

  20. Bilateral De Quervain Syndrome after Aromatase Inhibitor Administration: A Case Report and Review of the Literature

    PubMed Central

    Papadimitriou, Konstantinos; Kountourakis, Panteleimon; Morakis, Emmanouil; Vassiliou, Vassilios; Barbounis, Vasileios; Ardavanis, Alexandros

    2012-01-01

    Aromatase inhibitors are widely used as one of the main treatment options of both early and advanced hormone receptor-positive breast cancer in postmenopausal women. Unfortunately, musculoskeletal symptoms are often presented in patients treated with aromatase inhibitors (AIs), and, although the pathogenesis is unknown, postulated mechanisms have been described. Herein, to our knowledge, we present the first report of bilateral De Quervain syndrome related with AIs therapy with a review of the relevant literature. PMID:22567020

  1. The Evolutionary Tale and Future Directions of Aromatase Inhibitors in Breast Carcinoma.

    PubMed

    Bhattacharjee, Dipanjan; Kumari, Meena K; Avin, S; Babu Amberkar, Mohan V

    2017-03-27

    Aromatase inhibitors have often been likened to that of 'medical scalpels' for the treatment of breast carcinoma. By inhibiting the singular step of aromatisation, they have proven to be extremely effective allies in the treatment of breast cancer among postmenopausal women. However, their relevance soon may not be limited to the post-menopausal age group alone. Recent studies have hinted at their utility amongst the pre-menopausal women; combined with ovarian ablation techniques, aromatase inhibitors may prove to be equally effective and more, as compared to tamoxifen in this age-group. Additionally, explorations aimed at ascertaining their potential utility as an effective preventive strategy against breast carcinoma have yielded encouraging results. However, for aromatase inhibitors to be able to attain their full potential, further strategic fine-tuning aimed at maximising their efficacy and minimising their potentially far-reaching adverse effects, is the need of the hour. Despite the recent diversification, the issue of resistance to aromatase inhibitors in breast cancer threatens to derail the advances so gained till date. Fortunately, a few novel ploys have come to the fore, for instance combining aromatase inhibitors with HER-2 antibodies that could potentially help circumvent the menace of resistance in the near future. Till date, the utility of aromatase inhibitors can at best be described as one-dimensional. However, with the unearthing of potential new avenues for its application, this assortment of molecules today stands on the precipice of ushering in a new revolution in the treatment of breast carcinom.

  2. What do we know about the mechanisms of aromatase inhibitor resistance?

    PubMed Central

    Chen, Shiuan; Masri, Selma; Wang, Xin; Phung, Sheryl; Yuan, Yate-Ching; Wu, Xiwei

    2007-01-01

    Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. Yet, as with all prolonged drug therapy, resistance to aromatase inhibitors does develop. To date, the precise mechanism responsible for resistance to aromatase inhibitors is not completely understood. In this paper, several mechanisms of de novo/intrinsic resistance and acquired resistance to AIs are discussed. These mechanisms are hypothesized based on important findings from a number of laboratories. To better understand this question, our lab has generated, in vitro, breast cancer cell lines that are resistant to aromatase inhibitors. Resistant cell lines were generated over a prolonged period of time using the MCF-7aro (aromatase overexpressed) breast cancer line. These cell lines are resistant to the aromatase inhibitors letrozole, anastrozole and exemestane and the anti-estrogen tamoxifen, for comparison. Two types of resistant cell lines have been generated, those that grow in the presence of Testosterone (T) which is needed for cell growth, and resistant lines that are cultured in the presence of inhibitor only (no T). In addition to functional characterization of aromatase and ERα in these resistant cell lines, microarray analysis has been employed in order to determine differential gene expression within the aromatase inhibitor resistant cell lines versus tamoxifen, in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. We anticipate that our studies will generate important information on the mechanisms of AI resistance. Such information can be valuable for the development of treatment strategies against AI resistant breast cancers. PMID:17055257

  3. Sex reversal of the amphibian, Xenopus tropicalis, following larval exposure to an aromatase inhibitor.

    PubMed

    Olmstead, Allen W; Kosian, Patricia A; Korte, Joseph J; Holcombe, Gary W; Woodis, Kacie K; Degitz, Sigmund J

    2009-01-31

    Aromatase is a steroidogenic enzyme that catalyzes the conversion of androgens to estrogens in vertebrates. Modulation of this enzyme's activity by xenobiotic exposure has been shown to adversely affect gonad differentiation in a number of diverse species. We hypothesized that exposure to the aromatase inhibitor, fadrozole, during the larval development of the tropical clawed frog, Xenopus tropicalis, would result in masculinization of the developing female gonad. Tadpoles were exposed to fadrozole at nominal concentrations from 1 to 64 microg/L in a flow-through system from < 24 h post-fertilization (Nieuwkoop Faber (NF) stage 15-20) to metamorphosis (NF stage 66). At metamorphosis, morphologically examined gonads indicated complete masculinization of all tadpoles at concentrations of 16 microg/L and above and a significant bias in sex ratio towards males at concentrations of 1 microg/L and above. No effects on time to metamorphosis, body mass, or body length were observed. A random subsample of frogs was raised to reproductive maturity (39 weeks post-fertilization) in control water. All frogs exposed as tadpoles to 16 microg/L fadrozole or greater possessed testes at sexual maturity. Intersexed gonads characterized by the presence of both testicular and ovarian tissue were observed in 12% of frogs in the 4 microg/L treatment. No differences in estradiol, testosterone, or vitellogenin plasma concentrations were observed in exposed males or females compared to controls. Females in the 4 microg/L treatment possessed a significantly greater percentage of pre-vitellogenic oocytes than controls and were significantly smaller in body mass. No differences in sperm counts were observed in exposed males compared to controls. Results from this study demonstrate that larval exposure to an aromatase inhibitor can result in the complete masculinization of female gonads. These masculinized females are phenotypically indistinguishable from normal males at adulthood. Lower levels

  4. Different catalytic properties and inhibitor responses of the goldfish brain and ovary aromatase isozymes.

    PubMed

    Zhao, J; Mak, P; Tchoudakova, A; Callard, G; Chen, S

    2001-08-01

    The brain and ovarian aromatase isozymes of goldfish (Carassius auratus) are encoded by different CYP19 genes. This study measured aromatase activity in the goldfish brain tissues. For a direct comparison of the properties of the two aromatase isozymes, Chinese hamster ovary cells were stably transfected with brain- and ovary-derived cDNAs (respectively, p450 arom B and -A) and the properties of the expressed isozymes were compared. The kinetic parameters of the two isozymes were determined using androstenedione and testosterone as substrates and compared to those of human aromatase. Inhibition profile analyses on the two isozymes were performed using seven inhibitors [4-hydroxyandrostenedione, 7 alpha-(4'-amino)phenylthio-1,4-androstadiene-3,17-dione, bridge (2,19-methyleneoxy)androstene-3,17-dione, aminoglutethimide (AG), CGS 20267, ICI D1033, and vorozole]. Except for AG, the compounds tested were found to be much stronger inhibitors against the ovary enzyme than the brain enzyme. In addition, the ovary isoform was more sensitive to two phytoestrogens, chrysin and 7,8-dihydroxyflavone, than the brain form. These studies reveal that catalytic properties of the goldfish aromatase isoforms are significantly different from those of human aromatase. In addition, differences in the K(i) values of aromatase inhibitors for the two goldfish isoforms suggest structural variance in the active sites of these isozymes.

  5. Aromatase inhibitor-induced joint pain: melatonin's role.

    PubMed

    Burk, R

    2008-12-01

    Aromatase inhibitors (AIs) enjoy increasing use in breast cancer adjuvant therapy. But the joint pain associated with AIs significantly reduces patient adherence despite the clear survival benefits of this class of drugs. Two clues point to a novel hypothesis for this unexplained symptom. First, realizing that joint pain is associated with virtually all estrogen-depleting breast cancer treatments suggests that the cause is broader than this particular class of drugs. Second, the strongly circadian nature of these symptoms suggests circadian hormone involvement. This puts new light on some existing research findings: that estrogen depletion can increase pineal melatonin, that the ability of light to suppress pineal melatonin is more variable than once thought, and that an altered melatonin cycle is associated with rheumatoid arthritis patients, where identical circadian symptoms present. It is hypothesized that when AIs decrease estrogen levels, light-induced melatonin suppression (LIMS) loses efficacy, leading to an abnormal melatonin cycle as seen in rheumatoid arthritis patients, producing (via mechanisms not yet understood) the symptoms of morning stiffness. Not all frequencies of retinal light are equally effective at suppressing pineal melatonin; most artificial lighting has less relevant spectral density than sunlight. This hypothesis predicts that some patients can suppress the circadian joint pain associated with aromatase inhibitors merely by getting sufficient hours of daily retinal sunlight. A single patient history is discussed, in which a series of treatments had no effect on AI joint pain, while extended exposure to sunlight produced a definitive elimination of symptoms the next morning. To conclusively demonstrate the role of melatonin, light-emitting diodes of an appropriate frequency were mounted on a cap for the patient to wear. If worn first thing in the morning, the cap sharply curtailed the duration of morning stiffness. If worn for a

  6. Management of arthralgias associated with aromatase inhibitor therapy.

    PubMed

    Thorne, C

    2007-12-01

    For the upfront adjuvant therapy of postmenopausal estrogen receptor-positive breast cancer, the third-generation aromatase inhibitors (AIS) have shown a more favourable overall risk-benefit profile than has tamoxifen. Benefits of the ais include less frequent gynecologic, cerebrovascular, and thromboembolic adverse events; greater disease-free survival; and lower tumour recurrence. Although approximately 25% of postmenopausal women with early breast cancer report experiencing symptoms of arthralgia with ai therapy, 68-month data from the Arimidex, Tamoxifen, Alone or in Combination trial showed that, compared with tamoxifen, anastrozole treatment was associated with only a modest increase in the incidence of joint symptoms. The events, which were mostly mild-to-moderate in intensity, led to treatment withdrawal in 2% of patients on anastrozole as compared with 1% in the tamoxifen arm. The symptoms and changes correlate with clinical, biochemical, and radiologic findings in symptomatic women. To determine appropriate intervention, it is therefore essential to perform a comprehensive evaluation of musculoskeletal complaints to distinguish natural menopause-related degenerative disease from AI-related effects. The present review explores the advantages of differential diagnosis with an emphasis on history and physical and musculoskeletal examination; laboratory investigations are used to corroborate or rule out clinical impressions. The transient symptoms associated with the ais are manageable with an appropriate combination of lifestyle changes, including exercise and joint protection in conjunction with pharmacologic approaches.

  7. Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer.

    PubMed

    Abdalla, Mohamed M; Al-Omar, Mohamed A; Bhat, Mashooq A; Amr, Abdel-Galil E; Al-Mohizea, Abdullah M

    2012-05-01

    The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone(®)). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC(50) of 80 μM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer.

  8. The role of aromatase inhibitors in early breast cancer.

    PubMed

    Chung, Cathie T; Carlson, Robert W

    2003-04-01

    The role of hormonal therapy for the treatment of patients with early stage breast cancer has been evaluated in many studies. The results of these studies establish tamoxifen as the gold standard of hormonal therapy for the adjuvant treatment of hormone receptor-positive invasive breast cancer in pre- and postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast cancer in women at increased risk for the disease, including women with ductal carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased risk of uterine cancer in postmenopausal women, and rare occurrence of thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen, alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic activity. AIs function by inhibiting the peripheral conversion of adrenally synthesized androstenedione to estradiol through inhibition of the aromatase enzyme. AIs do not suppress estradiol synthesis by the ovary adequately. Therefore, AIs are effective in reducing circulating estradiol levels in postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin; Pharmacia, Peapack, NJ) have been associated with increased specificity and improved therapeutic index compared to nonselective AIs such as aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be superior to megestrol acetate in second-line therapy of postmenopausal women with metastatic breast cancer, and selective nonsteroidal AIs have shown to be superior to tamoxifen in first-line therapy of postmenopausal women with metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in combination) trial is the only published randomized trial comparing the efficacy of an AI to tamoxifen for the adjuvant treatment of women with early breast cancer. This large

  9. Synthesis and PET studies of [11C-cyano]letrozole (Femara), an aromatase inhibitor drug

    SciTech Connect

    kil K. E.; Biegon A.; Kil, K.-E.; Biegon, A.; Ding, Y.-S.; Fischer, A.; Ferrieri, R.A.; Kim, S.-W.; Pareto, D.; Schueller, M.J.; Fowler, J.S.

    2008-11-10

    Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone to estrone and estradiol respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole, Femara{reg_sign}) is a high affinity aromatase inhibitor (K{sub i}=11.5 nM) which has FDA approval for breast cancer treatment. Here we report the synthesis of carbon-11 labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile, 3) were prepared in two-step syntheses from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [{sup 11}C]cyano group was introduced via the tetrakis(triphenylphosphine)palladium(0) catalyzed coupling of [{sup 11}C]cyanide with the bromo-precursor (3). PET studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. The free fraction of letrozole in the plasma, log D, and the [{sup 11}C-cyano]letrozole fraction in the arterial plasma were also measured. [{sup 11}C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16 {+-} 2.21 Ci/{micro}mol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance followed by slow clearance of carbon-11 from the brain with no difference between brain regions. The brain kinetics was not affected by co-injection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9% and log D was 1.84. [{sup 11}C-cyano]Letrozole is readily synthesized via a palladium catalyzed coupling reaction with [{sup 11}C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase as revealed by the absence of regional specificity and saturability in brain regions, such as amygdala, which are known

  10. New aromatase inhibitors. Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine derivatives.

    PubMed

    Sonnet, P; Dallemagne, P; Guillon, J; Enguehard, C; Stiebing, S; Tanguy, J; Bureau, R; Rault, S; Auvray, P; Moslemi, S; Sourdaine, P; Séralini, G E

    2000-05-01

    We report herein the design and the synthesis of some aryl-substituted pyrrolizine and indolizine derivatives, on the basis of a hypothetical pharmacophore structure designed to fit the catalytic site of the human cytochrome P450 aromatase. The in vitro biological evaluation of these compounds allowed us to point out two new potent non-steroidal aromatase inhibitors, MR 20494 and MR 20492, with IC50 values in the range of 0.1 microM.

  11. The use of aromatase inhibitors in boys with short stature: what to know before prescribing?

    PubMed

    Linardi, Alessandra; Damiani, Durval; Longui, Carlos A

    2017-01-01

    Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.

  12. Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.

    PubMed

    Woo, L W Lawrence; Jackson, Toby; Putey, Aurélien; Cozier, Gyles; Leonard, Philip; Acharya, K Ravi; Chander, Surinder K; Purohit, Atul; Reed, Michael J; Potter, Barry V L

    2010-03-11

    Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.

  13. The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment

    PubMed Central

    Mitwally, Mohamed FM; Casper, Robert F; Diamond, Michael P

    2005-01-01

    Clinical utilization of ovulation stimulation to facilitate the ability of a couple to conceive has not only provided a valuable therapeutic approach, but has also yielded extensive information on the physiology of ovarian follicular recruitment, endometrial receptivity and early embryo competency. One of the consequences of the use of fertility enhancing agents for ovarian stimulation has been the creation of a hyperestrogenic state, which may influence each of these parameters. Use of aromatase inhibitors reduces hyperestrogenism inevitably attained during ovarian stimulation. In addition, the adjunct use of aromatase inhibitors during ovarian stimulation reduces amount of gonadotropins required for optimum stimulation. The unique approach of reducing hyperestrogenism, as well as lowering amount of gonadotropins without affecting the number of mature ovarian follicles is an exciting strategy that could result in improvement in the treatment outcome by ameliorating the deleterious effects of the ovarian stimulation on follicular development, endometrial receptivity, as well as oocyte and embryo quality. PMID:16202169

  14. Multiple Structural and Functional Abnormalities in the P450 Aromatase Expressing Transgenic Male Mice Are Ameliorated by a P450 Aromatase Inhibitor

    PubMed Central

    Li, Xiangdong; Strauss, Leena; Mäkelä, Sari; Streng, Tomi; Huhtaniemi, Ilpo; Santti, Risto; Poutanen, Matti

    2004-01-01

    The present study was undertaken to analyze the effect of a P450 aromatase inhibitor (finrozole) on 4-month-old transgenic mice expressing human P450 aromatase (P450arom) under the human ubiquitin C promoter (AROM+). AROM+ mice present several dysfunctions, such as adrenal and pituitary hyperplasia, cryptorchidism, Leydig cell hypertrophy and hyperplasia, and gynecomastia. The present study demonstrates that these abnormalities were efficiently treated by administration of a P450arom inhibitor, finrozole. The treatment normalized the reduced intratesticular and serum testosterone levels, while those of estradiol were decreased. The body weight and several affected organ weights were normalized with the treatment. Histological analysis revealed that both the pituitary and adrenal hyperplasia were diminished. Furthermore, the cryptorchid testes present in the untreated AROM+ males descended to scrotum, 4 to 15 days after inhibitor treatment. In addition, the disrupted spermatogenesis was recovered and qualitatively complete spermatogenesis appeared with the inhibitor treatment. This was associated with normalized structure of the interstitial tissue, as analyzed by immunohistochemical staining for Leydig cells and macrophages. One of the features was that the Leydig cell hypertrophy was markedly diminished in the treated mice. AROM+ mice also present with severe gynecomastia, while the development and differentiation of the mammary gland in AROM+ males was markedly diminished with the inhibitor treatment. Interestingly, the mammary gland involution was associated with the induction of androgen receptor in the epithelial cells, while estrogen receptors were still detectable in the epithelium. The data show that AROM+ mouse model is a novel tool to further analyze the use of P450arom inhibitors in the treatment of the dysfunctions in males associated with misbalanced estrogen to androgen ratio, such as pituitary adenoma, testicular dysfunction, and gynecomastia. PMID

  15. Lichen sclerosus in a breast cancer survivor on an aromatase inhibitor: a case report.

    PubMed

    Potter, Jennifer E; Moore, Kendra A

    2013-04-01

    Lichen sclerosus is a commonly misdiagnosed disease that is characterized by thinned, hypopigmented, crinkled skin that often forms a figure-eight shape around the vaginal and anal openings. We present a case of advanced lichen sclerosus in a 53-year-old female patient prescribed a nonsteroidal aromatase inhibitor after the excision of a breast cancer tumor. We present a diagnostic approach to lichen sclerosus by recognizing its common figure-eight pattern, and we review the known causes and treatment of lichen sclerosus. Research has shown that lichen sclerosus is more common in low estrogen states, and thus it is logical that aromatase inhibitors could increase a patient's risk for developing this disease. We therefore propose that all patients prescribed aromatase inhibitors undergo regular vulvo-vaginal exams to rule out lichen sclerosus and other hypoestrogen-related vulvo-vaginal problems.

  16. Making males from females: the effects of aromatase inhibitors on a parthenogenetic species of whiptail lizard.

    PubMed

    Wennstrom, K L; Crews, D

    1995-09-01

    The parthenogenetic whiptail lizard Cnemidophorus uniparens provides a good model for the study of sex determination and sexual differentiation because genetic variation is minimal and all unmanipulated embryos will develop as females. Thus any deviation from the established course of development can be identified as a treatment effect. Previous work has shown that early prenatal treatment with CGS16949A, a nonsteroidal aromatase inhibitor, causes hatchlings to develop as males. The present study explores more fully the effects of dosage and timing of application of CGS16949A and examines the sex-reversing potential of CGS20267, a new and reputedly more potent aromatase inhibitor. Eggs were treated with a range of dosages of the aromatase inhibitors. Hatchlings that received 1 microgram or more of either inhibitor were all male, while those that received 0.1 microgram or less were all female. No difference in potency between the two compounds was detected. Animals treated with 100 micrograms of CGS16949A on Day 20 of incubation or later were all female, while those treated on Day 5 were all male. Seven sex-reversed male parthenogens have been raised to sexual maturity. The animals appear similar morphologically and behaviorally to males of the sexually reproducing whiptail species. Spermatogenesis and spermiogenesis have been confirmed by histological examination of the testes and by postcopulatory cloacal swabs. Application of aromatase inhibitors has been shown to sex-reverse both avian and reptilian species. In mammals, the male-determining gene of the Y chromosome (SRY) may code for an intrinsic aromatase inhibitor. Studies show the gene's product has a binding domain which recognizes regulatory elements in the promoter of the aromatase gene.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase: structure-function studies and inhibitor development.

    PubMed

    Hong, Yanyan; Chen, Shiuan

    2011-07-04

    Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 are involved in the key steps of 17β-estradiol biosynthesis. Structure-function studies of aromatase, estrone sulfatase and 17β-hydroxysteroid dehydrogenase type 1 are important to evaluate the molecular basis of the interaction between these enzymes and their inhibitors. Selective and potent inhibitors of the three enzymes have been developed as antiproliferative agents in hormone-dependent breast carcinoma. New treatment strategies for hormone-dependent breast cancer are discussed.

  18. Aromatase inhibitors as add-on treatment for men with epilepsy.

    PubMed

    Harden, Cynthia; MacLusky, Neil J

    2005-01-01

    Manipulation of neurosteroids to treat epilepsy has been an area of active research. The effect of testosterone on brain excitability and seizure threshold has been mixed; the estradiol metabolite of testosterone increases brain excitability, while the reduced metabolite of testosterone, 3alpha-androstanediol, decreases brain excitability, likely through an action at the gamma-amino butyric acid A receptor. Therefore, the metabolites of testosterone produce opposite effects on brain excitability in seizure models. Aromatase is the enzyme for the conversion of testosterone to 17beta-estradiol. Aromatase inhibitors could decrease brain excitability by decreasing local estradiol levels and therefore, could be beneficial for the treatment of epilepsy. Aromatase inhibitors are US Food and Drug Administration-approved and have a long history of safe use in menopausal women with breast cancer. This review presents the results of using anastrazole in an open-label, add-on manner in a small group of men with epilepsy in order to improve seizures. The results suggested some effect on reduction of seizures and no side effects. Testosterone levels did increase, but not to above the normal range. Letrozole used in a single case was also beneficial for seizures. It was concluded that aromatase inhibitors may be a useful adjunct to the treatment of epilepsy, but habituation to the treatment may be limiting. Many men with epilepsy have low testosterone, and aromatase inhibition may be helpful in restoring levels to normal. Modulation of reproductive hormones by aromatase inhibition as well as enhancement of the 3alpha-androstanediol pathway may be an avenue of epilepsy treatment that would not produce sedative side effects, which is often a limiting factor with standard antiseizure medications. A further interesting result is that elevated follicle stimulating hormone and luteal stimulating hormone levels were associated with seizure reduction, suggesting that they may be a

  19. Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer.

    PubMed

    Lu, Wenjie Jessie; Desta, Zeruesenay; Flockhart, David A

    2012-01-01

    The mechanism of tamoxifen action in the treatment of breast cancer is believed to be via active metabolites that act as potent estrogen receptor antagonists. Attempts to identify relationships between active metabolite concentrations and clinical outcomes have produced mixed results. Since anti-estrogenic effects may be brought about not only by estrogen antagonism, but also by reduced estrogen synthesis, we tested the ability of tamoxifen and its principal metabolites to inhibit aromatase in vitro. The activity of human aromatase in both recombinant and placental microsomal preparations was measured using the rate of generation of a fluorescent metabolite in the presence and absence of multiple concentrations of tamoxifen, endoxifen, N-desmethyl-tamoxifen, and Z-4-hydroxy-tamoxifen. Aromatase inhibition was further characterized by measuring the inhibition of testosterone metabolism to estradiol. The biochemical mechanisms of inhibition were documented and their inhibitory potency was compared. Using recombinant human aromatase, endoxifen, and N-desmethyl-tamoxifen were able to inhibit aromatase activity with K (i) values of 4.0 and 15.9 μM, respectively. Detailed characterization of inhibition by endoxifen and N-desmethyl-tamoxifen indicated non-competitive kinetics for both inhibitors. Similarly, endoxifen-inhibited testosterone metabolism via a non-competitive mechanism. No appreciable inhibition by tamoxifen or Z-4-hydroxy-tamoxifen was observed at similar concentrations. The relative inhibitory potency was: endoxifen > N-desmethyl-tamoxifen > Z-4-hydroxy-tamoxifen > tamoxifen. Similar data were obtained in human placental microsomes. Endoxifen and N-desmethyl-tamoxifen were found to be potent inhibitors of aromatase. Inhibition by these tamoxifen metabolites may contribute to the variability in clinical effects of tamoxifen in patients with breast cancer. Relationships between tamoxifen metabolite concentrations and clinical outcomes may be complex

  20. Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

    PubMed Central

    Ji, Jin-zi; Lao, Ke-jing; Hu, Jie; Pang, Tao; Jiang, Zhen-zhou; Yuan, Hao-liang; Miao, Jing-shan; Chen, Xin; Ning, Shan-shan; Xiang, Hua; Guo, Yu-meng; Yan, Ming; Zhang, Lu-yong

    2014-01-01

    Aim: Aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). Methods: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. Results: The Z′ value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 μmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 μmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein. Conclusion: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor. PMID:25047514

  1. The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase.

    PubMed

    Banerjee, Susana; Zvelebil, Marketa; Furet, Pascal; Mueller-Vieira, Ursula; Evans, Dean B; Dowsett, Mitch; Martin, Lesley-Ann

    2009-06-01

    Endocrine therapy is well established for the treatment of breast cancer, and antiangiogenic agents are showing considerable promise. Targeting the vascular endothelial growth factor (VEGF) and estrogen receptor (ER) signaling pathways concomitantly may provide enhanced therapeutic benefit in ER-positive breast cancer. Therefore, the effects of the VEGF receptor (VEGFR) tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) were investigated using human breast cancer cell lines engineered to express aromatase. As expected in this system, estrogen (E2) or androstenedione induced a proliferative response and increased ER-mediated transcription in ER-positive cell lines expressing aromatase. However, surprisingly, in the presence of androstenedione, PTK/ZK suppressed both the androstenedione-stimulated proliferation and ER-mediated transcription. PTK/ZK alone and in the presence of E2 had no observable effect on proliferation or ER-mediated transcription. These effects result from PTK/ZK having previously unrecognized antiaromatase activity and PTK/ZK being a competitive aromatase inhibitor. Computer-assisted molecular modeling showed that PTK/ZK could potentially bind directly to aromatase. The demonstration that PTK/ZK inhibits aromatase and VEGFR indicates that agents cross-inhibiting two important classes of targets in breast cancer could be developed.

  2. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design

    PubMed Central

    Mirzaie, Sako; Chupani, Latifeh; Asadabadi, Ebrahim Barzegari; Shahverdi, Ahmad Reza; Jamalan, Mostafa

    2013-01-01

    Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of aromatase, synthesized by Bonfield et al. (2012[7]). In our computational study, the mentioned compound was used as the template for virtual screening. Between 286 selected compounds with 70 % of structural similarity to 2a, 150 of them showed lower docking energy in comparison with 2a. Compound 2a_1 with 11.2 kcal/mol had the lowest docking energy. Interaction of 2a_1 with aromatase was further investigated and compared with 2a and androstenedione (ASD) as a natural substrate of aromatase, through 20 ns of molecular dynamic simulation. Analysis of trajectories showed, while ASD interacts with aromatase through hydrogen bonds and 2a just interacts via hydrophobic forces, 2a_1 not only accommodates in the hydrophobic active site of aromatase in a suitable manner but it also makes a stable coordination with iron atom of aromatase heme group via OB. PMID:26417225

  3. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design.

    PubMed

    Mirzaie, Sako; Chupani, Latifeh; Asadabadi, Ebrahim Barzegari; Shahverdi, Ahmad Reza; Jamalan, Mostafa

    2013-01-01

    Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of aromatase, synthesized by Bonfield et al. (2012[7]). In our computational study, the mentioned compound was used as the template for virtual screening. Between 286 selected compounds with 70 % of structural similarity to 2a, 150 of them showed lower docking energy in comparison with 2a. Compound 2a_1 with 11.2 kcal/mol had the lowest docking energy. Interaction of 2a_1 with aromatase was further investigated and compared with 2a and androstenedione (ASD) as a natural substrate of aromatase, through 20 ns of molecular dynamic simulation. Analysis of trajectories showed, while ASD interacts with aromatase through hydrogen bonds and 2a just interacts via hydrophobic forces, 2a_1 not only accommodates in the hydrophobic active site of aromatase in a suitable manner but it also makes a stable coordination with iron atom of aromatase heme group via OB.

  4. Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor

    EPA Science Inventory

    The paper reports on the effects of a model aromatase inhibitor, fadrozole, on molecular and biochemical endpoints within the fathead minnow reproductive axis. Unlike previous studies, this work incorporated extensive time-course characterization over the course of an 8 d exposu...

  5. A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS) | Division of Cancer Prevention

    Cancer.gov

    E1Z11 is a study to determine whether certain genetic information can predict which breast cancer patients will discontinue treatment with AIs due to the development of musculoskeletal symptoms (MSS). Women with stage 1-111 breast cancer who are prescribed the aromatase inhibitor anastrozole as treatment may join. |

  6. Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor

    EPA Science Inventory

    The paper reports on the effects of a model aromatase inhibitor, fadrozole, on molecular and biochemical endpoints within the fathead minnow reproductive axis. Unlike previous studies, this work incorporated extensive time-course characterization over the course of an 8 d exposu...

  7. Computational methods for the design of potent aromatase inhibitors.

    PubMed

    Favia, Angelo Danilo; Nicolotti, Orazio; Stefanachi, Angela; Leonetti, Francesco; Carotti, Angelo

    2013-04-01

    It has long been considered that the most significant risks for breast cancer are gender and age but, as many other tumors, this cancer has also been undeniably linked to gene mutations. The vast majority of breast cancers in postmenopausal women are estrogen-responsive, a hormone which is biosynthesized from blood-circulating androgens through an aromatization reaction, catalyzed by aromatase (AR). One strategy, therefore, to combat breast cancer, has been to find compounds that can inhibit the activity of aromatase to reduce estrogen levels. The authors provide a broad and updated overview of the general structure-activity relationships and on the latest ligand- and structure-based approaches applied to the discovery of potent, selective and safer breast cancer drugs. Specifically the authors review the most consolidated techniques, based on structure-activity relationships, pharmacophore mapping, rigid and flexible molecular docking, as well as sophisticated and reliable protocols simulating critical biological events. The recently solved X-ray structures of aromatase represent solid milestones to breathe new life into the search of newer chemotypes with reduced risks of cross-reactivity toward other CYPs and safer pharmacological profiles. We anticipate that great benefits will arrive from the wealth of information obtained by integrating genomics, site-directed mutagenesis experiments with protein modeling. Furthermore, we welcome the advent of GPU technology that, in conjunction with dedicated algorithms, grants scientists an unprecedented point of view on physiologically relevant phenomena, occurring on the µs time scale, such as ligand binding/unbinding.

  8. Synthesis of aromatase inhibitors and dual aromatase steroid sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities.

    PubMed

    Bubert, Christian; Woo, L W Lawrence; Sutcliffe, Oliver B; Mahon, Mary F; Chander, Surinder K; Purohit, Atul; Reed, Michael J; Potter, Barry V L

    2008-11-01

    4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC(50)=0.26 nM) and the best DASI is 43 e (IC(50 aromatase)=0.45 nM, IC(50 STS)=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg(-1), single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.

  9. Nonsteroidal aromatase inhibitors for the treatment of breast cancer: an update.

    PubMed

    Gobbi, Silvia; Rampa, Angela; Belluti, Federica; Bisi, Alessandra

    2014-01-01

    Estrogens are known to be important in breast cancer growth in both pre- and post-menopausal women. Although circulating estrogen concentrations are very low after menopause, peripheral tissues generate sufficient concentrations to stimulate tumor growth. As aromatase is the rate-limiting enzyme in estrogen biosynthesis, inhibitors of this enzyme represent effective targeted therapy for breast cancer. Three compounds are now FDA approved and have become the first-choice endocrine drugs for postmenopausal breast cancer patients, since they are associated with superior activity and better general tolerability when compared with the estrogen receptor modulator tamoxifen. Nevertheless, some questions concerning the use of aromatase inhibitors for the treatment of breast cancer still need to be addressed, mainly related to their side-effects and the development of resistance, making research in this field still appealing. Many research groups, including our own, are still dealing with the search of new compounds that possess aromatase inhibitory properties. In this review an update of the latest achievements in the field of nonsteroidal aromatase inhibitors will be given.

  10. Design and synthesis of a new type of non steroidal human aromatase inhibitors.

    PubMed

    Sonnet, P; Guillon, J; Enguehard, C; Dallemagne, P; Bureau, R; Rault S Auvray, P; Moslemi, S; Sourdiane, P; Galopin, S; Séralini, G E

    1998-05-05

    The structure-activity relationship study of one of recently described aromatase inhibitors, compound 1 (MR20814), allowed us to design some related derivatives as potential new inhibitors. Among those we synthesized, chlorophenylpyridylmethylenetetrahydroindolizinone 5 (MR20492) exhibited in vitro a ten-fold higher inhibition of the enzyme (IC50 = 0.2 +/- 0.0 microM and Ki = 10.3 +/- 3.3 nM).

  11. Development of a new class of aromatase inhibitors: Design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives

    PubMed Central

    Bonfield, Kevin; Amato, Erica; Bankemper, Tony; Agard, Hannah; Steller, Jeffrey; Keeler, James M.; Roy, David; McCallum, Adam; Paula, Stefan; Ma, Lili

    2014-01-01

    Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis. Inhibition of aromatase is a new and promising approach to treat hormone-dependent breast cancer. We present here the design and development of isoflavanone derivatives as potential aromatase inhibitors. Structural modifications were performed on the A and B rings of isoflavanones via microwave-assisted, gold-catalyzed annulation reactions of hydroxyaldehydes and alkynes. The in vitro aromatase inhibition of these compounds was determined by fluorescence-based assays utilizing recombinant human aromatase (baculovirus/insect cell-expressed). The compounds 3-(4-phenoxyphenyl)chroman-4-one (1h), 6-methoxy-3-phenylchroman-4-one (2a) and 3-(pyridin-3-yl)chroman-4-one (3b) exhibited potent inhibitory effects against aromatase with IC50 values of 2.4 μM, 0.26 μM and 5.8 μM, respectively. Docking simulations were employed to investigate crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This report provides useful information on aromatase inhibition and serves as a starting point for the development of new flavonoid aromatase inhibitors. PMID:22444875

  12. Isolation and Characterization of Aromatase Inhibitors from Brassaiopsis glomerulata (Araliaceae)

    PubMed Central

    Balunas, Marcy J.; Su, Bin; Riswan, Soedarsono; Fong, Harry H.S.; Brueggemeier, Robert W.; Pezzuto, John M.; Kinghorn, A. Douglas

    2009-01-01

    The hexane- and ethyl acetate-soluble extracts of the leaves of Brassaiopsis glomerulata (Blume) Regel (Araliaceae), collected in Indonesia, were found to inhibit aromatase, the rate-limiting enzyme in the production of estrogens from androgens, in both enzyme- and cell-based aromatase inhibition (AI) assays. Bioassay-guided fractionation led to the isolation of six known compounds of the steroid and triterpenoid classes (1–6) from the hexane extract, of which 6β-hydroxystimasta-4-en-3-one (5), was moderately active in the cell-based AI assay. Fractionation of the ethyl acetate extract afforded seven pure isolates (7–13) of the modified peptide, fatty acid, monoterpenoid, and benzenoid types, including six known compounds and the new natural product, N-benzoyl-L-phenylalanine methyl ester (9). The absolute stereochemistry of 9 and the other two peptides, 7 and 8, was determined by Marfey’s analysis. Linoleic acid (10) was found to be active in the enzyme-based AI assay, while 9 and (−)-dehydrololiolide (12) showed activity in the cell-based AI assay. PMID:20161072

  13. Isolation and Characterization of Aromatase Inhibitors from Brassaiopsis glomerulata (Araliaceae).

    PubMed

    Balunas, Marcy J; Su, Bin; Riswan, Soedarsono; Fong, Harry H S; Brueggemeier, Robert W; Pezzuto, John M; Kinghorn, A Douglas

    2009-02-19

    The hexane- and ethyl acetate-soluble extracts of the leaves of Brassaiopsis glomerulata (Blume) Regel (Araliaceae), collected in Indonesia, were found to inhibit aromatase, the rate-limiting enzyme in the production of estrogens from androgens, in both enzyme- and cell-based aromatase inhibition (AI) assays. Bioassay-guided fractionation led to the isolation of six known compounds of the steroid and triterpenoid classes (1-6) from the hexane extract, of which 6β-hydroxystimasta-4-en-3-one (5), was moderately active in the cell-based AI assay. Fractionation of the ethyl acetate extract afforded seven pure isolates (7-13) of the modified peptide, fatty acid, monoterpenoid, and benzenoid types, including six known compounds and the new natural product, N-benzoyl-L-phenylalanine methyl ester (9). The absolute stereochemistry of 9 and the other two peptides, 7 and 8, was determined by Marfey's analysis. Linoleic acid (10) was found to be active in the enzyme-based AI assay, while 9 and (-)-dehydrololiolide (12) showed activity in the cell-based AI assay.

  14. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer.

    PubMed

    Miller, William R

    2003-08-01

    The natural history of breast cancer is closely linked with estrogens. These hormones influence both risk to the disease and growth of many established tumors. Consequently, measures that either inhibit the synthesis or block the mechanism of action of estrogens are attractive strategies for therapeutic intervention. This is particularly true in postmenopausal women in whom hormone responsiveness is common and estrogen synthesis is primarily sited peripherally in adipose tissue, muscle and breast tissue, rather than in the ovaries as in premenopausal women. In terms of inhibiting production, the most specific effects are best achieved by blocking the last step in biosynthesis, the conversion of androgens to estrogens by the heme-containing enzyme, aromatase. Two major classes of aromatase inhibitors have been developed and are currently in clinical use. Type I steroidal drugs include formestane and exemestane; they are androgen substrate analogues that bind competitively but irreversibly to the enzyme and have been marketed as "inactivators." Type II nonsteroidal inhibitors such as anastrozole and letrozole are triazoles; they bind reversibly to the enzyme and fit into the substrate binding site, such that azole nitrogens interact with the heme prosthetic group. This type of association provides exquisite potency for and specificity against the aromatase enzyme. These agents represent several generations of development, with each step in the evolution producing an increase in both potency and specificity. The latest aromatase inhibitors are drugs of immense potential that will undoubtedly play a major role in the management of postmenopausal women with hormone-dependent breast cancer. They also represent tools by which to elucidate the roles of both aromatase and estrogen in the development and growth of breast cancer.

  15. ALTERATIONS IN THE TRANSCRIPTOME AND PROTEOME OF ZEBRAFISH (DANIO RERIO) EXPOSED TO FADROZOLE, A MODEL AROMATASE INHIBITOR

    EPA Science Inventory

    Fadrozole is a reversible, competitive inhibitor of aromatase activity and therefore an endocrine-disrupting compound (EDC) that disrupts steroidogenesis by inhibiting the conversion of testosterone to 172-estradiol. While fadrozole is a therapeutic drug with generally no enviro...

  16. ALTERATIONS IN THE TRANSCRIPTOME AND PROTEOME OF ZEBRAFISH (DANIO RERIO) EXPOSED TO FADROZOLE, A MODEL AROMATASE INHIBITOR

    EPA Science Inventory

    Fadrozole is a reversible, competitive inhibitor of aromatase activity and therefore an endocrine-disrupting compound (EDC) that disrupts steroidogenesis by inhibiting the conversion of testosterone to 172-estradiol. While fadrozole is a therapeutic drug with generally no enviro...

  17. Benefit/risk for adjuvant breast cancer therapy with tamoxifen or aromatase inhibitor use by age, and race/ethnicity.

    PubMed

    Chlebowski, R T; Haque, R; Hedlin, H; Col, N; Paskett, E; Manson, J E; Kubo, J T; Johnson, K C; Wactawski-Wende, J; Pan, K; Anderson, G

    2015-12-01

    In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women's Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta-analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances.

  18. Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia Inducible Factor 1 (HIF 1) in Aromatase Inhibitor Resistant Breast Cancer

    DTIC Science & Technology

    2015-12-01

    ABSTRACT Prior to this study, aromatase inhibitor ( AI , ex. letrozole) resistance was associated withincreased dependence on growth factors and decreased...dependence on ERα. However, the role that such molecular changes play in AI resistance and the mechanism by which they elicit their effects were not...treatment of acquired AI resistance. 15. SUBJECT TERMS Breast cancer, aromatase inhibitors (ex. letrozole), drug resistance, cancer stem cells,nonhypoxic

  19. Effects of aromatase inhibitor on menopausal hyperplasia in a case of obesity.

    PubMed

    Koloszar, S; Pal, Z; Kereszturi, A; Vajda, G; Pal, A; Daru, J

    2012-02-01

    The aromatase inhibitor anastrazole proved effective in the treatment of endometrial hyperplasia and postmenopausal bleeding in an obese 65-year-old woman with high operative risk. During anastrazole administration for 12 months, the endometrial thickness decreased from 9.8 mm to 2.4 mm and the control endometrial histology showed an atrophic endometrium. Uterine bleeding did not occur in the post-treatment, 3-year follow-up period. The endometrial thicknesses measured yearly by ultrasonography were 2.9, 3.5 and 3.3 mm. The plasma estradiol levels increased from < 73 pmol/l post-treatment to 112, 98 and 103 pmol/l. This case demonstrates that long-term aromatase inhibitor treatment can result in a refractory status of the endometrium and the estradiol produced in the adipose tissue does not exert a proliferative effect.

  20. Sex Amphibian, Xenopus tropicalis, following Larval Exposure to an Aromatase Inhibitor

    EPA Science Inventory

    Aromatase is a steroidogenic enzyme that catalyzes the conversion of androgens to estrogens in vertebrates. Modulation of this enzyme’s activity by xenobiotic exposure has been shown to adversely affect gonadal differentiation in a number of diverse species. We hypothesized tha...

  1. Sex Amphibian, Xenopus tropicalis, following Larval Exposure to an Aromatase Inhibitor

    EPA Science Inventory

    Aromatase is a steroidogenic enzyme that catalyzes the conversion of androgens to estrogens in vertebrates. Modulation of this enzyme’s activity by xenobiotic exposure has been shown to adversely affect gonadal differentiation in a number of diverse species. We hypothesized tha...

  2. Mechanism-based categorization of aromatase inhibitors: a potential discovery and screening tool.

    PubMed

    Petkov, P I; Temelkov, S; Villeneuve, D L; Ankley, G T; Mekenyan, O G

    2009-10-01

    Cytochrome P450 aromatase is a key steroidogenic enzyme that converts androgens to estrogens in vertebrates. There is much interest in aromatase inhibitors (AIs) both because of their use as pharmaceuticals in the treatment of estrogen-sensitive breast cancers, and because a number of environmental contaminants can act as AIs, thereby disrupting endocrine function in humans and wildlife through suppression of circulating estrogen levels. The goal of the current work was to develop a mechanism-based structure-activity relationship (SAR) categorization framework highlighting the most important chemical structural features responsible for inhibition of aromatase activity. Two main interaction mechanisms were discerned: steroidal and non-steroidal. The steroid scaffold is most prominent when the structure of the target chemical is similar to the natural substrates of aromatase - androstenedione and testosterone. Chemicals acting by non-steroidal mechanism(s) possess a heteroatom (N, O, S) able to coordinate the heme iron of the cytochrome P450, and thus interfere with steroid hydroxylation. The specific structural boundaries controlling AI for both analyzed mechanisms were defined, and a software tool was developed that allowed a decision tree (profile) to be built discriminating AIs by mechanism and potency. An input chemical follows a profiling path and the structure is examined at each step to decide whether it conforms with the structural boundaries implemented in the decision tree node. Such a system would aid drug discovery efforts, as well as provide a screening tool to detect environmental contaminants that could act as AIs.

  3. Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors.

    PubMed

    Wang, Liewei; Ellsworth, Katarzyna A; Moon, Irene; Pelleymounter, Linda L; Eckloff, Bruce W; Martin, Yvette N; Fridley, Brooke L; Jenkins, Gregory D; Batzler, Anthony; Suman, Vera J; Ravi, Saranya; Dixon, J Michael; Miller, William R; Wieben, Eric D; Buzdar, Aman; Weinshilboum, Richard M; Ingle, James N

    2010-01-01

    Aromatase (CYP19) is a critical enzyme in estrogen biosynthesis and aromatase inhibitors (AI) are employed widely for endocrine therapy in postmenopausal women with breast cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in the CYP19 gene may alter the effectiveness of AI therapy in the neoadjuvant setting. Genomic DNA was obtained for sequencing from 52 women pre-AI and post-AI treatment in this setting. Additionally, genomic DNA obtained from 82 samples of breast cancer and 19 samples of normal breast tissue was subjected to resequencing. No differences in CYP19 sequence were observed between tumor and germ-line DNA in the same patient. A total of 48 SNPs were identified including 4 novel SNPs when compared with previous resequencing data. For genotype-phenotype association studies, we determined the levels of aromatase activity, estrone, estradiol, and tumor size in patients pre-AI and post-AI treatment. We defined two tightly linked SNPs (rs6493497 and rs7176005 in the 5'-flanking region of CYP19 exon 1.1) that were significantly associated with a greater change in aromatase activity after AI treatment. In a follow-up study of 200 women with early-stage breast cancer who were treated with adjuvant anastrozole, these same two SNPs were also associated with higher plasma estradiol levels in patients pre-AI and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed likely functional effects of these two SNPs on transcription of CYP19. Our findings indicate that two common genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to aromatase inhibitors.

  4. Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients.

    PubMed

    Eggemann, Holm; Ignatov, Atanas; Smith, Bobbie J; Altmann, Udo; von Minckwitz, Gunter; Röhl, Freidrich W; Jahn, Mark; Costa, Serban-Dan

    2013-01-01

    To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase inhibitors (N = 50). The median follow-up was 42.2 (range 2-115) months. Median age at diagnosis was 68 (range 36-91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p = 0.007). After the adjustment for the patient's age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13-2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be considered as the treatment of choice for hormone-receptor-positive male breast cancer.

  5. Aromatase inhibitors and their future role in post-menopausal women with early breast cancer.

    PubMed Central

    Lønning, P. E.

    1998-01-01

    Anastrozole is the first aromatase inhibitor to show a significant survival advantage over megestrol acetate in post-menopausal women with advanced breast cancer. The rationale for extending the use of aromatase inhibitors to the treatment of early breast cancer is based on the efficacy observed in the advanced setting, combined with good tolerability and a convenient dosing regimen. Furthermore, oestrogen deprivation by ovarian ablation (similar to oestrogen antagonism with tamoxifen) is already established as an effective adjuvant treatment in premenopausal women with modality breast cancer. Anastrozole produces a profound suppression of plasma oestrogen levels which is greater than that obtained with earlier aromatase inhibitors (formestane, aminoglutethimide) or megestrol acetate. This could account for the differences in clinical efficacy seen between anastrozole and megestrol acetate. In terms of benefits over other endocrine agents, anastrozole causes significantly less weight gain than megestrol acetate; it does not have the partial agonist activity of tamoxifen, and is unlikely to lead to tumour stimulation in patients resistant to tamoxifen or to exert proliferative effects on the endometrium. The lack of oestrogen agonist activity, however, may possibly have detrimental effects on bone mineral density and blood lipid profile. Current clinical trials are investigating the efficacy and safety of anastrozole in the early breast cancer setting. The results of these trials will help to determine whether anastrozole has any benefits over tamoxifen, the current treatment of choice in post-menopausal women with early breast cancer. PMID:9741783

  6. Steroidal inhibitors as chemical probes of the active site of aromatase.

    PubMed

    Brueggemeir, R W; Moh, P P; Ebrahimian, S; Darby, M V

    1993-03-01

    Androstenedione analogs containing 7 alpha-substituents have proven to be potent inhibitors of aromatase in human placental microsomes, in MCF-7 mammary cell cultures, and in JAr choriocarcinoma cells. Recent investigations have focused on the use of mechanism-based inhibitors, such as 7 alpha-substituted 1,4-androstadienediones, to biochemically probe the active site of aromatase. Inhibition kinetics were determined under initial velocity conditions using purified human placental cytochrome P450arom protein in a reconstituted system. Derivatives of 1,4-androstadiene-3,17-dione and 1,4,6-androstatriene-3,17-dione exhibited high affinity in the purified enzyme system. 7 alpha-(4'-Amino)phenylthio-1,4-androstadiene-3,17-dione, abbreviated 7 alpha-APTADD, demonstrated rapid time-dependent, first-order inactivation of reconstituted aromatase activity only in the presence of NADPH. The apparent Kinact for 7 alpha-APTADD is 11.8 nM, the first-order rate of inactivation is 2.72 x 10(-3) sec-1, and the half-time of inactivation at infinite inhibitor concentration is 4.25 min. The values for the rate constant and half-time of inactivation are similar to those observed in the placental microsomal assay system. Further studies were performed with radioiodinated 7 alpha-(4'-iodo)phenylthio-1,4-androstadienedione, 7 alpha-IPTADD, and the reconstituted aromatase system. Incubations with [125I] 7 alpha-IPTADD were followed by protein precipitation, solvent extraction, and column chromatography. Analysis of the isolated cytochrome P450arom by gel electrophoresis and autoradiography demonstrated the presence of only one radioactive band, which corresponded to the protein staining band for cytochrome P450arom. HPLC radiochromatographic analysis of the isolated cytochrome P450aroM confirmed the presence of only one radioactive peak coeluting with the u.v. peak for cytochrome P450arom. Peptide mapping analysis by reverse-phase HPLC of digested inhibitor-cytochrome P450arom complex

  7. Impact of yoga on functional outcomes in breast cancer survivors with aromatase inhibitor-associated arthralgias.

    PubMed

    Galantino, Mary Lou; Desai, Krupali; Greene, Laurie; Demichele, Angela; Stricker, Carrie Tompkins; Mao, Jun James

    2012-12-01

    Arthralgia affects postmenopausal breast cancer survivors (BCSs) receiving aromatase inhibitors (AIs). This study aims to establish the feasibility of studying the impact of yoga on objective functional outcomes, pain, and health-related quality of life (HR-QOL) for AI-associated arthralgia (AIAA). Postmenopausal women with stage I to III breast cancer who reported AIAA were enrolled in a single-arm pilot trial. A yoga program was provided twice a week for 8 weeks. The Functional Reach (FR) and Sit and Reach (SR) were evaluated as primary outcomes. Pain, as measured by the Brief Pain Inventory (BPI), self-reported Patient Specific Functional Scale (PSFS), and Functional Assessment of Cancer Therapy-Breast (FACT-B) were secondary outcomes. Paired t tests were used for analysis, and 90% provided data for assessment at the end of the intervention. Participants experienced significant improvement in balance, as measured by FR, and flexibility, as measured by SR. The PSFS improved from 4.55 to 7.21, and HR-QOL measured by FACT-B also improved; both P < .05. The score for the Pain Severity subscale of the BPI reduced. No adverse events nor development or worsening of lymphedema was observed. In all, 80% of participants adhered to the home program. Preliminary data suggest that yoga may reduce pain and improve balance and flexibility in BCSs with AIAA. A randomized controlled trial is needed to establish the definitive efficacy of yoga for objective functional improvement in BCSs related to AIAA.

  8. Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole.

    PubMed

    Li, Fengjuan; Wong, Tsz Yan; Lin, Shu-mei; Chow, Simon; Cheung, Wing-hoi; Chan, Franky L; Chen, Shiuan; Leung, Lai K

    2014-11-01

    Aromatase inhibitors (AIs) have been used as adjuvant therapeutic agents for breast cancer. Their adverse side effect on blood lipid is well documented. Some natural compounds have been shown to be potential AIs. In the present study, we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole (Femara; Novartis Pharmaceuticals, East Hanover, NJ) in a cell and a mouse model. In the in vitro experimental results for aromatase inhibition, the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM, respectively. Both letrozole and luteolin appeared to be competitive inhibitors. Subsequently, an animal model was used for the comparison. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. Luteolin was given by mouth at 5, 20, and 50 mg/kg, whereas letrozole was administered by intravenous injection. Similar to letrozole, luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation. The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL, cyclin-A/D1/E, CDK2/4, and increase in that of Bax-was about the same in both treatments. The most significant disparity was on blood lipids. In contrast to letrozole, luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile. These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs.

  9. Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer

    SciTech Connect

    Sun, Bin; Hoshino, Juma; Jermihov, Katie; Marler, Laura; Pezzuto, John M.; Mesecar, Andrew D.; Cushman, Mark

    2012-07-11

    A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC{sub 50} 0.59 {mu}M) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC{sub 50} 70 nM) and 84 (IC{sub 50} 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC{sub 50} of 80 {mu}M. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC{sub 50} 1.7 {mu}M and 0.27 {mu}M, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

  10. Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer.

    PubMed

    Sun, Bin; Hoshino, Juma; Jermihov, Katie; Marler, Laura; Pezzuto, John M; Mesecar, Andrew D; Cushman, Mark

    2010-07-15

    A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC50 0.59 microM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 microM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 microM and 0.27 microM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

  11. Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors that Also Modulate Estrogen Receptors

    PubMed Central

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; O'Neill, Elizaveta; Yu, Ge; Flockhart, David A.; Cushman, Mark

    2016-01-01

    A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment. PMID:26704594

  12. Aromatase Inhibitors for Endometriosis-Associated Infertility; Do We Have Sufficient Evidence?

    PubMed Central

    Abu Hashim, Hatem

    2016-01-01

    Orally active aromatase inhibitors (AIs) have gained attention for treatment of infertile women with endometriosis in whom aromatase p450 is aberrantly expressed. This review aimed to critically appraise and summarize the available evidence concerning the use of AIs for management of endometriosis-associated infertility. PubMed was searched to May 2015 with the following key words: endometriosis, infertility and aromatase. Priority was given for randomized controlled trials (RCTs) followed by other study designs. Main outcome measures were as follows: rates of clinical pregnancy, miscarriage and live birth as well as endocrine outcomes. Eighty-two abstracts were screened and six original articles were included. A RCT demonstrated that post-operative letrozole treatment did not improve spontaneous pregnancy rate. Another RCT reported no superiority of letrozole superovulation over clomiphene citrate (each combined with intrauterine insemination) in minimalmild endometriosis and previous laparoscopic treatment. Anastrozole significantly inhibited the growth of endometriotic cells and their estrogen production in culture. In assisted reproductive technology (ART) cycles, dual suppression (Agonist/anastrozole) was tested in a pilot study with a pregnancy rate of 45% however, high pregnancy loss (30%) occurred. A retrospective study showed that letrozole may improve endometrial receptivity in endometriotic patients undergoing in vitro fertilization (IVF). An opposite view from an in vitro study showed lower estradiol production and aromatase expression in cultured granulosa cells from endometriotic women undergoing IVF and marked reduction under letrozole. In conclusion, current evidence is limited. More trials are warranted to enhance our knowledge and provide a clear and unequivocal evidence to guide our clinical management of infertile women with endometriosis using AIs. PMID:27695608

  13. Methadone: a substrate and mechanism-based inhibitor of CYP19 (aromatase).

    PubMed

    Lu, Wenjie Jessie; Bies, Robert; Kamden, Landry K; Desta, Zeruesenay; Flockhart, David A

    2010-08-01

    The peripheral conversion of testosterone to estradiol by aromatase is the primary source of endogenous estrogen in postmenopausal women. Studies indicating that placental aromatase is able to metabolize methadone to its primary metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidin (EDDP), led us to test the hypothesis that methadone is able to act as an inhibitor of aromatase. Using recombinant human CYP19, we examined the ability of methadone to bring about either reversible or mechanism-based inhibition of the conversion of testosterone to estradiol. To test for reversible inhibition, racemic methadone or its metabolite EDDP or 2-ethyl-5-methyl-3, 3-diphenylpyrroline (EMDP) was incubated for 30 min with testosterone at the K(m) (4 microM). To test for mechanism-based inhibition, microsomal preincubations were performed for up to 30 min using racemic methadone (1-1000 microM), R- or S-methadone (0.5-500 microM), or EDDP or EMDP (10 and 100 microM) followed by incubation with testosterone at a V(max) concentration (50 microM). Racemic methadone, EDDP, and EMDP did not act as competitive inhibitors of CYP19. Preincubation of methadone, EDDP, or EMDP with CYP19 resulted in time- and concentration-dependent inhibition, indicating a mechanism-based reaction that destroys CYP19 activity. The K(I) and k(inact) values for racemic methadone were calculated to be 40.6 +/- 2.8 microM and 0.061 +/- 0.001 min(-1), respectively. No stereoselectivity was observed. Methadone is metabolized by CYP19 and may act as a potent inhibitor of CYP19 in vivo. These findings may contribute to variability in methadone clearance, to drug-drug interactions, and to side effects observed in individual patients.

  14. Pharmacophore modeling and in silico screening for new P450 19 (aromatase) inhibitors.

    PubMed

    Schuster, Daniela; Laggner, Christian; Steindl, Theodora M; Palusczak, Anja; Hartmann, Rolf W; Langer, Thierry

    2006-01-01

    Cytochrome P450 19 (P450 19, aromatase) constitutes a successful target for the treatment of breast cancer. This study analyzes chemical features common to P450 19 inhibitors to develop ligand-based, selective pharmacophore models for this enzyme. The HipHop and HypoRefine algorithms implemented in the Catalyst software package were employed to create both common feature and quantitative models. The common feature model for P450 19 includes two ring aromatic features in its core and two hydrogen bond acceptors at the ends. The models were used as database search queries to identify active compounds from the NCI database.

  15. Erythema multiforme after radiotherapy with aromatase inhibitor administration in breast-conservation treatment for breast cancer.

    PubMed

    Nakatani, Kimiko; Matsumoto, Masaaki; Ue, Hironobu; Nishioka, Akihito; Tanaka, Yousuke; Kodama, Hajime; Sasaguri, Shiro; Ogawa, Yasuhiro

    2008-01-01

    Generalized eruptions associated with radiotherapy such as erythema multiforme (EM), Steven-Johnson syndrome and toxic epidermal necrolysis are uncommon reactions. A few cases of generalized eruptions during and after radiotherapy have been reported with the use of anticonvulsants and anticancer drugs. However, no reports have described mucocutaneous reactions associated with radiotherapy and concurrent use of anastrozole, an aromatase inhibitor. This report describes EM occurring after radiotherapy performed during breast-conserving treatment for breast cancer in a patient who was taking oral anastrozole.

  16. Randomized, Blinded Trial of Vitamin D3 for Treating Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS)

    PubMed Central

    Shapiro, Alice C.; Adlis, Susan A.; Robien, Kim; Kirstein, Mark N.; Liang, Shuang; Richter, Sara A.; Lerner, Rachel E.

    2017-01-01

    Purpose To evaluate the efficacy and safety of vitamin D3 at 4,000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. Methods Single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stage I-IIIA breast cancer, taking AI and experiencing AIMSS (Breast Cancer Prevention Trial Symptom Scale-Musculoskeletal Subscale ≥1.5 (BCPT-MS)) were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n=56) or 4,000 IU D3 (n=57) daily for 6 months. The primary endpoint was change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general musculoskeletal pain; joint pain; muscle stiffness; range for each question: 0=not at all to 4=extremely). Results Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. Conclusions We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL). PMID:26868123

  17. Feasibility trial of electroacupuncture for aromatase inhibitor--related arthralgia in breast cancer survivors.

    PubMed

    Mao, James J; Bruner, Deborah W; Stricker, Carrie; Farrar, John T; Xie, Sharon X; Bowman, Marjorie A; Pucci, Donna; Han, Xiaoyan; DeMichele, Angela

    2009-06-01

    Arthralgia affects postmenopausal women receiving aromatase inhibitors (AIs) for breast cancer. Given the existing evidence for electroacupuncture (EA) for treatment of osteoarthritis in the general population, this study aims to establish the feasibility of studying EA for treating AI-related arthralgia. Postmenopausal women with stage I-III breast cancer who reported AI-related arthralgia were enrolled in a single-arm feasibility trial. EA was provided twice a week for 2 weeks followed by 6 weekly treatments. The protocol was based on Chinese medicine diagnosis of "Bi" syndrome with electrostimulation of needles around the painful joint(s). Pain severity of the modified Brief Pain Inventory was used as the primary outcome. Joint stiffness, joint interference, and Patient Global Impression of Change (PGIC) were secondary outcomes. Paired t tests were used for analysis. Twelve women were enrolled and all provided data for analysis. From baseline to the end of intervention, patients reported reduction in pain severity (from 5.3 to 1.9), stiffness (from 6.9 to 2.4), and joint symptom interference (from 4.7 to 0.8), all P < .001; 11/12 considered joint symptoms "very much better" based on the PGIC. Subjects also reported significant decrease in fatigue (from 4.4 to 1.9, P = .005) and anxiety (from 7.1 to 4.8, P = .01). No infection or development or worsening of lymphedema was observed. Preliminary data establish the feasibility of recruitment and acceptance as well as promising preliminary safety and effectiveness. A randomized controlled trial is warranted to establish the efficacy of EA for AI-related arthralgia in breast cancer survivors.

  18. Serum apelin levels and body composition changes in breast cancer patients treated with an aromatase inhibitor.

    PubMed

    Salman, Tarik; Demir, Leyla; Varol, Umut; Akyol, Murat; Oflazoglu, Utku; Yildiz, Yasar; Taskaynatan, Halil; Cengiz, Hakan; Guvendi, Guven; Kucukzeybek, Yuksel; Alacacioglu, Ahmet; Tarhan, Oktay

    2016-01-01

    The adipose tissue plays a role in carcinogenesis with the adipokines it generates. Apelin is an anti-obesigenic adipokine, and assumes roles in both vascularization and tumor cell proliferation. The present study aimed to investigate changes in apelin levels, in postmenopausal breast cancer (BC) patients receiving aromatase inhibitors (AIs). Forty early-stage postmenopausal BC patients treated with AIs with no history of chemotherapy administration were included in the study. At the beginning, we measured serum apelin levels in postmenopausal BC patients who were receiving AIs and healthy women of similar age and normal body mass index (BMI) (control group). We evaluated changes in the body composition, serum lipid profile and serum apelin levels at the beginning and the 12th month through anthropometric measurements and bioelectric impedance analysis. Forty subjects with postmenopausal BC had a median age of 57 years (range 44-82)). BC patients exhibited significantly higher apelin levels and body mass index (BMI) scores compared to the control group (p=0.0001, p=0.0001, respectively). The 12th month's measurements indicated reduced apelin levels in 24 patients (60%) and increased apelin levels in 16 patients (40%) compared to the initial figures. With respect to the parameters, the patients with reduced apelin levels had significantly different waist-to-hip ratio (WHR) and fat mass scores compared to those with higher apelin levels (p=0.008, p=0.047, respectively). This study showed that postmenopausal BC patients had high levels of apelin and high BMI scores. This finding suggests that apelin promoted carcinogenesis particularly in obese individuals. The massive and metabolic changes observed in the fat tissues of the postmenopausal BC patients receiving AIs will especially affect the BC-associated outcome.

  19. Gonadal development and growth of chickens and turkeys hatched from eggs injected with an aromatase inhibitor.

    PubMed

    Burke, W H; Henry, M H

    1999-07-01

    It was the purpose of these experiments to describe gonadal development and posthatching growth of genetic female chickens and turkeys following in ovo injection of the aromatase inhibitor Fadrazole (CGS 16949A) prior to incubation. In ovo injection of Fadrazole (CGS 16949A) resulted in the development of testes-like gonads in the majority of day-old genetic female chickens and turkey poults. Ninety-eight to 99% of these birds have masculine-type male genitalia at 1 d of age. Microscopic examination of the gonads of day-old genetic female chicks hatched from Fadrazole-treated eggs showed the presence of atypical seminiferous tubules in 3 of 18 individuals and the presence of ovarian follicles in 3 of 18 individuals. No germinal elements were seen in 12 individuals. The gonads in the majority (8/11) of day-old female poults from treated eggs showed the presence of atypical seminiferous tubules. Three of 11 individuals had structures characterized as disorganized or degenerate follicles. Between the day of hatch and 6 wk, gonads in an increasing proportion of female chickens from Fadrazole-treated eggs had normal appearing ovarian follicles. A similar trend was seen in the female turkeys between hatch and 12 wk of age. There were no differences in BW of female chickens hatched from Fadrazole-treated eggs and those from control eggs between the day of hatch and 6 wk of age. The pectoral muscle mass and fat pad weights of these birds did not differ. In one experiment, the BW of female turkeys hatched from Fadrazole-treated eggs was significantly greater than that of controls and equal to that of males at 3 and 6 wk of age. Thereafter, both types of females were of equal weight and significantly lighter than males. Fadrazole treatment did not affect pectoral muscle mass of either sex of turkeys.

  20. Aromatase inhibition rapidly affects in a reversible manner distinct features of birdsong

    PubMed Central

    Alward, Beau A.; de Bournonville, Catherine; Chan, Trevor T.; Balthazart, Jacques; Cornil, Charlotte A.; Ball, Gregory F.

    2016-01-01

    Recent evidence has implicated steroid hormones, specifically estrogens, in the rapid modulation of cognitive processes. Songbirds have been a useful model system in the study of complex cognitive processes including birdsong, a naturally learned vocal behavior regulated by a discrete steroid-sensitive telencephalic circuitry. Singing behavior is known to be regulated by long-term actions of estrogens but rapid steroid modulation of this behavior has never been examined. We investigated if acute actions of estrogens regulate birdsong in canaries (Serinus canaria). In the morning, male canaries sing within minutes after light onset. Birds were injected with fadrozole, a potent aromatase inhibitor, or vehicle within 2–5 minutes after lights on to implement a within-subjects experimental design. This single injection of fadrozole reduced the motivation to sing as well as song acoustic stereotypy, a measure of consistency over song renditions, on the same day. By the next day, however, all song measures that were affected had returned to baseline. This study indicates that estrogens also act in a rapid fashion to regulate two distinct features of song, a learned vocal behavior. PMID:27573712

  1. 3D QSAR studies, pharmacophore modeling and virtual screening on a series of steroidal aromatase inhibitors.

    PubMed

    Xie, Huiding; Qiu, Kaixiong; Xie, Xiaoguang

    2014-11-14

    Aromatase inhibitors are the most important targets in treatment of estrogen-dependent cancers. In order to search for potent steroidal aromatase inhibitors (SAIs) with lower side effects and overcome cellular resistance, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of SAIs to build 3D QSAR models. The reliable and predictive CoMFA and CoMSIA models were obtained with statistical results (CoMFA: q² = 0.636, r²(ncv) = 0.988, r²(pred) = 0.658; CoMSIA: q² = 0.843, r²(ncv) = 0.989, r²(pred) = 0.601). This 3D QSAR approach provides significant insights that can be used to develop novel and potent SAIs. In addition, Genetic algorithm with linear assignment of hypermolecular alignment of database (GALAHAD) was used to derive 3D pharmacophore models. The selected pharmacophore model contains two acceptor atoms and four hydrophobic centers, which was used as a 3D query for virtual screening against NCI2000 database. Six hit compounds were obtained and their biological activities were further predicted by the CoMFA and CoMSIA models, which are expected to design potent and novel SAIs.

  2. Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

    NASA Astrophysics Data System (ADS)

    Oprea, Tudor I.; García, Angel E.

    1996-06-01

    Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/Ki), with an explained variance r2 of 0.885, and a cross-validated q2 of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q2 for one component was 0.62 and 0.61, respectively, while r2 was 0.674. We demonstrate that the predictive r2 based on the mean activity (Ym) of the training set is misleading, while the test set Ym-based predictive r2 index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.

  3. Aromatase inhibitors in obese breast cancer patients are not associated with increased plasma estradiol levels.

    PubMed

    Diorio, Caroline; Lemieux, Julie; Provencher, Louise; Hogue, Jean-Charles; Vachon, Eric

    2012-11-01

    Obesity, in postmenopausal women, has been associated to a higher breast cancer incidence and worst prognosis. Some studies suggested a decrease in aromatase inhibitors (AI) efficacy in obese postmenopausal breast cancer patients, although estradiol levels were not measured. The purpose of the present study was to verify if estradiol levels are measurable in postmenopausal women under AI. If achievable, the goal is to compare the estradiol levels in lean versus obese postmenopausal women under AI treatment for non-metastatic breast cancer. Postmenopausal women were recruited in accordance to one of these four groups: lean [body mass index (BMI) of 18-25 kg/m(2)] under AI (n = 30), obese (BMI ≥ 30 kg/m(2)) under AI (n = 30), lean AI-naïve (n = 10), and obese AI-naïve (n = 10). Lean and obese women were matched according to their age. Estradiol levels were measured in plasma using an ELISA. The Wilcoxon signed-rank test was used to assess the significance of the differences between the groups. Estradiol levels in postmenopausal women under AI varied from 0 to 94.65 pg/ml with a median value of 0.98 pg/ml. Obese AI-naïve women had higher estradiol levels than lean AI-naïve women (p = 0.03). There was no difference in estradiol levels between lean and obese women under AI (p = 0.76). Despite very low plasma levels, it is possible to measure the estradiol levels in postmenopausal women under AI treatment. Our results suggest that the known impact of obesity on recurrence risk in women under AI treatment may not be due to incomplete aromatase inhibition. Further works are needed to examine closely the aromatase-independent pathways that are linking obesity to breast cancer risk and recurrence.

  4. EVALUATION OF THE AROMATASE INHIBITOR FADROZOLE IN A SHORT-TERM REPRODUCTION ASSAY WITH THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

    EPA Science Inventory

    Cytochrome P450 aromatase is a key enzyme in vertebrate steroidogenesis, catalyzing the conversion of C19 androgens to C18 estrogens such a B-estradiol (E2). The objective of this study was to assess effects of the CYP inhibitor fadrozole on fathead minnow reproductive endocrinol...

  5. GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors.

    PubMed

    Morandi, Andrea; Martin, Lesley-Ann; Gao, Qiong; Pancholi, Sunil; Mackay, Alan; Robertson, David; Zvelebil, Marketa; Dowsett, Mitch; Plaza-Menacho, Ivan; Isacke, Clare M

    2013-06-15

    Most breast cancers at diagnosis are estrogen receptor-positive (ER(+)) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ER(+) breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRα1, are upregulated in a subset of ER(+) breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in a model of aromatase inhibitor resistance. Furthermore, GDNF-RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER(+) cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer.

  6. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy

    PubMed Central

    Derzko, C.; Elliott, S.; Lam, W.

    2007-01-01

    Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements—all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement—most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)—may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be

  7. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy.

    PubMed

    Derzko, C; Elliott, S; Lam, W

    2007-12-01

    Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements-all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement-most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)-may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be

  8. Effects of a short-term exposure to the aromatase inhibitor fadrozole on steroid production and gene expression in the ovary of female fathead minnows (Pimephales promelas)

    EPA Science Inventory

    Cytochrome P450 aromatase is a steriodogenic enzyme that converts C19 androgens to C18 estrogens and is critical for normal reproduction in females. Fadrozole is a well-studied aromatase inhibitor that has been shown to suppress estrogen production in the ovaries of fish. Howev...

  9. Effects of a short-term exposure to the aromatase inhibitor fadrozole on steroid production and gene expression in the ovary of female fathead minnows (Pimephales promelas)

    EPA Science Inventory

    Cytochrome P450 aromatase is a steriodogenic enzyme that converts C19 androgens to C18 estrogens and is critical for normal reproduction in females. Fadrozole is a well-studied aromatase inhibitor that has been shown to suppress estrogen production in the ovaries of fish. Howev...

  10. Review of hormone-based treatments in postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors and fulvestrant

    PubMed Central

    Kümler, Iben; Knoop, Ann S; Jessing, Christina A R; Ejlertsen, Bent; Nielsen, Dorte L

    2016-01-01

    Background Endocrine therapy constitutes a central modality in the treatment of oestrogen receptor (ER)-positive advanced breast cancer. Purpose To evaluate the evidence for endocrine treatment in postmenopausal patients with advanced breast cancer focusing on the aromatase inhibitors, letrozole, anastrozole, exemestane and fulvestrant. Methods A review was carried out using PubMed. Randomised phase II and III trials reporting on ≥100 patients were included. Results 35 trials met the inclusion criteria. If not used in the adjuvant setting, a non-steroid aromatase inhibitor was the optimal first-line option. In general, the efficacy of the different aromatase inhibitors and fulvestrant was similar in tamoxifen-refractory patients. A randomised phase II trial of palbociclib plus letrozole versus letrozole alone showed significantly increased progression-free survival (PFS) when compared with endocrine therapy alone in the first-line setting (20.2 vs 10.2 months). Furthermore, the addition of everolimus to exemestane in the Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) study resulted in an extension of median PFS by 4.5 months after recurrence/progression on a non-steroid aromatase inhibitor. However, overall survival was not significantly increased. Conclusion Conventional treatment with an aromatase inhibitor or fulvestrant may be an adequate treatment option for most patients with hormone receptor-positive advanced breast cancer. Mammalian target of rapamycin (mTOR) inhibition and cyclin-dependent kinase 4/6 (CDK4/6) inhibition might represent substantial advances for selected patients in some specific settings. However, there is an urgent need for prospective biomarker-driven trials to identify patients for whom these treatments are cost-effective. PMID:27843622

  11. Gas chromatography-mass spectrometric study of 19-oxygenation of the aromatase inhibitor 19-methylandrostenedione with human placental microsomes.

    PubMed

    Numazawa, Mitsuteru; Nagaoka, Masao; Handa, Wakako; Yamada, Akane

    2006-06-01

    To gain insight into the catalytic function of aromatase, we studied 19-oxygenation of 19-methyl-substituted derivative of the natural substrate androstenedione (AD), compound 1, with human placental aromatase by use of gas chromatography-mass spectrometry (GC-MS). Incubation of the 19-methyl derivative 1 with human placental microsomes in the presence of NADPH under an aerobic condition did not yield a detectable amount of [19S]19-hydroxy product 2 or its [19R]-isomer 3 when the product was analyzed as the bis-methoxime-trimethylsilyl (TMS) derivative by GC-MS; moreover, the production of estrogen was not detected as the bis-TMS derivative of estradiol (detection limit: about 3 ng and 10 pg per injection for the 19-ol and estradiol, respectively). The results reveal that the 19-methyl steroid 1 does not serve as a substrate of aromatase, although it does serve as a powerful inhibitor of the enzyme.

  12. Structure-activity relationships of 2alpha-substituted androstenedione analogs as aromatase inhibitors and their aromatization reactions.

    PubMed

    Numazawa, Mitsuteru; Handa, Wakako; Hasegawa, Chie; Takahashi, Madoka

    2005-12-01

    Aromatase catalyzes the conversion of androstenedione (1a, AD) to estrone through three sequential oxygenations of the 19-methyl group. To gain insight into the spatial nature of the AD binding (active) site of aromatase in relation to the catalytic function of the enzyme, we tested for the ability of 2alpha-substituted (halogeno, alkyl, hydroxy, and alkoxy) ADs (1b-1i) to inhibit aromatase in human placental microsomes as well as their ability to serve as a substrate for the enzyme. All of the steroids inhibited the enzyme in a competitive manner with the apparent K(i)'s ranging from 45 to 1150 nM. 2alpha-Halogeno (F, Cl, and Br) and 2alpha-alkyl (CH3 and CH2CH3) steroids 1b-1f were powerful to good inhibitors (Ki=45-171 nM) whereas steroids 1g-1i, having an oxygen function (hydroxy or alkoxy) at C-2alpha, were poor inhibitors (Ki=670-1150 nM). Aromatization of some of the steroids with placental microsomes was analyzed by gas chromatography-mass spectrometry, indicating that the aromatization rate of the bromide 1d was about two-fold that of the natural substrate AD and that of 2alpha-methoxide 1h was similar to that of AD. Kinetic analysis of the aromatization of androgens revealed that a good substrate was not essentially a good inhibitor for aromatase.

  13. Cardiovascular Health among Black and White Breast Cancer Patients Initiating Aromatase Inhibitor Therapy.

    PubMed

    Gallicchio, Lisa; Calhoun, Carla; Riseberg, David; Helzlsouer, Kathy

    2017-03-01

    The purpose of this study was to compare the cardiovascular health of Black and White breast cancer patients undergoing adjuvant treatment. Baseline data from a cohort study of Black (n = 45) and White (n = 101) breast cancer patients initiating aromatase inhibitor treatment were analyzed. Participants had a cardiovascular health assessment, including carotid intimal medial thickness measurement, donated a blood sample, and completed a questionnaire. Atherosclerotic cardiovascular disease (ASCVD) event risk scores were calculated. Compared to their White counterparts, the Black patients had a significantly higher median ASCVD risk score (p = 0.009) and had a higher number of CVD risk factors (p < 0.05). Black patients were also more likely to have hypertension, diabetes, or to be obese than the White participants. The prevalence of cardiovascular disease and cardiovascular disease risk factors among Black and White breast cancer patients is high, and racial disparities exist which may have treatment implications. © 2016 Wiley Periodicals, Inc.

  14. Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

    NASA Astrophysics Data System (ADS)

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-12-01

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

  15. Induction of female-to-male sex change in adult zebrafish by aromatase inhibitor treatment.

    PubMed

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-12-02

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

  16. Hybrid flavan-chalcones, aromatase and lipoxygenase inhibitors, from Desmos cochinchinensis.

    PubMed

    Bajgai, Santi Prasad; Prachyawarakorn, Vilailak; Mahidol, Chulabhorn; Ruchirawat, Somsak; Kittakoop, Prasat

    2011-11-01

    Hybrid flavan-chalcones, desmosflavans A (1) and B (2), together with three known compounds, cardamonin (3), pinocembrin (4) and chrysin (5), were isolated from leaves of Desmos cochinchinensis. Cardamonin (3) and chrysin (5) exhibited potent antioxidant activity with 15.0 and 12.2 ORAC units. Desmosflavans A (1) and B (2), pinocembrin (4), and chrysin (5) were found to be inhibitors of aromatase with respective IC50 values of 1.8, 3.3, 0.9, and 0.8 μM. Desmosflavan A (1) inhibited lipoxygenase with the IC50 value of 4.4 μM. Desmosflavan A (1) exhibited cytotoxic activity with IC50 values of 0.29-3.75 μg/mL, while desmosflavan B (2) showed IC50 values of 1.71-27.0 μg/mL.

  17. Prevention of aromatase inhibitor-induced bone loss with alendronate in postmenopausal women: The BATMAN Trial.

    PubMed

    Lomax, Anna J; Yee Yap, Saw; White, Karen; Beith, Jane; Abdi, Ehtesham; Broad, Adam; Sewak, Sanjeev; Lee, Chooi; Sambrook, Philip; Pocock, Nicholas; Henry, Margaret J; Yeow, Elaine G; Bell, Richard

    2013-12-01

    Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures. In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70 mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1 mg daily), calcium and vitamin D. All osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm. At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate. There was a significant drop in lumbar spine (-5.4%) and hip (-4.5%) mean BMD, in the normal BMD group, none of whom received alendronate. Fracture data will be presented. In postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

  18. Growth Hormone With Aromatase Inhibitor May Improve Height in CYP11B1 Congenital Adrenal Hyperplasia.

    PubMed

    Hawton, Katherine; Walton-Betancourth, Sandra; Rumsby, Gill; Raine, Joseph; Dattani, Mehul

    2017-02-01

    With an estimated prevalence of 1 in 100 000 births, 11β-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in CYP11B1 Clinical features include virilization, early gonadotropin-independent precocious puberty, hypertension, and reduced stature. The current mainstay of management is with glucocorticoids to replace deficient steroids and to minimize adrenal sex hormone overproduction, thus preventing virilization and optimizing growth. We report a patient with CAH who had been suboptimally treated and presented to us at 6 years of age with precocious puberty, hypertension, tall stature, advanced bone age, and a predicted final height of 150 cm. Hormonal profiles and genetic analysis confirmed a diagnosis of 11β-hydroxylase deficiency. In addition to glucocorticoid replacement, the patient was commenced on growth hormone and a third-generation aromatase inhibitor, anastrozole, in an attempt to optimize his growth. After the initiation of this treatment, the patient's growth rate improved significantly and bone age advancement slowed. The patient reached a final height of 177.5 cm (0.81 SD score), 11.5 cm above his mid-parental height. This patient is only the second reported case of the use of an aromatase inhibitor in combination with growth hormone to optimize height in 11β-hydroxylase-deficient CAH. This novel treatment proved to be highly efficacious, with no adverse effects. It may therefore provide a promising option to promote growth in exceptional circumstances in individuals with 11β-hydroxylase deficiency presenting late with advanced skeletal maturation and consequent short stature.

  19. Acute Stress Differentially Affects Aromatase Activity in Specific Brain Nuclei of Adult Male and Female Quail

    PubMed Central

    Cornil, Charlotte A.; Balthazart, Jacques

    2011-01-01

    The rapid and temporary suppression of reproductive behavior is often assumed to be an important feature of the adaptive acute stress response. However, how this suppression operates at the mechanistic level is poorly understood. The enzyme aromatase converts testosterone to estradiol in the brain to activate reproductive behavior in male Japanese quail (Coturnix japonica). The discovery of rapid and reversible modification of aromatase activity (AA) provides a potential mechanism for fast, stress-induced changes in behavior. We investigated the effects of acute stress on AA in both sexes by measuring enzyme activity in all aromatase-expressing brain nuclei before, during, and after 30 min of acute restraint stress. We show here that acute stress rapidly alters AA in the male and female brain and that these changes are specific to the brain nuclei and sex of the individual. Specifically, acute stress rapidly (5 min) increased AA in the male medial preoptic nucleus, a region controlling male reproductive behavior; in females, a similar increase was also observed, but it appeared delayed (15 min) and had smaller amplitude. In the ventromedial and tuberal hypothalamus, regions associated with female reproductive behavior, stress induced a quick and sustained decrease in AA in females, but in males, only a slight increase (ventromedial) or no change (tuberal) in AA was observed. Effects of acute stress on brain estrogen production, therefore, represent one potential way through which stress affects reproduction. PMID:21878510

  20. Potential of aromatase inhibitors for ovulation and superovulation induction in infertile women.

    PubMed

    Mitwally, Mohamed F M; Casper, Robert F

    2006-01-01

    For almost half a century, the first-line treatment for ovulation induction in cases of anovulation, unexplained infertility, or mild male factor has been clomifene (clomiphene citrate). Clomifene is an effective and safely used oral agent, but is known to have relatively common antiestrogenic endometrial and cervical mucous adverse effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancies with clomifene compared with natural cycles. These drawbacks are mainly a result of the extended antiestrogenic effect of clomifene as a result of its accumulation in the body (clomifene isomers have a half-life of several days up to few weeks). Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of clomifene. Over the last few years several published studies, both controlled and noncontrolled, compared clomifene and treatment with aromatase inhibitors (AIs), either alone or in combination with gonadotropins, for ovulation induction or augmentation. These studies found AIs as effective as clomifene in inducing ovulation, with the major advantage of absence of any antiestrogenic adverse effects. Several other major advantages of AIs include the lower serum estrogen production per developing follicle resulting in more physiological estrogen levels around the time of ovulation and good pregnancy rates with a lower incidence of multiple pregnancy than with clomifene. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of gonadotropins required for optimal follicle recruitment and improve the response to gonadotropin stimulation in poor responders. Such preliminary evidence suggests that AIs may replace clomifene in the future because of similar efficacy with a reduced adverse-effect profile. However, we believe that definitive studies in the form of

  1. Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia-Inducible Factor 1 (HIF-1) in Aromatase Inhibitor Resistant Breast Cancer

    DTIC Science & Technology

    2013-10-01

    obese and overweight patients with ER+ breast cancer to neoadjuvant aromatase inhibitor therapy. My role in this clinical trial is to analyze HIF-1 and...with drug resistance in different cancer cell types, including chronic myeloid leukemia cells (Zhao et al. Oncogene. 2010), gastric cancer cells (Liu...Hypoxia- Inducible Factor 1 (HIF-1) in Aromatase Inhibitor Resistant Breast Cancer PRINCIPAL INVESTIGATOR: Armina Kazi CONTRACTING

  2. Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts

    PubMed Central

    Fearns, Antony; Martin, Lesley-Ann; Chiarugi, Paola; Isacke, Clare M.; Morandi, Andrea

    2016-01-01

    The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis. PMID:27602955

  3. A retrospective study on screening and management of osteoporosis in breast cancer women treated with aromatase inhibitors in Libya

    PubMed Central

    Abushwereb, Hanan Saaddedin; Elhabash, M.; Elhamshari, S.; Eshaefi, H.

    2016-01-01

    Summary Negative health effects of aromatase inhibitors (AI) treatments on bones such as osteoporosis are evidenced. This impact of the aromatase inhibitors on bone. This study aimed to improve the medical assistance given to patients under AI treatment to minimize secondary osteoporosis. Fifty Libyan postmenopausal women treated with AI to fight breast cancer were selected from attendants Tripoli Medical Center (TMC), Oncology Department during year 2014. A closed questionnaire was requested from each women including data about age, age at AI therapy, and types of AI, age at bone densitometry measurement, onset and symptoms of osteoporosis, treatment of osteoporosis and measurement of vitamin D and calcium supplement given. The study revealed a poor consideration given to apply the recommendation in cases suffering osteoporosis events. Our results suggest an active implementation of the guidelines concerning the high corporation levels that should be done between oncologist, specialist in osteoporosis, and patients to offer reliable diagnostic and post-therapy follow up. PMID:28228779

  4. A retrospective study on screening and management of osteoporosis in breast cancer women treated with aromatase inhibitors in Libya.

    PubMed

    Abushwereb, Hanan Saaddedin; Elhabash, M; Elhamshari, S; Eshaefi, H

    2016-01-01

    Negative health effects of aromatase inhibitors (AI) treatments on bones such as osteoporosis are evidenced. This impact of the aromatase inhibitors on bone. This study aimed to improve the medical assistance given to patients under AI treatment to minimize secondary osteoporosis. Fifty Libyan postmenopausal women treated with AI to fight breast cancer were selected from attendants Tripoli Medical Center (TMC), Oncology Department during year 2014. A closed questionnaire was requested from each women including data about age, age at AI therapy, and types of AI, age at bone densitometry measurement, onset and symptoms of osteoporosis, treatment of osteoporosis and measurement of vitamin D and calcium supplement given. The study revealed a poor consideration given to apply the recommendation in cases suffering osteoporosis events. Our results suggest an active implementation of the guidelines concerning the high corporation levels that should be done between oncologist, specialist in osteoporosis, and patients to offer reliable diagnostic and post-therapy follow up.

  5. Comparison of Subjective and Objective Hot Flash Measures Over Time Among Breast Cancer Survivors Initiating Aromatase Inhibitor Therapy

    PubMed Central

    Otte, Julie L.; Flockhart, David; Storniolo, Anna Maria; Schneider, Bryan; Azzouz, Faouzi; Lemler, Suzanne; Jeter, Stacie; Carpenter, Janet S.; Hayes, Daniel; Stearns, Vered; Henry, N. Lynn; Nguyen, Anne; Hayden, Jill; Wright, Laurie

    2009-01-01

    Objective Hot flashes are valuable indicators of physiologic condition and drug effect; however, subjective and objective measures do not always agree. No study has examined both subjective and objective hot flashes in women prescribed aromatase inhibitors. The study (1) compared subjective and objective hot flash measures, (2) examined changes in subjective and objective hot flashes over time, and (3) evaluated predictors of change in hot flashes in aromatase inhibitor-treated women. Design Subjects (n=135) were enrolled in a randomized clinical trial comparing exemestane and letrozole for the treatment of breast cancer. Hot flashes were assessed prior to starting drug and 1, 3, and 6 months later. Subjects wore a sternal skin conductance monitor for ≥ 24 hours at each time point. With each perceived hot flash, women pressed an event button and rated intensity and bother in a paper diary. Results Subjects were a mean age of 60 years and mainly Caucasian (92%). Across time points, monitor hot flashes were (1) significantly more frequent than diary and/or event button flashes (p<.05) and (2) moderately correlated with subjective measures (.35< r <.56). Monitor hot flashes did not significantly change over time with aromatase inhibitor therapy, whereas both diary and event button frequency significantly varied but in dissimilar patterns (51% non-linear). No consistent predictors of hot flashes across measures or time points were identified. Conclusions Findings indicated dissimilarities between subjective and objective measures of hot flashes. Despite statistical significance, there was little clinically meaningful change in hot flashes after initiating aromatase inhibitor therapy. PMID:19455068

  6. Novel highly potent and selective nonsteroidal aromatase inhibitors: synthesis, biological evaluation and structure-activity relationships investigation.

    PubMed

    Gobbi, Silvia; Zimmer, Christina; Belluti, Federica; Rampa, Angela; Hartmann, Rolf W; Recanatini, Maurizio; Bisi, Alessandra

    2010-07-22

    In further pursuing our search for potent and selective aromatase inhibitors, a new series of molecules was designed and synthesized, exploring possible structural modifications of a previously identified xanthone scaffold. Among them, highly potent compounds, with inhibitory activity in the low nanomolar range, were found. In particular, substitution of the heterocyclic oxygen atom in the xanthone core by a sulfur atom and/or increase in structure flexibility seemed to be favorable for the interaction with the enzyme.

  7. Breast Cancer, Aromatase Inhibitor Therapy, and Sexual Functioning: A Pilot Study of the Effects of Vaginal Testosterone Therapy

    PubMed Central

    Dahir, Melissa; Travers-Gustafson, Dianne

    2014-01-01

    Introduction Women with breast cancer have better cancer-related outcomes with the use of aromatase inhibitors (AIs), but the physiological suppression of estradiol can negatively affect sexual functioning because of unpleasant urogenital and vaginal symptoms. Local health care practitioners have observed that the benefits of vaginal testosterone in allaying these unpleasant symptoms in women with breast cancer are similar to the benefits of vaginal estrogen in women without breast cancer. Aim The aim of this study was to evaluate the effects of using a daily vaginal testosterone cream on the reported sexual health quality of life in women with breast cancer taking AI therapy. Methods Thirteen postmenopausal women with breast cancer on AI therapy and experiencing symptoms of sexual dysfunction were recruited from an oncology practice. The women were prescribed a 300 μg testosterone vaginal cream daily for 4 weeks. During the first study visit, a vaginal swab was obtained to rule out the presence of Candida species or Gardnerella vaginalis in participants. Women with positive vaginal swabs were treated prior to starting the vaginal testosterone therapy. Main Outcome Measure  The Female Sexual Function Index (FSFI) survey, measuring female sexual health quality of life, was administered during the first study visit and at the final study visit, after completing testosterone therapy. Results Twelve patients completed 4 weeks of daily vaginal testosterone therapy. When compared with baseline FSFI scores, there was a statistically significant improvement for individual domain scores of desire (P = 0.000), arousal (P = 0.002), lubrication (P = 0.018), orgasm (P = 0.005), satisfaction (P = 0.001), and pain (P = 0.000). Total domain scores reflecting sexual health quality of life also improved when compared with baseline (P = 0.000). Conclusions The use of a compounded testosterone vaginal cream applied daily for 4 weeks improves reported sexual health quality of life

  8. The aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) reduces disinhibitory behavior in intact adult male rats treated with a high dose of testosterone.

    PubMed

    Svensson, Anders I

    2010-01-20

    Anabolic androgenic steroids and high testosterone doses have been reported to induce impulsive behavior in man and behavioral disinhibition in rats. The purpose of the present study was to investigate whether aromatization of testosterone to estradiol is of importance for the behavioral disinhibiting effect of a high testosterone dose in adult male rats. Testosterone administered via five testosterone-filled silastic capsules implanted subcutaneously (s.c.) to non-castrated, group-housed rats for six days induced behavioral disinhibition in a modified Vogel's drinking conflict model and yielded supraphysiological serum levels of testosterone and increased accessory sex organ weights. Moreover, concurrent administration of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD; 60 mg/kg/day s.c.) decreased behavioral disinhibition in testosterone-treated rats (without affecting accessory sex organ weights) while behavior was not significantly affected in sham-treated animals. Since some reports indicate that ATD, in addition to inhibit aromatase, also may affect the binding of testosterone to the androgen receptor, the effect of the non-steroidal androgen receptor antagonist flutamide was investigated. Flutamide treatment did not affect disinhibited behavior in testosterone-treated rats. However, in sham-treated animals, flutamide (50mg/kg/day) produced behavioral disinhibition. These results suggest that estradiol is of importance in the mechanisms underlying behavioral disinhibition in non-castrated rats treated with a high testosterone dose. Speculatively, aromatization may be involved in pro-impulsive effects of high testosterone doses in humans.

  9. Exercise intervention in breast cancer patients with aromatase inhibitor-associated arthralgia: a pilot study.

    PubMed

    DeNysschen, C A; Burton, H; Ademuyiwa, F; Levine, E; Tetewsky, S; O'Connor, T

    2014-07-01

    Aromatase inhibitors (AIs) block estrogen synthesis and are commonly used as adjuvant treatments for breast cancer patients. A common side effect is joint pain. This was a pilot study to examine implementation of an exercise program in reducing joint pain and improving quality of life (QoL) and functional performance in breast cancer patients treated with AIs. Twenty-six participants completed an 8-week, home-based program that combined upper and lower body resistance exercises with self-selected aerobic exercises. We measured: (1) anthropometry (2) functional performance (grip strength, biceps curl to exhaustion, and sit-to-stand and cardiovascular endurance (3-min step test). Joint pain and QoL were assessed using self-administered surveys. Participants reported a significantly lower number of painful joints, an improvement in QoL and a reduction in depressive symptoms. Significant improvements in grip strength, biceps curl, and sit-to-stand (by 14%, 51% and 15% respectively) were also observed. However, we found no significant changes in cardiovascular endurance or in anthropometric measures. An 8-week, home-based exercise program may provide potential benefit to the breast cancer patients undergoing AI treatment by reducing joint pain, improving functional performance and QoL, and reducing depressive symptoms. Further studies are needed to confirm these results.

  10. Postmenopausal women with hormone receptor-positive breast cancer: balancing benefit and toxicity from aromatase inhibitors.

    PubMed

    Ingle, James N

    2013-08-01

    Extensive clinical trial experience is available for aromatase inhibitors (AIs) in postmenopausal women upon which to evaluate the balance of potential benefit and toxicities. A meta-analysis revealed an advantage for AIs over tamoxifen in the monotherapy setting for recurrence but not breast cancer mortality, and an advantage in both of these parameters for switching to an AI after several years of tamoxifen. Importantly, no indication of a deleterious effect of AIs was identified in terms of death without recurrence in these meta-analyses. Regarding serious adverse events (AEs), there are data indicating an increase in cardiovascular AEs and bone fractures but a lower incidence of thromboembolic phenomena and endometrial cancer with AIs vis-à-vis tamoxifen. There does not appear to be a difference in cerebrovascular AEs. Musculoskeletal AEs are the most common clinically important AEs as they are the most common cause of discontinuation of therapy, which can have an adverse effect on outcomes. The balance of benefit and toxicity favors the use of AIs in the adjuvant setting but the absolute benefit from AIs can be decreased in patients with advancing age or increasing comorbidities.

  11. Drug withdrawal in women with progressive metastatic breast cancer while on aromatase inhibitor therapy.

    PubMed

    Chavarri-Guerra, Y; Higgins, M J; Szymonifka, J; Cigler, T; Liedke, P; Partridge, A; Ligibel, J; Come, S E; Finkelstein, D; Ryan, P D; Goss, P E

    2014-11-25

    Acquiring resistance to endocrine therapy is common in metastatic hormone-receptor-positive breast cancer (MBC). These patients most often transition either to next-line endocrine therapy or to systemic chemotherapy. However, withdrawal of endocrine therapy and observation as is selectively practiced in prostate cancer is another potential strategy for breast cancer patients. A prospective, single-arm phase II trial of aromatase inhibitor (AI) withdrawal was performed in women with MBC, who had disease progression on AI therapy. The primary objective was to estimate the clinical benefit rate (defined as complete or partial response, or stable disease for at least 24 weeks, by RECIST criteria). Participants were monitored clinically and radiographically off all therapy at 8, 16 and 24 weeks after treatment and every 12 weeks thereafter until disease progression. Twenty-four patients (of 40 intended) were enrolled when the study was closed due to slow accrual. Clinical benefit rate overall was 46% (95% CI 26% to 67%). Median progression-free survival from time of AI withdrawal was 4 months. Two patients have remained progression free, off all treatment, for over 60 months. Despite suboptimal patient accrual, our results suggest that selected patients with metastatic breast cancer progressing on AI therapy can experience disease stabilisation and a period of observation after AI withdrawal. A randomised phase II trial is planned.

  12. Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy.

    PubMed

    Waltman, Nancy L; Ott, Carol D; Twiss, Janice J; Gross, Gloria J; Lindsey, Ada M

    2009-01-01

    Breast cancer survivors (BCSs) on aromatase inhibitor (AI) therapy often experience musculoskeletal symptoms (joint pain and stiffness, bone and muscle pain, and muscle weakness), and these musculoskeletal symptoms may be related to low serum levels of vitamin D. The primary purpose of this pilot exploratory study was to determine whether serum levels of 25-hydroxyvitamin D (25[OH]D) concentration were below normal (<30 ng/mL) in 29 BCSs on AI therapy and if musculoskeletal symptoms were related to these low vitamin D levels. The mean (SD) serum 25(OH)D level was 25.62 (4.93) ng/mL; 86% (n = 25) had levels below 30 ng/mL. Patients reported muscle pain in the neck and back, and there was a significant inverse correlation between pain intensity and serum 25(OH)D levels (r = -0.422; P < .05 [2 tailed]). This sample of BCSs taking AIs had below normal levels of serum 25(OH)D despite vitamin D supplements. This is one of the few studies to document a significant relationship between vitamin D levels and muscle pain in BCSs on AI therapy. Findings from this pilot study can be used to inform future studies examining musculoskeletal symptoms in BCSs on AI therapy and relationships with low serum levels of vitamin D.

  13. Inflammatory cytokines and aromatase inhibitor-associated musculoskeletal syndrome: a case–control study

    PubMed Central

    Henry, N L; Pchejetski, D; A'Hern, R; Nguyen, A T; Charles, P; Waxman, J; Li, L; Storniolo, A M; Hayes, D F; Flockhart, D A; Stearns, V; Stebbing, J

    2010-01-01

    Background: The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately 50% of AI-treated patients. Inflammatory mediators are associated with oestrogen signalling and may change with oestrogen depletion. We hypothesised that AIMSS may be associated with changes in circulating inflammatory markers. Methods: Patients with breast cancer were enroled in a trial of adjuvant AI therapy. Changes in pain and function during therapy were assessed prospectively. We selected 30 cases with AIMSS and 22 controls without AIMSS, matched for demographics and prior therapy. Serum samples collected at baseline and during treatment were assayed for multiple inflammatory cytokines and lipid mediators using multiplex assays. Results: Before AI therapy, mean serum concentrations of 6 of 36 assayed factors were statistically significantly lower in cases than controls (all P<0.003). No statistically significant changes during AI therapy relative to pre-treatment were observed between cases and controls for any of the inflammatory markers tested. Conclusion: AIMSS is probably not associated with a systemic inflammatory response. Pre-treatment cytokine levels may predict for development of AIMSS. PMID:20606683

  14. Sensitivity of New Zealand mudsnail Potamopyrgus antipodarum (Gray) to a specific aromatase inhibitor.

    PubMed

    Gust, M; Garric, J; Giamberini, L; Mons, R; Abbaci, K; Garnier, F; Buronfosse, T

    2010-03-01

    The freshwater prosobranch Potamopyrgus antipodarum (Molluska, Hydrobiidea, Smith 1889) has been proposed as a suitable species to assess the impact of endocrine disrupting compounds (EDC) in aquatic ecosystems. Steroid hormone biosynthesis pathway is potentially an important target for EDC, and vertebrate-like sex steroids seem to play a functional role in the control of mollusk reproduction. To assess the response and the sensitivity of P. antipodarum to disrupters of the steroid hormone biosynthesis pathway, we have experienced the action of a specific vertebrate aromatase inhibitor, fadrozole, acting on 17beta-estradiol synthesis in two separate 28 and 42d exposures. Fadrozole had effects consistent with the expected mechanism of action. A decrease of the reproduction parameters (such as on the number of neonates and number of embryos in the brood pouch) in a dose-dependant manner was observed. The steroids levels were also impaired with the ratio 17beta-estradiol/testosterone decreased by half in exposed snails. This shift of the steroids balance was accompanied by some alteration in the gonads histology and immunohistochemistry in fadrozole-exposed snails. This study highlights the value role of P. antipodarum as a test species for assessing EDC effects in aquatic wildlife.

  15. Skeletal adverse effects with aromatase inhibitors in early breast cancer: evidence to date and clinical guidance

    PubMed Central

    Servitja, Sonia; Martos, Tamara; Rodriguez Sanz, Maria; Garcia-Giralt, Natalia; Prieto-Alhambra, Daniel; Garrigos, Laia; Nogues, Xavier

    2015-01-01

    Aromatase inhibitors (AIs) are routinely used in the adjuvant treatment of women with hormone receptor-positive early breast cancer. Patients who receive AIs have an increased risk of bone loss and arthralgia compared with those treated with tamoxifen. In addition to the effects of AIs, the population of women with early breast cancer has a high prevalence of 25-hydroxyvitamin D (25(OH)D) insufficiency. In our experience 88% of patients had concentrations lower than 30 ng/ml. Vitamin D supplementation should be adapted to the baseline concentration. Another relevant finding in our research program was the close relationship between 25(OH)D levels and intensity of AI-related arthralgia (AIrA). A target concentration of 40 ng/ml 25(OH)D may prevent development of AIrA. We also demonstrate that AIrA is genetically determined: single nucleotide polymorphisms located in genes encoding key factors for the metabolism of estrogens and vitamin D (CYP17A1, VDR, and CYP27B1) are associated with self-reported arthralgia during AI therapy. We recommend establishing an individualized protocol of bone-health surveillance based on baseline and evolutionary clinical variables. PMID:26327926

  16. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis

    PubMed Central

    Zhao, Xihe; Liu, Lei; Li, Kai; Li, Wusheng; Zhao, Li; Zou, Huawei

    2015-01-01

    The third-generation aromatase inhibitors (AIs: anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancer complementing chemotherapy and surgery. Because of the absence of direct head-to-head comparisons of these AIs, an indirect comparison is needed for individual treatment choice. In this network systemic assessment, the cardiovascular (CV) side effects in using anastrozole, letrozole, and exemestane based on original studies on AIs vs placebo or tamoxifen were compared. We integrated all available direct and indirect evidences. The odds ratio (OR) of severe CV events for indirect comparisons between exemestane and anastrozole was 1.41 (95% confidence interval [CI] =0.49–2.78), letrozole and anastrozole was 1.80 (95% CI =0.40–3.92), and letrozole and exemestane was 1.46 (95% CI =0.34–3.4). OR of subgroup risk for AIs and tamoxifen were all >1 except for thrombolism risk subgroup. The results showed that the total and severe CV risk ranking is letrozole, exemestane, and anastrozole in descending order. None of the AIs showed advantages in CV events than tamoxifen except for thromboembolism event incidence. PMID:26491345

  17. SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

    PubMed Central

    Wang, Yuanzhong; Zhou, Dujin; Phung, Sheryl; Warden, Charles; Rashid, Rumana; Chan, Nymph; Chen, Shiuan

    2017-01-01

    Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer. PMID:28174265

  18. A Pilot Study of Website Information Regarding Aromatase Inhibitors: Dietary Supplement Interactions

    PubMed Central

    McDermott, Cara L.; Hsieh, Angela A.; Sweet, Erin S.; Tippens, Kimberly M.

    2011-01-01

    Abstract Objectives Patients who have hormone receptor–positive breast cancer and who are taking aromatase inhibitors (AIs) should understand the benefits and risks of concomitant dietary supplement (DS) use. The International Society for Integrative Oncology (SIO) encourages patients to discuss DS use with their health care practitioners. The objective was to conduct a pilot study rating Internet websites from the perspective of health care practitioners for information about AI–DS interactions. Design Five (5) Internet websites suggested by SIO were evaluated using the DISCERN instrument rating tool. The available AI–DS information on these websites was rated by 4 evaluators: 2 naturopathic doctors, 1 oncology pharmacy resident, and a pharmacy student. Results The overall rankings ranged from 1.6 to 3.9, with considerable variability in the type of information available from the websites. The interevaluator rankings of the websites ranged from 0.44 to 0.89. The evaluators consistently found the most reliable, unbiased, and comprehensive information on AI–DS interactions at the Natural Medicines Comprehensive Database and Memorial Sloan-Kettering Cancer Center websites. However, more than one database was needed for provision of optimal patient information on AI–DS interactions. Conclusions In order to effectively advise patients regarding AI–DS interactions, more than one website should be evaluated to assess the potential efficacy and safety of DS in women whose breast cancer is being treated with an AI. PMID:22087614

  19. Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor.

    PubMed Central

    Zilembo, N.; Noberasco, C.; Bajetta, E.; Martinetti, A.; Mariani, L.; Orefice, S.; Buzzoni, R.; Di Bartolomeo, M.; Di Leo, A.; Laffranchi, A.

    1995-01-01

    The androstenedione derivative, exemestane (FCE 24304), is a new orally active irreversible aromatase inhibitor. Fifty-six post-menopausal advanced breast cancer patients entered this study to evaluate the activity of four low exemestane doses in reducing oestrogen levels. The drug's tolerability and clinical efficacy were also assessed. Exemestane was orally administered to four consecutive groups at daily doses of 25, 12.5, 5 and 2.5 mg, and the changes in oestrogen, gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate levels were evaluated. Drug selectivity was studied by measuring 17-hydroxycorticosteroid urinary levels. After 7 days of treatment, mean oestrone and oestradiol levels had decreased by respectively 64% and 65% (a decrease which was maintained over time); in the 2.5 mg group, oestrone sulphate levels also decreased by 74%. Gonadotrophin levels were significantly higher, whereas no changes in the other serum hormone levels or any interference with adrenal synthesis were detected. Treatment tolerability was satisfactory: nausea and dyspepsia were reported in 16% of patients. The overall objective response rate was 18%. In conclusion, exemestane is effective in reducing oestrogen levels at all of the tested doses and shows interesting clinical activity. PMID:7547212

  20. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    PubMed

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.

  1. Menopausal-type symptoms among breast cancer patients on aromatase inhibitor therapy.

    PubMed

    Gallicchio, L; MacDonald, R; Wood, B; Rushovich, E; Helzlsouer, K J

    2012-08-01

    To examine self-reported menopausal-type symptoms among breast cancer patients on aromatase inhibitors (AIs) compared to women of the same age who had not been diagnosed with cancer, and to determine whether the percentage of breast cancer patients experiencing these symptoms changed over the first 6 months of AI treatment. Data from a 6-month cohort study of 100 breast cancer patients initiating AI therapy and of 200 women of a similar age without a history of cancer were analyzed. At baseline (prior to the initiation of AI therapy among the breast cancer patients), 3 months, and 6 months, a comprehensive questionnaire was administered to participants that ascertained data on the experiencing of specific menopausal-type symptoms. The data showed statistically significant increases in the prevalence of certain symptoms from baseline to either follow-up point among the breast cancer patients; these symptoms included hot flushes, night sweats, pain during intercourse, hair loss, forgetfulness, depression, difficulty falling asleep, and interrupted sleep. Additionally, breast cancer patients were more likely than the women in the comparison group to report the new onset of many of these same symptoms during the follow-up time period. Because bothersome symptoms and side-effects are a major reason for discontinuation and non-adherence to treatment, symptoms should be monitored and addressed by oncologists so that the breast cancer patient can maintain her quality of life and remain adherent to the treatment schedule.

  2. Screening of aromatase inhibitors in traditional Chinese medicines by electrophoretically mediated microanalysis in a partially filled capillary.

    PubMed

    Zhao, Haiyan; Chen, Zilin

    2013-08-01

    An electrophoretically mediated microanalysis method with partial filling technique was developed for screening aromatase inhibitors in traditional Chinese medicine. The in-capillary enzymatic reaction was performed in 20 mM sodium phosphate buffer (pH 7.4), and sodium phosphate buffer (20 mM, pH 8.0) was used as a background electrolyte. A long plug of coenzyme reduced β-nicotinamide adenine dinucleotide 2'-phosphate hydrate dissolved in the reaction buffer was hydrodynamically injected into a fused silica capillary followed by the injection of reaction buffer, enzyme, and substrate solution. The reaction was initiated with a voltage of 5 kV applied to the capillary for 40 s. The voltage was turned off for 20 min to increase the product amount and again turned on at a constant voltage of 20 kV to separate all the components. Direct detection was performed at 260 nm. The enzyme activity was directly assayed by measuring the peak area of the produced β-nicotinamide adenine dinucleotide phosphate and the decreased peak area indicated the aromatase inhibition. Using the Lineweaver-Burk equation, the Michaelis-Menten constant was calculated to be 50 ± 4.5 nM. The method was applied to the screening of aromatase inhibitors from 15 natural products. Seven compounds were found to have potent AR inhibitory activity.

  3. Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

    PubMed Central

    Takagi, K; Ishida, T; Miki, Y; Hirakawa, H; Kakugawa, Y; Amano, G; Ebata, A; Mori, N; Nakamura, Y; Watanabe, M; Amari, M; Ohuchi, N; Sasano, H; Suzuki, T

    2013-01-01

    Background: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. Methods: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis. Results: Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues. Conclusion: These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens. PMID:23756858

  4. Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment.

    PubMed

    Takagi, K; Ishida, T; Miki, Y; Hirakawa, H; Kakugawa, Y; Amano, G; Ebata, A; Mori, N; Nakamura, Y; Watanabe, M; Amari, M; Ohuchi, N; Sasano, H; Suzuki, T

    2013-07-09

    Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis. Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues. These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.

  5. Long-term treatment of residual or recurrent low-grade endometrial stromal sarcoma with aromatase inhibitors: A report of two cases and a review of the literature

    PubMed Central

    RYU, HYEWON; CHOI, YOON-SEOK; SONG, IK-CHAN; YUN, HWAN-JUNG; JO, DEOG-YEON; KIM, SAMYONG; LEE, HYO JIN

    2015-01-01

    Endometrial stromal sarcoma (ESS) occurs rarely and accounts for only 0.2% of all uterine malignancies. ESS usually expresses estrogen and progesterone receptors, and is regarded as hormone-sensitive. Due to the rarity of these tumors, there are only few case series on the use of aromatase inhibitors in the treatment of low-grade ESS. The present study reports the cases of two patients with residual or recurrent low-grade ESS who experienced long-term disease-free survival following treatment with letrozole. The study also reviews the literature with regard to the data on aromatase inhibitors used in patients with low-grade ESS. In total, 30 patients with recurrent or residual low-grade ESS who were treated with aromatase inhibitors were identified, including the present cases. Among the 30 patients, the overall response rate of advanced low-grade ESS to aromatase inhibitors was 77.4% (complete response, 25.8%; partial response, 51.6%) and the disease control rate was 90.3%. The response rate of first-line treatment was similar to that of second-line therapy or higher (84.6 vs. 72.2%; P=0.453). Duration of aromatase inhibitor treatment ranged from 1.5 to 168 months (median, 26.5 months). The aromatase inhibitors showed minimal adverse effects. In conclusion, aromatase inhibitors, particularly third-generation drugs, are a well-tolerated class of medications that are effective in the treatment of advanced low-grade ESS, with a favorable toxicity profile. PMID:26722331

  6. Effects of the traditional Chinese medicine Yi Shen Jian Gu granules on aromatase inhibitor-associated musculoskeletal symptoms: a study protocol for a multicenter, randomized, controlled clinical trial.

    PubMed

    Peng, Nan; Zhang, Yi; Ma, Cong; Yu, Ming-Wei; Yang, Guo-Wang; Fu, Qi; Xu, Wei-Ru; Wang, Xiao-Min

    2014-05-15

    Aromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. One of the main adverse effects of AIs is musculoskeletal symptoms, which leads to a lower quality of life and poor adherence to AI treatment. To date, no effective management of aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) has been developed. To determine whether the traditional Chinese medicine Yi Shen Jian Gu granules could effectively manage AIMSS we will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial. Patients experiencing musculoskeletal symptoms after taking AIs will be enrolled and treated with traditional Chinese medicine or placebo for 12 weeks. The primary outcome measures include Brief Pain Inventory-Short Form, Western Ontario and McMaster Universities Osteoarthritis Index, and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands, which will be obtained at baseline and at 4, 8, 12 and 24 weeks. The results of this study will provide a new strategy to help relieve AIMSS. ISRCTN06129599 (assigned 14 August 2013).

  7. Effects of the traditional Chinese medicine Yi Shen Jian Gu granules on aromatase inhibitor-associated musculoskeletal symptoms: a study protocol for a multicenter, randomized, controlled clinical trial

    PubMed Central

    2014-01-01

    Background Aromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. One of the main adverse effects of AIs is musculoskeletal symptoms, which leads to a lower quality of life and poor adherence to AI treatment. To date, no effective management of aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) has been developed. Methods/design To determine whether the traditional Chinese medicine Yi Shen Jian Gu granules could effectively manage AIMSS we will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial. Patients experiencing musculoskeletal symptoms after taking AIs will be enrolled and treated with traditional Chinese medicine or placebo for 12 weeks. The primary outcome measures include Brief Pain Inventory-Short Form, Western Ontario and McMaster Universities Osteoarthritis Index, and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands, which will be obtained at baseline and at 4, 8, 12 and 24 weeks. Discussion The results of this study will provide a new strategy to help relieve AIMSS. Trial registration ISCTN: ISRCTN06129599 (assigned 14 August 2013). PMID:24885324

  8. Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients.

    PubMed

    Hertz, Daniel L; Henry, N Lynn; Rae, James M

    2017-04-01

    The third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are highly effective for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. AIs inhibit the aromatase (CYP19A1)-mediated production of estrogens. Most patients taking AIs achieve undetectable blood estrogen concentrations resulting in drug efficacy with tolerable side effects. However, some patients have suboptimal outcomes, which may be due, in part, to inherited germline genetic variants. This review summarizes published germline genetic associations with AI treatment outcomes including systemic AI concentrations, estrogenic response to AIs, AI treatment efficacy and AI treatment toxicities. Significant associations are highlighted with commentary about prioritization for future validation to identify pharmacogenetic predictors of AI treatment outcomes that can be used to inform personalized treatment decisions in patients with estrogen receptor-positive breast cancer.

  9. Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma.

    PubMed

    Fujii, Rika; Hanamura, Toru; Suzuki, Takashi; Gohno, Tatsuyuki; Shibahara, Yukiko; Niwa, Toshifumi; Yamaguchi, Yuri; Ohnuki, Koji; Kakugawa, Yoichiro; Hirakawa, Hisashi; Ishida, Takanori; Sasano, Hironobu; Ohuchi, Noriaki; Hayashi, Shin-ichi

    2014-10-01

    Aromatase inhibitors (AI) are commonly used to treat postmenopausal estrogen-receptor (ER)-positive breast carcinoma. However, resistance to AI is sometimes acquired, and the molecular mechanisms underlying such resistance are largely unclear. Recent studies suggest that AI treatment increases androgen activity during estrogen deprivation in breast carcinoma, but the role of the androgen receptor (AR) in breast carcinoma is still a matter of controversy. The purpose of this study is to examine the potential correlation between the AR- and AI-resistant breast carcinoma. To this end, we performed immunohistochemical analysis of 21 pairs of primary breast carcinoma and corresponding AI-resistant recurrent tissue samples and established two stable variant cell lines from ER-positive T-47D breast carcinoma cell line as AI-resistance models and used them in in vitro experiments. Immunohistochemical analysis demonstrated that the expression of prostate-specific antigen (PSA) and Ki-67 were significantly higher and ER and progesterone receptor (PR) were lower in recurrent lesions compared to the corresponding primary lesions. Variant cell lines overexpressed AR and PSA and exhibited neither growth response to estrogen nor expression of ER. Androgen markedly induced the proliferation of these cell lines. In addition, the expression profile of androgen-induced genes was markedly different between variant and parental cell lines as determined by microarray analysis. These results suggest that in some cases of ER-positive breast carcinoma, tumor cells possibly change from ER-dependent to AR-dependent, rendering them resistant to AI. AR inhibitors may thus be effective in a selected group of patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Enzymic aromatization of 6-alkyl-substituted androgens, potent competitive and mechanism-based inhibitors of aromatase.

    PubMed

    Numazawa, M; Yoshimura, A; Oshibe, M

    1998-01-01

    To gain insight into the relationships between the aromatase inhibitory activity of 6-alkyl-substituted androgens, potent competitive inhibitors, and their ability to serve as a substrate of aromatase, we studied the aromatization of a series of 6alpha- and 6beta-alkyl (methyl, ethyl, n-propyl, n-pentyl and n-heptyl)-substituted androst-4-ene-3,17-diones (ADs) and their androsta-1,4-diene-3,17-dione (ADD) derivatives with human placental aromatase, by gas chromatography-mass spectrometry. Among the inhibitors examined, ADD and its 6alpha-alkyl derivatives with alkyl functions less than three carbons long, together with 6beta-methyl ADD, are suicide substrates of aromatase. All of the steroids, except for 6beta-n-pentyl ADD and its n-heptyl analogue as well as 6beta-n-heptyl AD, were found to be converted into the corresponding 6-alkyl oestrogens. The 6-methyl steroids were aromatized most efficiently in each series, and the aromatization rate essentially decreased in proportion to the length of the 6-alkyl chains in each series, where the 6alpha-alkyl androgens were more efficient substrates than the corresponding 6beta isomers. The Vmax of 6alpha-methyl ADD was approx. 2.5-fold that of the natural substrate AD and approx. 3-fold that of the parent ADD. On the basis of this, along with the facts that the rates of a mechanism-based inactivation of aromatase by ADD and its 6alpha-methyl derivative are similar, it is implied that alignment of 6alpha-methyl ADD in the active site could favour the pathway leading to oestrogen over the inactivation pathway, compared with that of ADD. The relative apparent Km values for the androgens obtained in this study are different from the relative Ki values obtained previously, indicating that there is a difference between the ability to serve as an inhibitor and the ability to serve as a substrate in the 6-alkyl androgen series.

  11. Enzymic aromatization of 6-alkyl-substituted androgens, potent competitive and mechanism-based inhibitors of aromatase.

    PubMed Central

    Numazawa, M; Yoshimura, A; Oshibe, M

    1998-01-01

    To gain insight into the relationships between the aromatase inhibitory activity of 6-alkyl-substituted androgens, potent competitive inhibitors, and their ability to serve as a substrate of aromatase, we studied the aromatization of a series of 6alpha- and 6beta-alkyl (methyl, ethyl, n-propyl, n-pentyl and n-heptyl)-substituted androst-4-ene-3,17-diones (ADs) and their androsta-1,4-diene-3,17-dione (ADD) derivatives with human placental aromatase, by gas chromatography-mass spectrometry. Among the inhibitors examined, ADD and its 6alpha-alkyl derivatives with alkyl functions less than three carbons long, together with 6beta-methyl ADD, are suicide substrates of aromatase. All of the steroids, except for 6beta-n-pentyl ADD and its n-heptyl analogue as well as 6beta-n-heptyl AD, were found to be converted into the corresponding 6-alkyl oestrogens. The 6-methyl steroids were aromatized most efficiently in each series, and the aromatization rate essentially decreased in proportion to the length of the 6-alkyl chains in each series, where the 6alpha-alkyl androgens were more efficient substrates than the corresponding 6beta isomers. The Vmax of 6alpha-methyl ADD was approx. 2.5-fold that of the natural substrate AD and approx. 3-fold that of the parent ADD. On the basis of this, along with the facts that the rates of a mechanism-based inactivation of aromatase by ADD and its 6alpha-methyl derivative are similar, it is implied that alignment of 6alpha-methyl ADD in the active site could favour the pathway leading to oestrogen over the inactivation pathway, compared with that of ADD. The relative apparent Km values for the androgens obtained in this study are different from the relative Ki values obtained previously, indicating that there is a difference between the ability to serve as an inhibitor and the ability to serve as a substrate in the 6-alkyl androgen series. PMID:9405288

  12. AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies.

    PubMed

    Wong, Cynthie; Wang, Xin; Smith, David; Reddy, Kaladhar; Chen, Shiuan

    2012-07-01

    Aromatase inhibitors (AI) are currently the first line therapy for estrogen receptor (ER)-positive postmenopausal women. De novo AI resistance is when a patient intrinsically does not respond to an AI therapy as well as other targeted endocrine therapy. To characterize this type of resistance and to examine potential therapies for treatment, we have generated two cell models for de novo resistance. These models derive from MCF-7 cells that stably overexpress aromatase and Akt (AKT-aro) or HER2 (HER2-aro). Evaluation of these cell lines revealed that the activities of aromatase and ER were inhibited by AI and ICI 187280 (ICI) treatment, respectively; however, cell growth was resistant to therapy. Proliferation in the presence of the pure anti-estrogen ICI, indicates that these cells do not require ER for cell growth and distinguishes these cells from the acquired AI resistant cells. We further determined that the HSP90 inhibitor 17-DMAG suppressed the growth of the AI-resistant cell lines studied. Our analysis revealed 17-DMAG-mediated decreased expression of growth promoting signaling proteins. It was found that de novo AI resistant AKT-aro and HER2-aro cells could not be resensitized to letrozole or ICI by treatment with 17-DMAG. In summary, we have generated two cell lines which display the characteristics of de novo AI resistance. Together, these data indicate the possibility that HSP90 inhibitors may be a viable therapy for endocrine therapy resistance although additional clinical evaluation is needed.

  13. Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer

    PubMed Central

    Gadaleta, Raffaella Maria; Corleone, Giacomo; Fabris, Sonia; Kempe, Mannus H.; Vershure, Pernette J.; Barozzi, Iros; Vircillo, Valentina; Hong, Sung-Pil; Perone, Ylenia; Saini, Massimo; Trumpp, Andreas; Viale, Giuseppe; Neri, Antonino; Ali, Simak; Colleoni, Marco Angelo; Pruneri, Giancarlo; Minucci, Saverio

    2017-01-01

    Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, estrogen receptor (ERα) positive breast cancer (BCa) patients are treated with adjuvant endocrine therapy2 including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, over 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases: in this study, 21.5% of AI-treated, relapsed patients had acquired CYP19A1 gene (aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer genes including ESR1 and CYP19A1. Strikingly, CYP19A1amp cells also emerge in vitro but only in AI resistant models. CYP19A1 amplification causes increased aromatase activity and estrogen-independent ERα binding to target genes resulting in CYP19A1amp cells displaying decreased sensitivity to AI treatment. Collectively these data suggest that AI treatment itself selects for acquired CYP19A1 amplification and promotes local autocrine estrogen signalling in AI resistant metastatic patients. PMID:28112739

  14. The aromatase inhibitor letrozole and inhibitors of insulin-like growth factor I receptor synergistically induce apoptosis in in vitro models of estrogen-dependent breast cancer

    PubMed Central

    Lisztwan, Joanna; Pornon, Astrid; Chen, Bin; Chen, Shiuan; Evans, Dean B

    2008-01-01

    Introduction Endocrine-dependent, estrogen receptor positive breast cancer cells proliferate in response to estrogens, synthesized by the cytochrome p450 aromatase enzyme. Letrozole is a potent nonsteroidal aromatase inhibitor that is registered for the treatment of postmenopausal women with advanced metastatic breast cancers and in the neoadjuvant, early, and extended adjuvant indications. Because crosstalk exists between estrogen receptor and insulin-like growth factor I receptor (IGF-IR), the effect of combining a selective IGF-IR inhibitor (NVP-AEW541) with letrozole was assessed in two independent in vitro models of estrogen-dependent breast cancer. Methods MCF7 and T47D cells stably expressing aromatase (MCF7/Aro and T47D/Aro) were used as in vitro models of aromatase-driven breast cancer. The role of the IGF-IR pathway in breast cancer cells stimulated only by 17β-estradiol or androstenedione was assessed by proliferation assays. The combination of letrozole and NVP-AEW541 was assessed for synergy in inhibiting cell proliferation using Chou-Talalay derived equations. Finally, combination or single agent effects on proliferation and apoptosis were assessed using proliferation assays, flow cytometry, and immunoblotting. Results Both MCF7 and T47D cells, as well as MCF7/Aro and T47D/Aro, exhibited sensitivity to inhibition of 17β-estradiol dependent proliferation by NVP-AEW541. Letrozole combined with NVP-AEW541 synergistically inhibited androstenedione-dependent proliferation in aromatase-expressing cells with combination index values of 0.6 or less. Synergistic combination effects correlated with higher levels of apoptosis as compared with cells treated with the single agent alone. Treatment with either agent also appeared to inhibit IGF-IR signalling via phosphoinositide 3-kinase. Notably, IGF-IR inhibition had limited effect on estrogen-dependent proliferation in the cell lines, but was clearly required for survival, suggesting that the combination of

  15. Cost effectiveness of fracture prevention in postmenopausal women who receive aromatase inhibitors for early breast cancer.

    PubMed

    Ito, Kouta; Blinder, Victoria S; Elkin, Elena B

    2012-05-01

    Aromatase inhibitors (AIs) increase the risk of osteoporosis and related fractures in postmenopausal women who receive adjuvant AIs for hormone receptor (HR) -positive early breast cancer (EBC). We compared the cost effectiveness of alternative screening and treatment strategies for fracture prevention. We developed a Markov state transition model to simulate clinical practice and outcomes in a hypothetical cohort of women age 60 years with HR-positive EBC starting a 5-year course of AI therapy after primary surgery for breast cancer. Outcomes were quality-adjusted life-years (QALYs), lifetime cost, and incremental cost-effectiveness ratio (ICER). We compared the following strategies: no intervention; one-time bone mineral density (BMD) screening and selective bisphosphonate therapy in women with osteoporosis or osteopenia; annual BMD screening and selective bisphosphonate therapy in women with osteoporosis or osteopenia; and universal bisphosphonate therapy. ICERs for annual BMD screening followed by oral bisphosphonates for those with osteoporosis, annual BMD screening followed by oral bisphosphonates for those with osteopenia, and universal treatment with oral bisphosphonates were $87,300, $129,300, and $283,600 per QALY gained, respectively. One-time BMD screening followed by oral bisphosphonates for those with osteoporosis or osteopenia was dominated. Our results were sensitive to age at the initiation of AI therapy, type of bisphosphonates, post-treatment residual effect of bisphosphonates, and a potential adjuvant benefit of intravenous bisphosphonates. In postmenopausal women receiving adjuvant AIs for HR-positive EBC, a policy of baseline and annual BMD screening followed by selective treatment with oral bisphosphonates for those diagnosed with osteoporosis is a cost-effective use of societal resources.

  16. Quantitative ultrasound and DXA measurements in aromatase inhibitor-treated breast cancer women receiving denosumab.

    PubMed

    Catalano, A; Gaudio, A; Morabito, N; Basile, G; Agostino, R M; Xourafa, A; Atteritano, M; Morini, E; Natale, G; Lasco, A

    2017-08-01

    Denosumab has been proven to reduce fracture risk in breast cancer (BC) women under aromatase inhibitors (AIs). Quantitative ultrasound (QUS) provides information on the structure and elastic properties of bone. Our aim was to assess bone health by phalangeal QUS and by dual-energy X-ray absorptiometry (DXA), and to evaluate bone turnover in AIs-treated BC women receiving denosumab. 35 Postmenopausal BC women on AIs were recruited (mean age 61.2 ± 4.5 years) and treated with denosumab 60 mg administered subcutaneously every 6 months. Phalangeal QUS parameters [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), Bone Transmission Time (BTT)] and DXA at lumbar spine and femoral neck were performed. Serum C-telopeptide of type 1 collagen (CTX) and bone-specific alkaline phosphatase (BSAP) were also measured. The main outcomes were compared with a control group not receiving denosumab (n = 39). In patients treated with denosumab, differently from controls, QUS and DXA measurements improved after 24 months, and a reduction of CTX and BSAP was detected at 12 and 24 months in comparison to baseline (P < 0.05). The percent changes (Δ) of QUS measurements were significantly associated with ΔBMD at femoral neck, and ΔCTX and ΔBSAP were associated with ΔBMD at lumbar spine (r = -0.39, P = 0.02; r = -0.49, P = 0.01, respectively). Denosumab preserves bone health as assessed by phalangeal QUS and DXA. Since inexpensive and radiation-free, phalangeal QUS may be considered in the follow-up of AIs-treated BC women receiving denosumab.

  17. Height Increment and Laboratory Profile of Boys Treated With Aromatase Inhibitors With or Without Growth Hormone.

    PubMed

    Pedrosa, Ludmila Fernandes; de Oliveira, Joice Marquez; Thomé, Paula Roberta Vieira; Kochi, Cristiane; Damiani, Durval; Longui, Carlos Alberto

    2017-08-31

    Aromatase inhibitors (AIs) have been used to recover height loss due to their capacity to delay growth plate closure. Long-term studies describing final heights are needed to determine the efficacy and safety profiles of these drugs for the treatment of impaired growth. This study aims to identify the therapeutic efficiency of AIs in improve growth and to describe potential adverse effects during treatment. Retrospective data analysis of 96 adolescents, among which 22 patients already attained near-final height, were followed at outpatient clinics of two referral centers. Patients were all in puberty and present idiopathic decrease in predicted adult height. Patients were treated with Anastrozole (ANZ: 1 mg/day) or Letrozole (LTZ: 2.5 mg/day) with/without recombinant human growth hormone (0.05 mg/kg/day) for 1.0 to 3.5 years (2.1±1.2 years). Height gain, body mass index, lipid, liver enzyme, gonadotropins and testosterone levels were described before and at the end of treatment. Predicted adult height (PAH) and NF height were compared with the TH. The height SDS (adjusted to bone age) significantly increased (p<0.05) in all groups [0.8±0.7 (ANZ), 0.7±0.7 (ANZ+GH), 0.3±0.5 (LTZ), and 1.2±0.8 (LTZ+GH)]; the latter group exhibited the highest increment of PAH and growth recovery to the TH (p<0.004). No significant side effects were observed. AI treatment, especially when used in association with GH was able to improve growth and the attainment of familial target height. © Georg Thieme Verlag KG Stuttgart · New York.

  18. Red versus white wine as a nutritional aromatase inhibitor in premenopausal women: a pilot study.

    PubMed

    Shufelt, Chrisandra; Merz, C Noel Bairey; Yang, YuChing; Kirschner, Joan; Polk, Donna; Stanczyk, Frank; Paul-Labrador, Maura; Braunstein, Glenn D

    2012-03-01

    An increased risk of breast cancer is associated with alcohol consumption; however, it is controversial whether red wine increases this risk. Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogen and occur naturally in grapes, grape juice, and red, but not white wine. We tested whether red wine is a nutritional AI in premenopausal women. In a cross-over design, 36 women (mean age [SD], 36 [8] years) were assigned to 8 ounces (237 mL) of red wine daily then white wine for 1 month each, or the reverse. Blood was collected twice during the menstrual cycle for measurement of estradiol (E2), estrone (E1), androstenedione (A), total and free testosterone (T), sex hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle stimulating hormone (FSH). Red wine demonstrated higher free T vs. white wine (mean difference 0.64 pg/mL [0.2 SE], p=0.009) and lower SHBG (mean difference -5.0 nmol/L [1.9 SE], p=0.007). E2 levels were lower in red vs. white wine but not statistically significant. LH was significantly higher in red vs. white wine (mean difference 2.3 mIU/mL [1.3 SE], p=0.027); however, FSH was not. Red wine is associated with significantly higher free T and lower SHBG levels, as well as a significant higher LH level vs. white wine in healthy premenopausal women. These data suggest that red wine is a nutritional AI and may explain the observation that red wine does not appear to increase breast cancer risk.

  19. Efficacy of Exemestane in Korean Patients with Metastatic Breast Cancer after Failure of Nonsteroidal Aromatase Inhibitors

    PubMed Central

    Lee, June Koo; Lee, Daewon; Kim, Ji-Yeon; Lim, Yoojoo; Lee, Eunyoung; Moon, Hyeong-Gon; Kim, Tae-Yong; Han, Sae-Won; Oh, Do-Youn; Lee, Se-Hoon; Han, Wonshik; Kim, Dong-Wan; Kim, Tae-You; Noh, Dong-Young

    2013-01-01

    Purpose Exemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported. Methods Data on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months). Results The median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs. Conclusion Exemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment. PMID:23593084

  20. Perceived barriers to treatment predict adherence to aromatase inhibitors among breast cancer survivors.

    PubMed

    Brier, Moriah J; Chambless, Dianne L; Gross, Robert; Chen, Jinbo; Mao, Jun J

    2017-01-01

    Although poor adherence to hormonal therapies such as aromatase inhibitors (AIs) is widely documented, to the authors' knowledge less is known regarding whether health beliefs predict treatment nonadherence. The objective of the current study was to evaluate the relationship between health beliefs (perceived susceptibility to breast cancer, perceived benefits of AI treatment, and perceived barriers to AI treatment) and adherence to AIs. Postmenopausal women with early-stage, estrogen receptor-positive breast cancer who were currently receiving treatment with an AI completed the 3-factor Health Beliefs and Medication Adherence in Breast Cancer scale and questionnaires concerning their demographics and symptoms. Adherence data (treatment gaps and premature discontinuation) were abstracted from participants' medical charts. Logistic regression analyses were conducted to evaluate the relationship between health beliefs and adherence. Among 437 participants, 93 (21.3%) were nonadherent. Those who perceived greater barriers to their AI treatment were more likely to demonstrate AI nonadherence behaviors by the end of their treatment period compared with those who reported fewer barriers to AI therapy (adjusted odds ratio, 1.71; 95% confidence interval, 1.03-2.86 [P = .04]). In contrast, perceived susceptibility to cancer recurrence and perceived benefits of AIs did not appear to predict AI adherence. Minority individuals were found to have lower perceived susceptibility to breast cancer recurrence and higher perceived barriers to AI treatment (P<.05 for both). Greater perceived barriers appeared to predict nonadherence to AIs. Interventions addressing women's negative beliefs regarding the challenges of AI treatment are needed to help optimize adherence in survivors of breast cancer. Cancer 2017;169-176. © 2016 American Cancer Society. © 2016 American Cancer Society.

  1. [Survival of breast cancer patients treated with inhibitors of the aromatase vs tamoxifen].

    PubMed

    Castelazo Rico, Germán; Molotla Xolalpa, Donaji; Basavilvazo Rodríguez, María Antonia; Angeles Victoria, Leobardo; Zárate, Arturo; Hernández Valencia, Marcelino

    2004-10-01

    In Mexico the breast cancer occupies the second place as cause of death by oncological illness and the etiology is considered multifactorial. The systemic treatment of this cancer is necessarily after the surgery and simultaneously when radiotherapy is used; therefore the recent introduction of newly non toxics and efficient antiestrogens which block the effect of estrogens from circulation have become drugs of first line in the metastasis illness. To compare the clinical evolution and the survival of patients with locally advanced breast cancer and metastasis with the use of two therapeutic modalities. Under informed consent 20 patients with diagnosis of breast cancer and out of oncological therapeutic processing were included. Randomly an inhibitor of the aromatase (anastrozole, 1 mg for day) was used in 10 patients and in the other 10 patients tamoxifen (20 mg for day) both for 2 years, subject to verification of positive estrogens-progesterone receptors. Half of the patients of each group had a clinical stage III. The most frequent histological diagnosis was the ductal carcinoma in 70% of the group with tamoxifen use, while in anastrozole group was 90%; the mastectomy prior to the tamoxifen was carried out in 60% of the patients and in 50% of the group with anastrozole. The acceptable response to the processing in the patients with tamoxifen was complete in the 60% of the cases, but with the use of anastrozole was 80%; survival in the group with anastrozole was of 100% in two years of follow up, while in women that received tamoxifen the survival was 90% (p<0.001). The use of anastrozole improved the survival as well as the quality of life, showing no side effects in this group of patients.

  2. Cost-effectiveness of full coverage of aromatase inhibitors for Medicare beneficiaries with early breast cancer.

    PubMed

    Ito, Kouta; Elkin, Elena; Blinder, Victoria; Keating, Nancy; Choudhry, Niteesh

    2013-07-01

    Rates of nonadherence to aromatase inhibitors (AIs) among Medicare beneficiaries with hormone receptor-positive early breast cancer are high. Out-of-pocket drug costs appear to be an important contributor to this and may be addressed by eliminating copayments and other forms of patient cost sharing. The authors estimated the incremental cost-effectiveness of providing Medicare beneficiaries with full prescription coverage for AIs compared with usual prescription coverage under the Medicare Part D program. A Markov state-transition model was developed to simulate AI use and disease progression in a hypothetical cohort of postmenopausal Medicare beneficiaries with hormone receptor-positive early breast cancer. The analysis was conducted from the societal perspective and considered a lifetime horizon. The main outcome was an incremental cost-effectiveness ratio, which was measured as the cost per quality-adjusted life-year (QALY) gained. For patients receiving usual prescription coverage, average quality-adjusted survival was 11.35 QALYs, and lifetime costs were $83,002. For patients receiving full prescription coverage, average quality-adjusted survival was 11.38 QALYs, and lifetime costs were $82,728. Compared with usual prescription coverage, full prescription coverage would result in greater quality-adjusted survival (0.03 QALYs) and less resource use ($275) per beneficiary. From the perspective of Medicare, full prescription coverage was cost-effective (incremental cost-effectiveness ratio, $15,128 per QALY gained) but not cost saving. Providing full prescription coverage for AIs to Medicare beneficiaries with hormone receptor-positive early breast cancer would both improve health outcomes and save money from the societal perspective. Copyright © 2013 American Cancer Society.

  3. Joint pain severity predicts premature discontinuation of aromatase inhibitors in breast cancer survivors

    PubMed Central

    2013-01-01

    Background Premature discontinuation of aromatase inhibitors (AIs) in breast cancer survivors compromises treatment outcomes. We aimed to evaluate whether patient-reported joint pain predicts premature discontinuation of AIs. Methods We conducted a retrospective cohort study of postmenopausal women with breast cancer on AIs who had completed a survey about their symptom experience on AIs with specific measurements of joint pain. The primary outcome was premature discontinuation of AIs, defined as stopping the medication prior to the end of prescribed therapy. Multivariate Cox regression modeling was used to identify predictors of premature discontinuation. Results Among 437 patients who met eligibility criteria, 47 (11%) prematurely discontinued AIs an average of 29 months after initiation of therapy. In multivariate analyses, patient-reported worst joint pain score of 4 or greater on the Brief Pain Inventory (BPI) (Hazard Ratio [HR] 2.09, 95% Confidence Interval [CI] 1.14-3.80, P = 0.016) and prior use of tamoxifen (HR 2.01, 95% CI 1.09-3.70, P = 0.026) were significant predictors of premature discontinuation of AIs. The most common reason for premature discontinuation was joint pain (57%) followed by other therapy-related side effects (30%). While providers documented joint pain in charts for 82% of patients with clinically important pain, no quantitative pain assessments were noted, and only 43% provided any plan for pain evaluation or management. Conclusion Worst joint pain of 4 or greater on the BPI predicts premature discontinuation of AI therapy. Clinicians should monitor pain severity with quantitative assessments and provide timely management to promote optimal adherence to AIs. PMID:24004677

  4. A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors.

    PubMed

    Schech, Amanda; Yu, Stephen; Goloubeva, Olga; McLenithan, John; Sabnis, Gauri

    2015-08-01

    Obesity is a risk factor for breast cancer progression. Breast cancer patients who are overweight or obese or have excess abdominal fat have an increased risk of local or distant recurrence and cancer-related death. Hormone depletion therapies can also cause weight gain, exacerbating the risk for these patients. To understand the effect of obesity on hormone-dependent human breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat and 17% kcal sucrose (high fat sucrose diet (HFSD)), 10% kcal fat (low fat diet (LFD)), or a standard chow diet (chow). The mice fed the HFSD developed metabolic abnormalities consistent with the development of obesity such as weight gain, high fasting blood glucose, and impaired glucose tolerance. These mice also developed hyperinsulinemia and insulin resistance. The obese mice also had a higher tumor growth rate compared to the lean mice. Furthermore, the obese mice showed a significantly reduced responsiveness to letrozole. To understand the role of obesity in this reduced responsiveness, we examined the effect of insulin on the growth of MCF-7Ca cells in response to estrogen or letrozole. The presence of insulin rendered MCF-7Ca cells less responsive to estrogen and letrozole. Exogenous insulin treatment of MCF-7Ca cells also resulted in increased p-Akt as well as ligand-independent phosphorylation of ERα. These findings suggest that diet-induced obesity may result in reduced responsiveness of tumors to letrozole due to the development of hyperinsulinemia. We conclude that obesity influences the response and resistance of breast cancer tumors to aromatase inhibitor treatment. © 2015 Society for Endocrinology.

  5. Aromatase Inhibitor-Associated Bone Fractures: A Case-Cohort GWAS and Functional Genomics

    PubMed Central

    Liu, Mohan; Goss, Paul E.; Ingle, James N.; Kubo, Michiaki; Furukawa, Yoichi; Batzler, Anthony; Jenkins, Gregory D.; Carlson, Erin E.; Nakamura, Yusuke; Schaid, Daniel J.; Chapman, Judy-Anne W.; Shepherd, Lois E.; Ellis, Matthew J.; Khosla, Sundeep; Wang, Liewei

    2014-01-01

    Bone fractures are a major consequence of osteoporosis. There is a direct relationship between serum estrogen concentrations and osteoporosis risk. Aromatase inhibitors (AIs) greatly decrease serum estrogen levels in postmenopausal women, and increased incidence of fractures is a side effect of AI therapy. We performed a discovery case-cohort genome-wide association study (GWAS) using samples from 1071 patients, 231 cases and 840 controls, enrolled in the MA.27 breast cancer AI trial to identify genetic factors involved in AI-related fractures, followed by functional genomic validation. Association analyses identified 20 GWAS single nucleotide polymorphism (SNP) signals with P < 5E-06. After removal of signals in gene deserts and those composed entirely of imputed SNPs, we applied a functional validation “decision cascade” that resulted in validation of the CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 genes. These genes all displayed estradiol (E2)-dependent induction in human fetal osteoblasts transfected with estrogen receptor-α, and their knockdown altered the expression of known osteoporosis-related genes. These same genes also displayed SNP-dependent variation in E2 induction that paralleled the SNP-dependent induction of known osteoporosis genes, such as osteoprotegerin. In summary, our case-cohort GWAS identified SNPs in or near CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 that were associated with risk for bone fracture in estrogen receptor-positive breast cancer patients treated with AIs. These genes displayed E2-dependent induction, their knockdown altered the expression of genes related to osteoporosis, and they displayed SNP genotype-dependent variation in E2 induction. These observations may lead to the identification of novel mechanisms associated with fracture risk in postmenopausal women treated with AIs. PMID:25148458

  6. Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library.

    PubMed

    Chen, Shiuan; Hsieh, Jui-Hua; Huang, Ruili; Sakamuru, Srilatha; Hsin, Li-Yu; Xia, Menghang; Shockley, Keith R; Auerbach, Scott; Kanaya, Noriko; Lu, Hannah; Svoboda, Daniel; Witt, Kristine L; Merrick, B Alex; Teng, Christina T; Tice, Raymond R

    2015-10-01

    Multiple mechanisms exist for endocrine disruption; one nonreceptor-mediated mechanism is via effects on aromatase, an enzyme critical for maintaining the normal in vivo balance of androgens and estrogens. We adapted the AroER tri-screen 96-well assay to 1536-well format to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library. In this assay, screening with compound alone identifies estrogen receptor alpha (ERα) agonists, screening in the presence of testosterone (T) identifies AIs and/or ERα antagonists, and screening in the presence of 17β-estradiol (E2) identifies ERα antagonists. Screening the Tox-21 library in the presence of T resulted in finding 302 potential AIs. These compounds, along with 31 known AI actives and inactives, were rescreened using all 3 assay formats. Of the 333 compounds tested, 113 (34%; 63 actives, 50 marginal actives) were considered to be potential AIs independent of cytotoxicity and ER antagonism activity. Structure-activity analysis suggested the presence of both conventional (eg, 1, 2, 4, - triazole class) and novel AI structures. Due to their novel structures, 14 of the 63 potential AI actives, including both drugs and fungicides, were selected for confirmation in the biochemical tritiated water-release aromatase assay. Ten compounds were active in the assay; the remaining 4 were only active in high-throughput screen assay, but with low efficacy. To further characterize these 10 novel AIs, we investigated their binding characteristics. The AroER tri-screen, in high-throughput format, accurately and efficiently identified chemicals in a large and diverse chemical library that selectively interact with aromatase.

  7. Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library

    PubMed Central

    Chen, Shiuan; Hsieh, Jui-Hua; Huang, Ruili; Sakamuru, Srilatha; Hsin, Li-Yu; Xia, Menghang; Shockley, Keith R.; Auerbach, Scott; Kanaya, Noriko; Lu, Hannah; Svoboda, Daniel; Witt, Kristine L.; Merrick, B. Alex; Teng, Christina T.; Tice, Raymond R.

    2015-01-01

    Multiple mechanisms exist for endocrine disruption; one nonreceptor-mediated mechanism is via effects on aromatase, an enzyme critical for maintaining the normal in vivo balance of androgens and estrogens. We adapted the AroER tri-screen 96-well assay to 1536-well format to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library. In this assay, screening with compound alone identifies estrogen receptor alpha (ERα) agonists, screening in the presence of testosterone (T) identifies AIs and/or ERα antagonists, and screening in the presence of 17β-estradiol (E2) identifies ERα antagonists. Screening the Tox-21 library in the presence of T resulted in finding 302 potential AIs. These compounds, along with 31 known AI actives and inactives, were rescreened using all 3 assay formats. Of the 333 compounds tested, 113 (34%; 63 actives, 50 marginal actives) were considered to be potential AIs independent of cytotoxicity and ER antagonism activity. Structure-activity analysis suggested the presence of both conventional (eg, 1, 2, 4, - triazole class) and novel AI structures. Due to their novel structures, 14 of the 63 potential AI actives, including both drugs and fungicides, were selected for confirmation in the biochemical tritiated water-release aromatase assay. Ten compounds were active in the assay; the remaining 4 were only active in high-throughput screen assay, but with low efficacy. To further characterize these 10 novel AIs, we investigated their binding characteristics. The AroER tri-screen, in high-throughput format, accurately and efficiently identified chemicals in a large and diverse chemical library that selectively interact with aromatase. PMID:26141389

  8. Reduced estradiol synthesis by letrozole, an aromatase inhibitor, is protective against development of pentylenetetrazole-induced kindling in mice.

    PubMed

    Rashid, Davood; Panda, B P; Vohora, Divya

    2015-11-01

    Neurosteroids, such as testosterone and their metabolites, are known to modulate neuronal excitability. The enzymes regulating the metabolism of these neurosteroids, thus, may be targeted as a noval strategy for the development of new antiepileptic drugs. The present work targeted two such enzymes i,e aromatase and 5α-reductase in order to explore the potential of letrozole (an aromatase inhibitor) on pentylenetetrazole (PTZ)-induced kindling in mice and the ability of finasteride (a 5α-reductase inhibitor) to modulate any such effects. PTZ (30 mg/kg, i.p.), when administered once every two days (for a total of 24 doses) induced kindling in Swiss albino mice. Letrozole (1 mg/kg, p.o.), administered prior to PTZ, significantly reduced the % incidence of kindling, delayed mean onset time of seizures and reduced seizure severity score. Letrozole reduced the levels of plasma 17β-estradiol after induction of kindling. The concurrent administration of finasteride and letrozole produced effects similar to letrozole on PTZ-kindling and on estradiol levels. This implies that the ability of letrozole to redirect the synthesis of dihydrotestosterone (DHT) and 5α-androstanediol from testosterone doesn't appear to play a significant role in the protective effects of letrozole against PTZ kindling. Letrozole, however, increased the levels of 5α-DHT in mice plasma. The aromatase inhibitors, thus, may be exploited for inhibiting the synthesis of proconvulsant (17β-estradiol) and/or redirecting the synthesis of anticonvulsant (DHT and 5α-androstanediol) neurosteroids.

  9. Prognostic impact of progesterone receptor status combined with body mass index in breast cancer patients treated with adjuvant aromatase inhibitor.

    PubMed

    Ohara, Masahiro; Akimoto, Etsushi; Noma, Midori; Matsuura, Kazuo; Doi, Mihoko; Kagawa, Naoki; Itamoto, Toshiyuki

    2015-11-01

    Aromatase inhibitors have played a central role in endocrine therapy for the treatment of estrogen receptor (ER)-positive breast cancer in postmenopausal patients. However, prognostic factors for recurrence following such treatment have not been identified. The current study aimed to validate the prognostic value of endocrine-related progesterone receptor (PgR) status combined with body mass index (BMI). Among 659 consecutive patients with primary breast cancer who underwent curative surgery between 2002 and 2012, 184 postmenopausal patients with ER-positive (ER+) and human epidermal growth factor receptor type 2-negative (HER2-) breast cancer who were treated with adjuvant aromatase inhibitor therapy were assessed. The patients were assigned to groups based on BMI, according to the WHO cut-off value: ≥25 kg/m(2) (high, H) or <25 kg/m(2) (low, L). Positive nodal status, negative PgR status, BMI-H and a high Ki-67 labeling index (≥20%) were found to be significantly associated with a short recurrence-free interval (RFI) upon univariate analysis (P=0.048, 0.007, 0.027, and 0.012, respectively). The patients were further grouped based on their combined PgR/BMI status. The RFI was significantly shorter in the PgR- and/or BMI-H group compared with that of the PgR+/BMI-L group (P=0.012). Multivariate analysis revealed PgR- tumors and/or BMI-H and positive nodal status to be independent prognostic factors (P=0.012 and 0.020, respectively). The present findings indicate that PgR/BMI status may serve as a practical tool in the management of ER+ and HER2- breast cancer in patients treated with adjuvant aromatase inhibitors.

  10. Synthesis and evaluation of benzoxazolinonic imidazoles and derivatives as non-steroidal aromatase inhibitors.

    PubMed

    Nativelle-Serpentini, Celine; Moslemi, Safa; Yous, Said; Park, Chang Ha; Lesieur, Daniel; Sourdaine, Pascal; Séralini, Gilles-Eric

    2004-04-01

    New compounds were tested in vitro on aromatase activity in human placental and equine testicular microsomes. Equine aromatase, very well characterized biochemically, is used as a comparative model to understand the mechanism of aromatase inhibition. Among 15 molecules screened, 5 of them (11-15) strongly inhibit human and equine aromatases with IC50 values ranging from 13-85nM and from 23-103nM respectively. These results were corroborated by Ki/Km values. Moreover, spectral studies showed a type II spectrum with both enzymes, which is characteristic of an interaction between the nitrogen atom of the molecule and the heme of the cytochrome P450. Compound 12, which has the lowest IC50 and Ki/Km ratio, inactivates aromatase in a dose and time-dependent manner. This might be very important for the treatment of estrogen-dependent diseases such as breast cancer. Finally, MTT assays on E293 cells revealed that the molecules were not cytotoxic.

  11. Modulation of aromatase activity as a mode of action for endocrine disrupting chemicals in a marine fish.

    PubMed

    Mills, Lesley J; Gutjahr-Gobell, Ruth E; Zaroogian, Gerald E; Horowitz, Doranne Borsay; Laws, Susan C

    2014-02-01

    The steroidogenic enzyme aromatase catalyzes the conversion of androgens to estrogens and therefore plays a central role in reproduction. In contrast to most vertebrates, teleost fish have two distinct forms of aromatase. Because brain aromatase activity in fish is up to 1000 times that in mammals, fish may be especially susceptible to negative effects from environmental endocrine-disrupting chemicals (EDCs) that impact aromatase activity. In this study, the effects of estradiol (E2), ethynylestradiol (EE2), octylphenol (OP), and androstatrienedione (ATD) on reproduction and aromatase activity in brains and gonads from the marine fish cunner (Tautogolabrus adspersus) was investigated. The purpose of the study was to explore the relationship between changes in aromatase activity and reproductive output in a marine fish, as well as compare aromatase activity to two commonly used indicators of EDC exposure, plasma vitellogenin (VTG) and gonadosomatic index (GSI). Results with E2, EE2, and ATD indicate that aromatase activity in cunner brain and ovary are affected differently by exposure to these EDCs. In the case of E2 and EE2, male brain aromatase activity was signficantly increased by these treatments, female brain aromatase activity was unaffected, and ovarian aromatase activity was significantly decreased. Treatment with the aromatase inhibitor ATD resulted in significantly decreased aromatase activity in male and female brain, but had no significant impact on ovarian aromatase activity. Regardless of test chemical, a decrease or an increase in male brain aromatase activity relative to controls was associated with decreased egg production in cunner and was also correlated with significant changes in GSI in both sexes. E2 and EE2 significantly elevated plasma VTG in males and females, while ATD had no significant effect. Treatment of cunner with OP had no significant effect on any measured endpoint. Overall, results with these exposures indicate EDCs that impact

  12. Metabolomic, behavioral, and reproductive effects of the aromatase inhibitor fadrozole hydrochloride on the unionid mussel Lampsilis fasciola.

    PubMed

    Leonard, Jeremy A; Cope, W Gregory; Barnhart, M Christopher; Bringolf, Robert B

    2014-09-15

    Androgen-induced masculinization of female aquatic biota poses concerns for natural population stability. This research evaluated the effects of a twelve day exposure of fadrozole hydrochloride on the metabolism and reproductive status of the unionid mussel Lampsilis fasciola. Although this compound is not considered to be widespread in the aquatic environment, it was selected as a model aromatase (enzyme that converts testosterone to estradiol) inhibitor. Adult mussels were exposed to a control and 3 concentrations of fadrozole (2μg/L, 20μg/L, and 50μg/L), and samples of gill tissue were taken on days 4 and 12 for metabolomics analysis. Gills were used because of the variety of critical processes they mediate, such as feeding, ion exchange, and siphoning. Daily observed mussel behavior included female mantle display, foot protrusion, siphoning, and larval (glochidia) releases. Glochidia mortality was significantly higher in the 20μg/L treatment. Fewer conglutinate (packets of glochidia) releases were observed in the 50μg/L treatment, and mortality was highly correlated to release numbers. Foot protrusion was significantly higher in females in nearly all treatments, including the control, during the first 4days of observations. However, this sex difference was observed only in the 50μg/L treatment during the last 8days. Generally, metabolites were significantly altered in female gill tissue in the 2μg/L treatment whereas males were mostly affected only at the highest (50μg/L) treatment. Both sexes also revealed significant reductions in fadrozole-induced metabolic effects in gill tissue sampled after 12days compared to tissue sampled after 4days, indicating time-dependent mechanisms of disruptions in metabolic pathways and homeostatic processes to compensate for such disruptions. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Periodontal Health in Women with Early Stage Postmenopausal Breast Cancer Newly on Aromatase Inhibitors: A Pilot Study

    PubMed Central

    Taichman, LS; Inglehart, MR; Giannobile, W; Braun, T; Kolenic, G; Van Poznak, C

    2015-01-01

    Background Aromatase inhibitor (AI) use results in low estrogen levels which in turn affect bone mineral density (BMD). Periodontitis, alveolar bone loss, and tooth loss are associated with low BMD. The goal of this study was to assess the prevalence of periodontitis, perceived oral health, and evaluate salivary biomarkers in postmenopausal women who are early stage (I-IIIA) breast cancer (BCa) survivors and receive adjuvant AI therapy. Methods Participants included 58 postmenopausal women; 29 with BCa on AIs and 29 controls without BCa diagnoses. Baseline periodontal status was assessed with: (1) periodontal pocket depth (PD); (2) bleeding on probing (BOP); and (3) attachment loss (AL). Demographic and dental utilization information was gathered by questionnaire. Linear regression modeling was used to analyze the outcomes. Results No differences in mean PD or the number of teeth were found. The AI group had significantly more sites with BOP (27.8 vs. 16.7; p = 0.02), higher worst-site AL (5.2 mm vs. 4.0 mm; p < 0.01) and more sites with dental calculus than did controls (18.2 vs. 6.4; p < 0.001). Linear regression adjusted for income, tobacco use, and dental insurance, and previous radiation and chemotherapy exposure demonstrated AI use increased CAL over 2 mm (95% CI: 0.46 -3.92). Median salivary osteocalcin and Tumor Necrosis Factor levels were significantly higher in the BCa group than the control group. Conclusions This first investigation of the periodontal status of women initiating adjuvant AI therapy identifies this population as having an increased risk for periodontitis (NCT1272570). PMID:25672657

  14. Phase II study of glucosamine with chondroitin on aromatase inhibitor-associated joint symptoms in women with breast cancer

    PubMed Central

    Greenlee, Heather; Crew, Katherine D.; Shao, Theresa; Kranwinkel, Grace; Kalinsky, Kevin; Maurer, Matthew; Brafman, Lois; Insel, Beverly; Tsai, Wei Yann

    2013-01-01

    Purpose Many women with hormone receptor-positive breast cancer discontinue effective aromatase inhibitor (AI) treatment due to joint symptoms. Methods We conducted a single-arm, open-label, phase II study evaluating glucosamine-sulfate (1,500 mg/day)+ chondroitin-sulfate (1,200 mg/day) for 24 weeks to treat joint pain/stiffness in postmenopausal women with early stage breast cancer who developed moderate-to-severe joint pain after initiating AIs. The primary endpoint was improvement in pain/stiffness at week 24 assessed by the Outcome Measure in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Secondary endpoints assessed changes in pain, stiffness, and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index for hips/knees and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) for hands/wrists. The Brief Pain Inventory (BPI) assessed pain interference, severity, and worst pain. Results Of 53 patients enrolled, 39 were evaluable at week 24. From baseline to week 24, 46 % of patients improved according to OMERACT-OARSI criteria. At week 24, there were improvements (all P<0.05) in pain and function as assessed by WOMAC and M-SACRAH, and in pain interference, severity, and worst pain as assessed by BPI. Estradiol levels did not change from baseline. The most commonly reported side effects were headache (28 %), dyspepsia (15 %), and nausea (17 %). Conclusions In this single-arm study, 24 weeks of glucosamine/chondroitin resulted in moderate improvements in AI-induced arthralgias, with minimal side effects, and no changes in estradiol levels. These results suggest a need to evaluate efficacy in a placebo-controlled trial. PMID:23111941

  15. Identifying socio-demographic and clinical characteristics associated with medication beliefs about aromatase inhibitors among postmenopausal women with breast cancer.

    PubMed

    Salgado, Teresa M; Davis, Emily J; Farris, Karen B; Fawaz, Souhiela; Batra, Peter; Henry, N Lynn

    2017-06-01

    Non-adherence/persistence to adjuvant endocrine therapy can negatively impact survival. Beliefs about medicines are known to affect adherence. This study aims to identify socio-demographic and clinical characteristics associated with medication beliefs among women taking aromatase inhibitors (AIs). Women completed an online survey on beliefs about AI therapy [Beliefs about Medicines Questionnaire (BMQ)], beliefs about breast cancer [Assessment of Survivor Concerns scale (ASC)], and depression [Personal Health Questionnaire depression scale (PHQ-8)]. Socio-demographic and clinical characteristics were collected. Bivariate analyses and linear regression models were performed to investigate relationships between variables. A total of 224 women reported currently taking AI therapy and were included in the analysis. Significantly higher concern beliefs were found among women who had at least mild depression, experienced side effects from AIs, and previously stopped therapy with another AI. Significant correlations were found between concern and necessity beliefs and cancer and health worry. Women age 70 and older displayed less fear of cancer recurrence and health worry, and a trend towards lower necessity and concern beliefs. No differences were found for other variables. In the regression model, greater necessity beliefs were found with increases in the number of current prescription medications (B = 1.06, 95% CI 0.31-1.81, p = 0.006) and shorter duration of current AI therapy (B = -0.65, 95% CI -1.23 to -0.07, p = 0.029), whereas greater concern beliefs were associated with higher depression scores (B = 1.19, 95% CI 0.35-2.03, p = 0.006). Medication necessity and concern beliefs were associated with a definable subset of patients who may be at higher risk for non-persistence.

  16. Effects of a purported aromatase and 5α-reductase inhibitor on hormone profiles in college-age men.

    PubMed

    Wilborn, Colin; Taylor, Lem; Poole, Chris; Foster, Cliffa; Willoughby, Darryn; Kreider, Richard

    2010-12-01

    The purpose of this study was to determine the effects of an alleged aromatase and 5-α reductase inhibitor (AI) on strength, body composition, and hormonal profiles in resistance-trained men. Thirty resistance-trained men were randomly assigned in a double-blind manner to ingest 500 mg of either a placebo (PL) or AI once per day for 8 wk. Participants participated in a 4-d/wk resistance-training program for 8 wk. At Weeks 0, 4, and 8, body composition, 1-repetition-maximum (1RM) bench press and leg press, muscle endurance, anaerobic power, and hormonal profiles were assessed. Statistical analyses used a 2-way ANOVA with repeated measures for all criterion variables (p ≤ .05). Significant Group × Time interaction effects occurred over the 8-wk period for percent body fat (AI: -1.77% ± 1.52%, PL: -0.55% ± 1.72%; p = .048), total testosterone (AI: 0.97 ± 2.67 ng/ml, PL: -2.10 ± 3.75 ng/ml; p = .018), and bioavailable testosterone (AI: 1.32 ± 3.45 ng/ml, PL: -1.69 ± 3.94 ng/ml; p = .049). Significant main effects for time (p ≤ .05) were noted for bench- and leg-press 1RM, lean body mass, and estradiol. No significant changes were detected among groups for Wingate peak or mean power, total body weight, dihydrotestosterone, hemodynamic variables, or clinical safety data (p > .05). The authors concluded that 500 mg of dailyAI supplementation significantly affected percent body fat, total testosterone, and bioavailable testosterone compared with a placebo in a double-blind fashion.

  17. The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model

    PubMed Central

    2014-01-01

    Background Breast cancer is the most frequently diagnosed cancer in women in the United States. Approximately 70% of breast cancers are diagnosed in postmenopausal women. Major clinical trials and experimental studies showed that aromatase inhibitors are effective against postmenopausal breast cancer. Despite their effectiveness in reducing tumor recurrence, aromatase inhibitors have adverse effects on the cardiovascular system and increase osteoporosis and bone fractures. Our study is aimed at investigating the role of natural steroid hormones on serum cardiovascular and bone resorption markers in an established mouse model mimicking postmenopausal breast cancer. Methods Ovariectomized nude mice were transplanted with MCF-7 breast cancer cells constitutively expressing aromatase. The mice were treated with different combinations and doses of steroids, [estrogen (25 pg, 40 pg, 100 pg), progesterone (6 ng) and testosterone (50 ng)] along with dehydroepiandrostenedione (100 ug). Serum levels of HDL, LDL/VLDL, free and total cholesterol, total and bone specific alkaline phosphatase and triglycerides were analyzed after 5, 10 and 15 months. Results Free cholesterol and LDL/VLDL levels in serum were reduced in groups mimicking estrous cycle and menstrual cycle hormones treatment. HDL cholesterol was increased in all the hormone treated groups except the estrous cycle-mimicking group. Bone specific alkaline phosphatase was decreased in menstrual cycle levels of estrogen and progesterone treatment. Conclusions All together our results show that use of natural hormones in appropriate combinations have beneficial effects on cardiac and bone toxicity, along with better tumor reduction than current treatments. PMID:25023195

  18. Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to the Aromatase Inhibitor Fadrozole

    EPA Science Inventory

    A variety of chemicals present in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. The objective of this study was to provide a detailed characterization of the molecular and biochemical responses of female fathead minnows to a m...

  19. Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to the Aromatase Inhibitor Fadrozole

    EPA Science Inventory

    A variety of chemicals present in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. The objective of this study was to provide a detailed characterization of the molecular and biochemical responses of female fathead minnows to a m...

  20. Aromatase inhibitors decrease radiation-induced lung fibrosis: Results of an experimental study.

    PubMed

    Altinok, A Y; Yildirim, S; Altug, T; Sut, N; Ober, A; Ozsahin, E M; Azria, D; Bese, N S

    2016-08-01

    In experimental and clinical trials, tamoxifen (TAM) has been shown to increase radiation-induced lung fibrosis (RILF). Furthermore, aromatase inhibitors (AI) have been shown to be superior to TAM in the adjuvant setting and preclinical data suggest that letrozole (LET) sensitizes breast cancer cells to ionizing radiation in other studies. In this experimental study, we evaluated whether AI have any impact on the development of RILF in rats. 60 female wistar- albino rats were divided into 6 groups: Control (group A), RT alone (group B), RT + TAM (group C), RT + anastrozole (ANA group D), RT + LET (group E), and RT + exemestane (EXE, group F). RT consisted of 30 Gy in 10 fractions to both lungs with an anterior field at 2 cm depth. Equivalent doses for 60 kg adult dose per day of TAM, ANA, LET, and EXE were calculated according to the mean weight of rats and orally administrated with a feeding tube. Percentage of lung with fibrosis was quantified with image analysis of histological sections of the lung. The mean score values were calculated for each group. the significance of the differences among groups were calculated using one way ANOVA test and Tukey HSD post-hoc test. Mean values of fibrosis were 1.7, 5.9, 6.7, 2.5, 2 and 2.2 for groups A, B, C, D, E, and F, respectively (p = 0.000). TAM increased RT-induced lung fibrosis but without statistical significance. Groups treated with RT + AI showed significantly less lung fibrosis than groups treated with RT alone or RT + TAM (p = 0.000). RT + AI groups showed nearly similar RT-induced lung fibrosis than control group. In this study, we found that AI decreased RT-induced lung fibrosis to the control group level suggesting protective effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Profiles of miRNAs matched to biology in aromatase inhibitor resistant breast cancer

    PubMed Central

    Hoppe, Reiner; Fan, Ping; Büttner, Florian; Winter, Stefan; Tyagi, Amit K.; Cunliffe, Heather; Jordan, V. Craig; Brauch, Hiltrud

    2016-01-01

    Aromatase inhibitor (AI) resistance during breast cancer treatment is mimicked by MCF-7:5C (5C) and MCF-7:2A (2A) cell lines that grow spontaneously. Survival signaling is reconfigured but cells are vulnerable to estradiol (E2)-inducible apoptosis. These model systems have alterations of stress related pathways including the accumulation of endoplasmic reticulum, oxidative, and inflammatory stress that occur prior to E2-induced apoptosis. We investigated miRNA expression profiles of 5C and 2A to characterize their AI resistance phenotypes. Affymetrix GeneChip miRNA2.0 arrays identified 184 miRNAs differentially expressed in 2A and 5C compared to E2-free wild-type MCF-7:WS8. In 5C, 34 miRNAs of the DLK1-DIO3 locus and miR-31 were overexpressed, whereas miR-222 was low. TCGA data revealed poor and favorable overall survival for low miR-31 and miR-222 levels, respectively (HR=3.0, 95% CI:1.9-4.8; HR=0.3, 95% CI:0.1-0.6). Targets of deregulated miRNAs were identified using CLIP-confirmed TargetScan predictions. KEGG enrichment analyses for 5C- and 2A-specific target gene sets revealed pathways associated with cell proliferation including insulin, mTOR, and ErbB signaling as well as immune response and metabolism. Key genes overrepresented in 5C- and 2A-specific pathway interaction networks including EGFR, IGF1R and PIK3R1 had lower protein levels in 5C compared to 2A and were found to be differentially modulated by respective miRNA sets. Distinct up-regulated miRNAs from the DLK1-DIO3 locus may cause these attenuative effects as they are predicted to interact with corresponding 3′ untranslated regions. These new miRNA profiles become an important regulatory database to explore E2-induced apoptotic mechanisms of clinical relevance for the treatment of resistant breast cancer. PMID:27659519

  2. Treatment of idiopathic short stature: effects of gonadotropin-releasing hormone analogs, aromatase inhibitors and anabolic steroids.

    PubMed

    Dunkel, Leo

    2011-01-01

    Modulation of sex steroid action on the growth plate can, at least theoretically, increase adult height in children and adolescents with idiopathic short stature. Gonadotropin-releasing hormone (GnRH) analog therapy during adolescence has been shown effective in a placebo-controlled study, but to obtain clinically significant increases in adult height, the treatment duration must be lengthy (several years). Furthermore, such treatment seems to compromise bone health and, because of the resulting delay in pubertal development, likely has psychosocial consequences. Therefore, GnRH analogs are no longer recommended to augment height in adolescents with short stature and normally timed puberty. Aromatase inhibitors are probably more effective than GnRH analogs in promoting increased adult height in children with short stature and, unlike GnRH analogs, do not delay pubertal development in males. However, due to a dearth of safety data with aromatase inhibitors for the treatment of short stature, their use outside a research setting is currently not recommended. Positive effects of anabolic steroids on adult height have not been documented.

  3. Endocrine sex reversal of gonads by the aromatase inhibitor Letrozole (CGS 20267) in Emys orbicularis, a turtle with temperature-dependent sex determination.

    PubMed

    Richard-Mercier, N; Dorizzi, M; Desvages, G; Girondot, M; Pieau, C

    1995-12-01

    In embryos of Emys orbicularis, the sexual differentiation of gonads is influenced by the incubation temperature of eggs. Estrogens administered during the thermosensitive period result in the feminization of gonads at 25 degrees (male-producing temperature), whereas an antiestrogen or aromatase inhibitors masculinize the gonads at 30 degrees (female-producing temperature). The nonsteroidal aromatase inhibitor Letrozole induces gonads with different degrees of masculinization, from ovary-like to testis-like. The present study examines the endocrine function of such masculinized gonads, at the end of embryonic life. Aromatase activity (which is involved in estrogen synthesis in ovary) and the status of Müllerian ducts (the regression of which reflects the secretion of a putative anti-Müllerian hormone by the Sertoli cells) were examined. One month after treatment with Letrozole, the gonads of embryos presented various levels of aromatase activity. There was a strong correlation among aromatase activity, gonadal structure, and Müllerian duct status; high levels of aromatase (similar or close to those in control females) were found in ovary-like gonads; intermediate levels were found in gonads (masculinized ovaries or ovotestes?) exhibiting a cortex and a composite medulla containing a mixture of ovarian lacunae and testicular cord-like structures; low levels (similar or close to those in control males) were found in strongly masculinized gonads (testis-like or ovotestes). Müllerian ducts were regressing in the majority of embryos with gonads containing low levels of aromatase activity. In these individuals, gonads functioned as embryonic testes. These results confirm the implication of estrogens in gonadal differentiation. The origin of these hormones is controversial, so that the aromatase activity was compared in gonads, in the undissociated adrenal-mesonephric complex (AM), and in different parts of this complex during the thermosensitive period. At the female

  4. Synthesis and biochemical studies of 7 alpha-substituted androsta-1,4-diene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase.

    PubMed

    Ebrahimian, S; Chen, H H; Brueggemeier, R W

    1993-09-01

    Several 7 alpha-thiosubstituted derivatives of androstenedione have demonstrated effective inhibition of aromatase, the cytochrome P450 enzyme complex responsible for the biosynthesis of estrogens. Introduction of an additional double bond in the A ring resulted in 7 alpha-(4'-amino)phenylthioandrosta-1,4-diene-3,17-dione (7 alpha-APTADD), a potent inhibitor that inactivated aromatase by an enzyme-catalyzed process. Additional 7 alpha-thiosubstituted androsta-1,4-diene-3,17-dione derivatives were designed to further examine enzyme-catalyzed inactivation. Two halogenated and one unsubstituted 7 alpha-phenylthioandrosta-1,4-diene-3,17-diones were synthesized via an acid-catalyzed conjugate Michael addition of substituted thiophenols with androsta-1,4,6-triene-3,17-dione. Two 7 alpha-naphthylthioandrosta-1,4-diene-3,17-diones were synthesized via either acid-catalyzed or based-catalyzed conjugate Michael addition of substituted thionaphthols with androsta-1,4,6-triene-3,17-dione. These agents were evaluated for aromatase inhibitory activity in the human placental microsomal preparation. Under initial velocity assay conditions of low product formation, the inhibitors demonstrated potent inhibition of aromatase, with apparent Ki's ranging from 12 to 27 nM. Furthermore, these compounds produced time-dependent, first-order inactivation of aromatase in the presence of NADPH, whereas no aromatase inactivation was observed in the absence of NADPH. This enzyme-activated irreversible inhibition, also referred to as mechanism-based inhibition, can be prevented by the substrate androstenedione. Thus, the apparent Ki values for these inhibitors are consistent with earlier studies on 7 alpha-substituted competitive inhibitors that indicate bulky substituents can be accommodated at the 7 alpha-position.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Aromatase inhibitors block natural sex change and induce male function in the protandrous black porgy, Acanthopagrus schlegeli Bleeker: possible mechanism of natural sex change.

    PubMed

    Lee, Yan-Horn; Yueh, Wen-Shiun; Du, Jin-Lien; Sun, Lian-Tien; Chang, Ching-Fong

    2002-06-01

    The objectives of the present study were to investigate the effects of oral administration of aromatase inhibitors on sex change, milt volume, 11-ketotestosterone (11-KT), and LH in plasma; aromatase activity in gonad, pituitary, and brain in the protandrous fish, black porgy (Acanthopagus schlegeli Bleeker). Two-year-old functional male black porgy were divided into two groups; one was fed a control diet and the other was fed a diet mixed with aromatase inhibitors (AIs; fadrozole and 1,4,6-androstatriene-3,17-dione, each 10 mg/kg feed) for 8.5 mo. A significantly higher gonadosomatic index was observed in the AI group. Fish treated with AIs showed complete suppression of natural sex change. Significantly higher levels of plasma 11-KT, LH, and milt volume were shown in the AI group than the controls. Lower aromatase activity in the gonad, pituitary, forebrain, midbrain, and hindbrain in concordance with the suppression of sex change was observed in the AI group. The data show that aromatase is directly involved in the mechanism of natural sex change of protandrous black porgy. AIs also enhanced male function in concordance with the elevated plasma levels of 11-KT and spermiation in milt volume.

  6. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status.

    PubMed

    Parsanezhad, Mohammad Ebrahim; Azmoon, Mina; Alborzi, Saeed; Rajaeefard, Abdoreza; Zarei, Afsun; Kazerooni, Talieh; Frank, Vivian; Schmidt, Ernst Hienrich

    2010-01-01

    To examine and compare the efficacy and safety of GnRH agonist (GnRHa) vs. aromatase inhibitor in premenopausal women with leiomyomas. Multicenter, randomized, controlled clinical trial. University hospitals. A total of 70 subjects with a single uterine myoma measuring >or=5 cm. Subjects were randomized into two groups with use of a random table. They were treated with aromatase inhibitor (group A) or GnRHa (group B). Group A received letrozole (2.5 mg/d) for 12 weeks. Group B received triptorelin (3.75 mg/mo) for 12 weeks. Measurement of myoma volume and E(2), FSH, LH, and T levels. Total myoma volume decreased by 45.6% in group A and 33.2% in group B. Reductions in myoma volume in the two groups were statistically significant. There was no significant change in hormonal milieu in group A. The serum level of hormones significantly decreased in group B by the 12th week of treatment. Uterine myoma volume was successfully reduced by use of an aromatase inhibitor. Rapid onset of action and avoidance of initial gonadotropin flare with an aromatase inhibitor may be advantageous for short-term management of women with myomas of any size who are to be managed transiently and who wish to avoid surgical intervention, specifically women with unexplained infertility having uterine myoma. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  7. Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrosole: Microarray Analysis for Hypothesis Generation

    EPA Science Inventory

    A part of an overall program of research aimed at examining system-wide responses of the hypothalamic-pituitary-gonadal axis in fish to endocrine active chemicals acting through a variety of modes of action, we exposed zebrafish (Danio rerio) to the aromatase inhibitor fadrozole ...

  8. Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrosole: Microarray Analysis for Hypothesis Generation

    EPA Science Inventory

    A part of an overall program of research aimed at examining system-wide responses of the hypothalamic-pituitary-gonadal axis in fish to endocrine active chemicals acting through a variety of modes of action, we exposed zebrafish (Danio rerio) to the aromatase inhibitor fadrozole ...

  9. Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrozole: Microarray analysis and Hypothesis Generation

    EPA Science Inventory

    As part of a research effort examining system-wide responses of the hypothalamic-pituitary-gonadal (HPG) axis in fish to endocrine active chemicals (EACs) with different modes of action, we exposed zebrafish (Danio rerio) to 25 or 100 ìg/L of the aromatase inhibitor fadrozole for...

  10. Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrozole: Microarray analysis and Hypothesis Generation

    EPA Science Inventory

    As part of a research effort examining system-wide responses of the hypothalamic-pituitary-gonadal (HPG) axis in fish to endocrine active chemicals (EACs) with different modes of action, we exposed zebrafish (Danio rerio) to 25 or 100 ìg/L of the aromatase inhibitor fadrozole for...

  11. Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies

    PubMed Central

    Mojaddami, Ayyub; Sakhteman, Amirhossein; Fereidoonnezhad, Masood; Faghih, Zeinab; Najdian, Atena; Khabnadideh, Soghra; Sadeghpour, Hossein; Rezaei, Zahra

    2017-01-01

    Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue. PMID:28255310

  12. Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review.

    PubMed

    Ioannides, S J; Barlow, P L; Elwood, J M; Porter, D

    2014-09-01

    Aromatase inhibitors (AIs) decrease the production of oestrogen, decreasing stimulation of hormone receptor-positive breast cancer. Theoretically, AIs may be less effective in obese women, due to the greater quantity of aromatase in peripheral fatty tissue. We performed a systematic review to assess the effect of obesity on AI efficacy in breast cancer treatment. The review followed PRISMA guidelines. Studies included were interventional or observational studies with comparison groups, of postmenopausal women with hormone receptor-positive breast cancer on treatment with an AI, alone or in combination with other drugs, in which body mass index or another measure of obesity was recorded. Studies in all languages were included; if published as an abstract only, authors were contacted for further information. Outcome measures included overall survival, disease-free survival or time to progressive disease, survival from the start of therapy, mortality measures, local or distant recurrence of primary cancer and time to recurrence. Of 2,344 citations identified from five databases, eight studies met the criteria for inclusion; three randomised controlled trials and five retrospective cohort studies. Due to variability in study factors, it was not possible to perform a quantitative meta-analysis. However, the systematic review showed a trend towards a negative effect of obesity on AI efficacy. There is evidence of a negative effect of obesity on AI efficacy in postmenopausal hormone receptor-positive breast cancer, but the size of the effect cannot be assessed. More information is needed before clinical recommendations are made.

  13. From nonsteroidal aromatase inhibitors to multifunctional drug candidates: classic and innovative strategies for the treatment of breast cancer.

    PubMed

    Gobbi, Silvia; Cavalli, Andrea; Bisi, Alessandra; Recanatini, Maurizio

    2008-01-01

    Aromatase is the enzyme responsible for the conversion of androgens to estrogens and represents the main source of local estrogens in post-menopausal breast cancer tissue. Nonsteroidal aromatase inhibitors (NSAIs) are able to reduce growth-stimulatory effects of estrogens in hormone-dependent breast cancer, and third generation NSAIs are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic advanced breast cancer. Nevertheless, some issues in this area still need to be addressed and research efforts are aimed both at identifying new molecules of therapeutic interest and at exploring different options for the modulation of this enzyme. In this review, an update of the latest developments in the field of NSAIs is presented, to provide a broad view on the recent progress in this area. Beside classical structure-activity relationships studies and development of natural product derivatives, rational approaches for both ligand- and structure-based design are described. Moreover, novel strategies for the development of multitarget-directed molecules are also presented. Finally, some possible future developments in this research area are briefly considered.

  14. [Criteria for evaluating the effectiveness of aromatase inhibitors in the neoadjuvant treatment of patients with endometrial carcinoma].

    PubMed

    Bershteĭn, L M; Danilova, M A; Kovalevskiĭ, A Iu; Gershfel'd, E D; Poroshina, T E; Tsyrlina, T E; Meshkova, I E; Turkevich, E A; Maksimov, S Ia

    2009-01-01

    Clinical and experimental effects of neoadjuvant treatment of endometrial cancer patients with non-steroidal aromatase inhibitors: letrozole (femara, n=10, 2.5 mg/day, 14 days), anastrozole (arimidex, n=15,1 mg/day, 28 days) and exemestane (aromazine, n=13, 25 mg/day, 14 days) were compared. Administration of anastrozole was mostly frequently followed by pain relief in the lower abdomen and/or decreased rates of uterine discharge. Endometrial wall thickness (M-echo signal) decreased significantly in 60% of patients receiving anastrozole, exemestane - 58.3% and letrozole - 40%. Substantial drop in intratumoral aromatase and blood estradiol levels occurred more frequently after anastrozole and letrozole while progesterone receptor levels in tumor were markedly lower after exemestane administration. Assay of blood LH (except letrozole), FSH and cholesterol appeared to be of less relevance. On the contrary, significance of assessment of marker Ki-67 expression, which, in the case of anastrozole, dropped in 6 out of 12 patients after a 28-day course, could hardly be underestimated.

  15. Combating breast cancer with non-steroidal aromatase inhibitors (NSAIs): Understanding the chemico-biological interactions through comparative SAR/QSAR study.

    PubMed

    Adhikari, Nilanjan; Amin, Sk Abdul; Saha, Achintya; Jha, Tarun

    2017-09-08

    It is a challenging task to design target-specific and less toxic non-steroidal aromatase inhibitors (NSAIs) though the modeling studies for designing anti-aromatase molecules have been continuing for more than two decades to fight the dreaded estrogen-dependent breast cancer. In this article, different validated QSAR models are developed and analyzed to understand important physicochemical and structural parameters modulating the aromatase inhibitory activity of NSAIs. Physicochemical properties such as molar refractivity and dipole moment are found to be the most important parameters for controlling aromatase inhibition. This indicates the characteristic of bulky, complex and steric properties as well as, the flexibility of molecules is playing pivotal roles for aromatase inhibition. In many cases, hydrophobicity also plays important contribution. Regarding the structural point of view, some important indicator parameters are also found to be important for aromatase inhibitory activity. Though azole function is playing a crucial role by coordinating the heme moiety of the aromatase enzyme, the imidazole or the imidazolylmethyl ring systems may be better NSAIs than triazole, tetrazole or other azoles. The 4-pyridylmethyl group containing compounds are also found to be better NSAIs. The QSAR study, in a nutshell, provides a detailed understanding of the effectivity of NSAIs which is dependent mainly on the shape and size as well as the steric features of molecules and the heme-coordinator azole functions. These findings may open up a new horizon for designing new potential NSAIs that can be effective to reduce the mortality rate of breast cancer in future. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. The effect of the aromatase inhibitor, 4-(phenylthio)-4-androstene-3,17-dione, on dimethylbenz(A)anthracene-induced rat mammary tumors.

    PubMed

    Abul-Hajj, Y J

    1989-01-01

    4-(Phenylthio)-4-androstene-3,17-dione (4-PTAD), a known inhibitor of human placental aromatase, was examined as a growth inhibitor of DMBA-induced rat mammary tumors. Subcutaneous administration of 4-PTAD at dose levels of 25 or 50 mg/kg/day caused a significant decrease in hormone-dependent tumor growth. Resumption of tumor growth occurred when either the administration of inhibitor was stopped or when inhibitor was coadministered with estradiol indicating that suppression of tumor growth was due to inhibition of estrogen biosynthesis. Additionally, plasma levels of estradiol were found to be lower in the animals treated with 4-PTAD. The major metabolite of 4-PTAD in vitro was identified as 4-(phenylthio)-4-androstene-17 beta-ol-3-one and was found to have 60% of the aromatase inhibitory activity of 4-PTAD.

  17. Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study.

    PubMed

    Galeazzi, Roberta; Massaccesi, Luca

    2012-03-01

    CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking-molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)-namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones.

  18. A qualitative exploration of the impact of yoga on breast cancer survivors with aromatase inhibitor-associated arthralgias.

    PubMed

    Galantino, Mary Lou; Greene, Laurie; Archetto, Benjamin; Baumgartner, Melissa; Hassall, Paula; Murphy, Joanna Kluz; Umstetter, Jamie; Desai, Krupali

    2012-01-01

    Arthralgia affects postmenopausal breast cancer survivors (BCS) receiving aromatase inhibitors (AI), which may result in reduced function and long-term well-being. This is an exploratory, qualitative investigation of BCS who participated in a yoga-based program to understand impact on joint pain and various aspects of quality of life (QOL) through a yoga program. Social cognitive theory was used and provided the foundation for developing a yoga intervention through sources of efficacy information: (1) performance accomplishment, (2) structured experience, (3) verbal support from instructor and group, and (4) physical feedback. Ten postmenopausal women with stage I-III breast cancer and AI associated arthralgia (AIAA) received yoga twice a week for eight weeks for 90 minutes and were instructed to continue in a home-based yoga program. We used social cognitive theory (SCT) to structure a yoga intervention as an ongoing physical activity to manage joint pain and function. Participants completed journal reflections on their experience and received weekly phone calls. Data was collected and analyzed using qualitative methods. Member checks were completed and emergent themes were explored and agreed upon by the research team to ensure reliability and validity of data. Several emergent themes were discovered: Empowerment: Importance of Camaraderie, Community, and Sharing; Pain Relief; Increased Physical Fitness (Energy, Flexibility, and Function); Relieved Stress/Anxiety and Transferability of Yoga through Breathing. These themes were identified through instructor observation, participant observation, and weekly phone call documentation. Participants experienced an eight-week yoga intervention as an effective physical activity and support group that fostered various improvements in quality of life (QOL) and reduction in AIAA. Participants were highly motivated to improve physical fitness levels and reduce pain. This study revealed benefits from alternative forms of

  19. [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer].

    PubMed

    Sakurai, Kenichi; Fujisaki, Shigeru; Suzuki, Shuhei; Adachi, Keita; Nagashima, Saki; Masuo, Yuki; Tomita, Ryouichi; Gonda, Kenji; Enomoto, Katsuhisa; Amano, Sadao; Matsuo, Sadanori; Umeda, Nao

    2015-10-01

    We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy.

  20. Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1.

    PubMed

    Fusi, Camilla; Materazzi, Serena; Benemei, Silvia; Coppi, Elisabetta; Trevisan, Gabriela; Marone, Ilaria M; Minocci, Daiana; De Logu, Francesco; Tuccinardi, Tiziano; Di Tommaso, Maria Rosaria; Susini, Tommaso; Moneti, Gloriano; Pieraccini, Giuseppe; Geppetti, Pierangelo; Nassini, Romina

    2014-12-08

    Use of aromatase inhibitors (AIs), exemestane, letrozole and anastrozole, for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. The electrophilic nature of AIs suggests that they may target the transient receptor potential ankyrin 1 (TRPA1) channel, a major pathway in pain transmission and neurogenic inflammation. AIs evoke TRPA1-mediated calcium response and current in rodent nociceptors and human cells expressing the recombinant channel. In mice, AIs produce acute nociception, which is exaggerated by pre-exposure to proalgesic stimuli, and, by releasing sensory neuropeptides, neurogenic inflammation in peripheral tissues. AIs also evoke mechanical allodynia and decreased grip strength, which do not undergo desensitization on prolonged AI administration. These effects are markedly attenuated by TRPA1 pharmacological blockade or in TRPA1-deficient mice. TRPA1 is a major mediator of the proinflammatory/proalgesic actions of AIs, thus suggesting TRPA1 antagonists for the treatment of pain symptoms associated with AI use.

  1. Patient-Reported Outcomes and Early Discontinuation in Aromatase Inhibitor-Treated Postmenopausal Women With Early Stage Breast Cancer.

    PubMed

    Kadakia, Kunal C; Snyder, Claire F; Kidwell, Kelley M; Seewald, Nicholas J; Flockhart, David A; Skaar, Todd C; Desta, Zereunesay; Rae, James M; Otte, Julie L; Carpenter, Janet S; Storniolo, Anna M; Hayes, Daniel F; Stearns, Vered; Henry, N Lynn

    2016-05-01

    Early discontinuation of aromatase inhibitors (AIs) is common and leads to poor outcomes but is challenging to predict. In the Exemestane and Letrozole Pharmacogenetics trial, a high rate of early discontinuation due to intolerance was observed. We hypothesized that early changes in patient-reported outcomes (PROs) predict AI discontinuation and that biochemical factors are associated with changes in PROs. Postmenopausal women with early-stage breast cancer enrolled in a prospective randomized trial of exemestane versus letrozole completed questionnaires at baseline and serially over 24 months to assess overall quality of life (EuroQOL Visual Analog Scale [VAS]); mood; and multiple symptoms, including a musculoskeletal symptom cluster. A joint mixed-effects/survival model was used to estimate the effect of the change in PROs on AI discontinuation. Associations between biochemical factors and change in PROs were examined. A total of 490 patients were analyzed. Worsening of EuroQOL VAS and the musculoskeletal cluster were associated with the highest risk for early discontinuation (hazard ratio [HR], 2.77 [95% confidence interval (CI), 2.72-2.81; p = .015]; HR, 4.39 [95% CI, 2.40-8.02; p < .0001], respectively). Pharmacokinetics and estrogen metabolism were not consistently associated with change in PRO measures. No clinically significant differences in any PRO between AIs were observed. Changes in PROs early during AI therapy were associated with treatment discontinuation. Identification of these changes could be used to target interventions in patients at high risk for early discontinuation. Early changes in patient-reported outcomes (PROs) can predict nonpersistence to aromatase inhibitor therapy. If used in clinical practice, PROs might identify women at highest risk for early discontinuation and allow for interventions to improve tolerance before significant toxicities develop. Further research is needed to improve capturing PROs in routine clinical practice.

  2. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer.

    PubMed

    Iveson, T J; Smith, I E; Ahern, J; Smithers, D A; Trunet, P F; Dowsett, M

    1993-01-15

    A phase I study was performed of CGS 20267, an oral nonsteroidal, highly potent, and selective aromatase inhibitor, in 21 postmenopausal patients with advanced breast cancer. The patients were recruited in 3 successive groups of 7, receiving 0.1, 0.5, and 2.5 mg p.o./day, respectively. All patients had received at least one prior endocrine treatment (range, 1-4), and six patients had received prior chemotherapy. The treatment was very well tolerated, and no toxicity was seen at any of the three doses. There was a statistically significant suppression of estradiol (E2) and estrone (E1) levels by 74% and 79% from baseline levels, respectively (P < 0.0001). Suppression occurred in all three patient groups, with many patients having serum concentrations of estradiol and estrone, which were below the limit of detection of the assays (3 and 10 pM, respectively), which corresponds to a maximum measurable estrogen suppression of 86%. CGS 20267 had no significant effect on serum levels of follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, and aldosterone. Seven (33%, 95% confidence interval, 15-57%) of the 21 patients have responded to treatment (one complete remission, 6 partial remissions according to criteria of the Union Internationale contre le Cancer), and 6 are still responding to CGS 20267 (duration of response; 4+, 6+, 6+, 9+, 9, 12+, and 12+ months). Five have had stable disease for more than 3 months, and 9 had progressive disease. These results suggest that CGS 20267 is a very potent and specific aromatase inhibitor, and phase II studies are now required to confirm its clinical efficacy.

  3. Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors

    PubMed Central

    2011-01-01

    Introduction Aromatase inhibitor-associated arthralgia (AIAA) is a common and often debilitating symptom in breast cancer survivors. Since joint symptoms have been related to estrogen deprivation through the menopausal transition, we hypothesized that genetic polymorphisms in CYP19A1, the final enzyme in estrogen synthesis, may be associated with the occurrence of AIAA. Methods We performed a cross-sectional study of postmenopausal women with stage 0 to III breast cancer receiving adjuvant aromatase inhibitor (AI) therapy. Patient-reported AIAA was the primary outcome. DNA was genotyped for candidate CYP19A1 polymorphisms. Serum estrogen levels were evaluated by radioimmunoassay. Multivariate analyses were performed to examine associations between AIAA and genetic variants controlling for possible confounders. Results Among 390 Caucasian participants, 50.8% reported AIAA. Women carrying at least one 8-repeat allele had lower odds of AIAA (adjusted odds ratio (AOR) 0.41, 95% confidence interval (CI) 0.21 to 0.79, P = 0.008) after adjusting for demographic and clinical covariates. Estradiol and estrone were detectable in 47% and 86% of subjects on AIs, respectively. Although these post-AI levels were associated with multiple genotypes, they were not associated with AIAA. In multivariate analyses, women with more recent transition into menopause (less than five years) were significantly more likely to report AIAA than those greater than ten years post-menopause (AOR 3.31, 95% CI 1.72 to 6.39, P < 0.001). Conclusions Functional polymorphism in CYP19A1 and time since menopause are associated with patient-reported AIAA, supporting the hypothesis that the host hormonal environment contributes to the pathophysiology of AAIA. Prospective investigation is needed to further delineate relationships between host genetics, changing estrogen levels and AIAA. PMID:21251330

  4. New aromatase inhibitors. Synthesis and biological activity of pyridyl-substituted tetralone derivatives.

    PubMed

    Bayer, H; Batzl, C; Hartmann, R W; Mannschreck, A

    1991-09-01

    The (E)-2-(4-pyridylmethylene)-1-tetralones 1-7 (1, H; 2, 5-OCH3; 3, 6-OCH3; 4, 7-OCH3; 5, 5-OH; 6, 6-OH; 7, 7-OH) were obtained by aldol condensation of the corresponding 1-tetralones with 4-pyridinecarboxaldehyde, and in the case of the OH compounds 5 and 7 subsequent ether cleavage of the OCH3-substituted 2-(4-pyridylmethylene)-1-tetralones. Catalytic hydrogenation of 1-4 gave the 2-(4-pyridylmethyl)-1-tetralones 8-11 (8, H; 9, 5-OCH3; 10, 6-OCH3; 11, 7-OCH3). Subsequent ether cleavage of 9-11 led to the corresponding OH compounds 12-14 (12, 5-OH; 13, 6-OH; 14, 7-OH). The enantiomers of 11 and 12 were separated semipreparatively by HPLC on triacetylcellulose. All compounds (1-14) showed an inhibition of human placental aromatase exhibiting relative potencies from 2.2 to 213 [compounds 6 and (+)-12, respectively; aromatase inhibitory potency of aminoglutethimide (AG) = 1]. The compounds exhibited no or only a weak inhibition of desmolase [cholesterol side chain cleavage enzyme; maximum activity shown by 12, 23% inhibition (25 microM); AG, 53% inhibition (25 microM)]. In vivo, however, the compounds were not superior to AG as far as the reduction of the plasma estradiol concentration and the mammary carcinoma (MC) inhibiting properties are concerned (PMSG-primed SD rats as well as DMBA-induced MC of the SD rat, pre- and postmenopausal experiments, and the transplantable MXT-MC of the BD2F1 mouse). This is due to a fast decrease of the plasma E2 concentration inhibiting effect as could be shown by a kinetic experiment. In addition, select compounds inhibited rat ovarian aromatase much less than human placental aromatase (12, factor of 10). Estrogenic effects as a cause for the poor in vivo activity of the test compounds could be excluded, since they did not show affinity for the estrogen receptor.

  5. MCF-7aro/ERE, a novel cell line for rapid screening of aromatase inhibitors, ERalpha ligands and ERRalpha ligands.

    PubMed

    Lui, Ki; Tamura, Takaya; Mori, Taisuke; Zhou, Dujin; Chen, Shiuan

    2008-07-15

    We have previously generated a breast cancer cell line, MCF-7aro, which over-expresses aromatase and is also ER positive. Recently, this MCF-7aro cell line was stably transfected with a promoter reporter plasmid, pGL3-Luc, containing three repeats of estrogen responsive element (ERE). Experiments using MCF-7aro/ERE have demonstrated that it is a novel, non-radioactive screening system for aromatase inhibitors (AIs), ERalpha ligands and ERRalpha ligands. The screening is carried out in a 96-well plate format. To evaluate this system, the cells were cultured overnight in charcoal-dextran stripped FBS medium supplemented with 0.1 nM testosterone or 17beta-estradiol, and various concentrations of antiestrogens or AIs. We found that the luciferase activity was induced when the cells were cultured either in the presence of testosterone or 17beta-estradiol. Furthermore, a 50% decrease in luciferase activity could be achieved when the cells were cultured in the presence of testosterone together with letrozole, anastrozole, tamoxifen or fulvestrant (concentrations being 75 nM, 290 nM, 100 nM, and 5 nM, respectively), compared to the testosterone-only cultured cells. Using this assay system, we confirmed that 3(2'-chlorophenyl)-7-methoxy-4-phenylcoumarin is an agonist of ER. Furthermore, genestein has been shown to be a ligand of ERRalpha because its binding could be blocked by an ERRalpha inverse agonist, XCT790. These results indicate that MCF-7aro/ERE is a novel cell line for rapid screening of AIs, ERalpha ligands and ERRalpha ligands.

  6. Use of Aromatase Inhibitors in Large Cell Calcifying Sertoli Cell Tumors: Effects on Gynecomastia, Growth Velocity, and Bone Age

    PubMed Central

    Crocker, Melissa K.; Gourgari, Evgenia; Stratakis, Constantine A.

    2014-01-01

    Context: Large cell calcifying Sertoli cell tumors (LCCSCT) present in isolation or, especially in children, in association with Carney Complex (CNC) or Peutz-Jeghers Syndrome (PJS). These tumors overexpress aromatase (CYP19A1), which leads to increased conversion of delta-4-androstenedione to estrone and testosterone to estradiol. Prepubertal boys may present with growth acceleration, advanced bone age, and gynecomastia. Objective: To investigate the outcomes of aromatase inhibitor therapy (AIT) in prepubertal boys with LCCSCTs. Design: Case series of a very rare tumor and chart review of cases treated at other institutions. Setting: Tertiary care and referral center. Patients: Six boys, five with PJS and one with CNC, were referred to the National Institutes of Health for treatment of LCCSCT. All patients had gynecomastia, testicular enlargement, and advanced bone ages, and were being treated by their referring physicians with AIT. Interventions: Patients were treated for a total of 6–60 months on AIT. Main Outcome Measures: Height, breast tissue mass, and testicular size were all followed; physical examination, scrotal ultrasounds, and bone ages were obtained, and hormonal concentrations and tumor markers were measured. Results: Tumor markers were negative. All patients had decreases in breast tissue while on therapy. Height percentiles declined, and predicted adult height moved closer to midparental height as bone age advancement slowed. Testicular enlargement stabilized until entry into central puberty. Only one patient required unilateral orchiectomy. Conclusions: Patients with LCCSCT benefit from AIT with reduction and/or elimination of gynecomastia and slowing of linear growth and bone age advancement. Further study of long-term outcomes and safety monitoring are needed but these preliminary data suggest that mammoplasty and/or orchiectomy may be foregone in light of the availability of medical therapy. PMID:25226294

  7. Aurora kinase A and B as new treatment targets in aromatase inhibitor-resistant breast cancer cells.

    PubMed

    Hole, Stine; Pedersen, Astrid M; Lykkesfeldt, Anne E; Yde, Christina W

    2015-02-01

    Aromatase inhibitors (AIs) are used for treatment of estrogen receptor α (ER)-positive breast cancer; however, resistance is a major obstacle for optimal outcome. This preclinical study aimed at identifying potential new treatment targets in AI-resistant breast cancer cells. Parental MCF-7 breast cancer cells and four newly established cell lines, resistant to the AIs exemestane or letrozole, were used for a functional kinase inhibitor screen. A library comprising 195 different compounds was tested for preferential growth inhibition of AI-resistant cell lines. Selected targets were validated by analysis of cell growth, cell cycle phase distribution, protein expression, and subcellular localization. We identified 24 compounds, including several inhibitors of Aurora kinases e.g., JNJ-7706621 and barasertib. Protein expression of Aurora kinase A and B was found upregulated in AI-resistant cells compared with MCF-7, and knockdown studies showed that Aurora kinase A was essential for AI-resistant cell growth. In AI-resistant cell lines, the clinically relevant Aurora kinase inhibitors alisertib and danusertib blocked cell cycle progression at the G2/M phase, interfered with chromosome alignment and spindle pole formation, and resulted in preferential growth inhibition compared with parental MCF-7 cells. Even further growth inhibition was obtained when combining the Aurora kinase inhibitors with the antiestrogen fulvestrant. Our study is the first to demonstrate that Aurora kinase A and B may be treatment targets in AI-resistant cells, and our data suggest that therapy targeting both ER and Aurora kinases may be a potent treatment strategy for overcoming AI resistance in breast cancer.

  8. Durable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders: a case report.

    PubMed

    Martin-Romano, P; Jurado, M; Idoate, M A; Arbea, L; Hernandez-Lizoain, J L; Cano, D; Paramo, J A; Martin-Algarra, S

    2017-04-19

    Chemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response. A 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life. This case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.

  9. Data of aromatase inhibitors alone and in combination with raloxifene on microarchitecture of lumbar vertebrae and strength test in femoral diaphysis of VCD treated ovotoxic mice.

    PubMed

    Kalam, Abul; Talegaonkar, Sushama; Vohora, Divya

    2017-02-01

    Currently, the third generation aromatase inhibitors are the drugs of choice for treatment of early and advanced breast cancer in postmenopausal women. The negative impact of these drugs on bone health is the significant limiting factor during this therapy. Here we report the effect of two aromatase inhibitors viz. letrozole and exemestane alone and in combination with raloxifene on lumbar vertebrae and femoral diaphysis after one month of treatment but no discernible effects were observed on bone when tested by micro CT and strength test except in trabecular number which was reduced in lumbar vertebrae following letrozole and exemestane. Further studies with letrozole and exemestane should be done at higher doses for longer duration of time to check whether effects are observed in other parameters as well. The data is an extension of our published work in Mol. Cell Endocrinology (A. Kalam, S. Talegaonkar, D. Vohora, 2017) [1] describing letrozole-induced bone loss on femoral epiphysis and its reversal by raloxifene.

  10. Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay.

    PubMed

    Jacobsen, Naja Wessel; Hansen, Cecilie Hurup; Nellemann, Christine; Styrishave, Bjarne; Halling-Sørensen, Bent

    2015-10-01

    Selective serotonin reuptake inhibitors are known to have a range of disorders that are often linked to the endocrine system e.g. hormonal imbalances, breast enlargement, sexual dysfunction, and menstrual cycle disorders. The mechanisms behind most of these disorders are not known in details. In this study we investigated whether the endocrine effect due to SSRI exposure could be detected in well adopted in vitro steroidogenesis assays, two versions of the aromatase enzyme inhibition assay and the H295R cell assay. The five drugs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, were shown to inhibit the aromatase enzyme in both types of aromatase assays. The IC50 values ranged from 3 to 600 μM. All five SSRIs, were further investigated in the H295R cell line. All compounds altered the steroid secretion from the cells, the lowest observed effect levels were 0.9 μM and 3.1 μM for sertraline and fluvoxamine, respectively. In general the H295R cell assay was more sensitive to SSRI exposure than the two aromatase assays, up to 20 times more sensitive. This indicates that the H295R cell line is a better tool for screening endocrine disrupting effects. Our findings show that the endocrine effects of SSRIs may, at least in part, be due to interference with the steroidogenesis.

  11. A molecular model for the interaction between vorozole and other non-steroidal inhibitors and human cytochrome P450 19 (P450 aromatase).

    PubMed

    Koymans, L M; Moereels, H; Vanden Bossche, H

    1995-06-01

    In a previous study (Vanden Bossche et al., Breast Cancer Res. Treat. 30 (1994) 43) the interaction between (+)-S-vorozole and the I-helix of cytochrome P450 19 (P450 aromatase) has been reported. In the present study we extended the "I-helix model" by incorporating the C-terminus of P450 aromatase. The crystal structures of P450 101 (P450 cam), 102 (P450 BM-3) and 108 (P450 terp) reveal that the C-terminus is structurally conserved and forms part of their respective substrate binding pocket. Furthermore, the present study is extended to the interaction between P450 aromatase and its natural substrate androstenedione and the non-steroidal inhibitors (-)-R-vorozole, (-)-S-fadrozole, R-liarozole and (-)-R-aminoglutethimide. It is found that (+)-S-vorozole, (-)-S-fadrozole and R-liarozole bind in a comparable way to P450 aromatase and interact with both the I-helix (Glu302 and Asp309) and C-terminus (Ser478 and His480). The weak activity of (-)-R-aminoglutethimide might be attributed to a lack of interaction with the C-terminus.

  12. Linkage of routinely collected oncology clinical data with health insurance claims data--an example with aromatase inhibitors, tamoxifen, and all-cause mortality.

    PubMed

    Dore, David D; Liang, Caihua; Ziyadeh, Najat; Norman, Heather; Bayliss, Martha; Seeger, John D

    2012-05-01

    Studies of cancer based solely on health insurance claims data typically lack information on cancer clinical characteristics that are strong predictors of treatment and prognosis. Our objective was to evaluate routinely collected cancer clinical data for adjustment of confounding using an example evaluation of mortality associated with aromatase inhibitors and tamoxifen. This cohort study identified women with breast cancer from 2008 through 2010 using health insurance claims data linked to clinical information on stage at diagnosis, current clinical status, histology, and other clinical markers. Estimated mortality rates (MRs) and 95% confidence intervals (CI) were compared between users of aromatase inhibitors or tamoxifen, adjusted for claims-identified covariates and additionally for the clinical variables using propensity scores and proportional hazards regression models. The overall (n = 7974) estimated MR was 69/1000 person-years (95%CI = 62-76 person-years), 308/1000 person-years (95% CI = 273-345 person-years) for women with metastasis, and 12/1000 person-years (95%CI = 8-16 person-years) for women without active cancer. Propensity score matching of aromatase inhibitor users (n = 777) with tamoxifen users (n = 535) removed many, but not all, covariate imbalances. The hazard ratios (HRs) of all-cause mortality comparing users of aromatase inhibitors with tamoxifen users ranged from 1.0 to 1.6, with the HR most similar to previous clinical trials (0.87) coming from the claims-only analysis. We were able to address potential unmeasured confounders by linking clinical information to the claims data; however, there was no apparent improvement in confounding control in the chosen example. Conditioning eligibility on the clinical data restricted the sample size substantially. Copyright © 2012 John Wiley & Sons, Ltd.

  13. Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia-Inducible Factor 1 (HIF-1) in Aromatase Inhibitor Resistant Breast Cancer

    DTIC Science & Technology

    2012-10-01

    respectively. Third , expression of HER2 and HIF-1 was also analyzed in another aromatase inhibitor (AI)-resistant cell line . Exemestane-resistant...combined with letrozole versus letrozole and placebo as first- line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin...to identify other relevant factors involved that can be used as biomarkers of AI resistance or targets for therapy . One such factor may include HIF-1

  14. Concordant effects of aromatase inhibitors on gene expression in ER+ Rat and human mammary cancers and modulation of the proteins coded by these genes.

    PubMed

    Lu, Yan; You, Ming; Ghazoui, Zara; Liu, Pengyuan; Vedell, Peter T; Wen, Weidong; Bode, Ann M; Grubbs, Clinton J; Lubet, Ronald A

    2013-11-01

    Aromatase inhibitors are effective in therapy/prevention of estrogen receptor-positive (ER⁺) breast cancers. Rats bearing methylnitrosourea (MNU)-induced ER⁺ mammary cancers were treated with the aromatase inhibitor vorozole (1.25 mg/kg BW/day) for five days. RNA expression showed 162 downregulated and 180 upregulated (P < 0.05 and fold change >1.5) genes. Genes modulated by vorozole were compared with published data from four clinical neoadjuvant trials using aromatase inhibitors (anastrozole or letrozole). More than 30 genes and multiple pathways exhibited synchronous changes in animal and human datasets. Cell-cycle genes related to chromosome condensation in prometaphase [anaphase-prometaphase complex (APC) pathway, including Aurora-A kinase, BUBR1B, TOP2, cyclin A, cyclin B CDC2, and TPX-2)] were downregulated in animal and human studies reflecting the strong antiproliferative effects of aromatase inhibitors. Comparisons of rat arrays with a cell culture study where estrogen was removed from MCF-7 cells showed decreased expression of E2F1-modulated genes as a major altered pathway. Alterations of the cell cycle and E2F-related genes were confirmed in a large independent set of human samples (81 pairs baseline and two weeks anastrozole treatment). Decreases in proliferation-related genes were confirmed at the protein level for cyclin A2, BuRB1, cdc2, Pttg, and TPX-2. Interestingly, the proteins downregulated in tumors were similarly downregulated in vorozole-treated normal rat mammary epithelium. Finally, decreased expression of known estrogen-responsive genes (including TFF, 1,3, progesterone receptor, etc.) were decreased in the animal model. These studies demonstrate that gene expression changes (pathways and individual genes) are similar in humans and the rat model.

  15. Coadministration of the aromatase inhibitor formestane and an isopropanolic extract of black cohosh in a rat model of chemically induced mammary carcinoma.

    PubMed

    Nisslein, Thomas; Freudenstein, Johannes

    2007-04-01

    Non-steroidal as well as steroidal aromatase inhibitors are currently being discussed as alternatives to tamoxifen in the first-line treatment of patients with hormone-dependent breast cancer. Many of these women are in a postmenopausal state and additionally troubled by climacteric complaints. Naturally occurring symptoms like hot flushes and night sweats can be triggered or augmented by anti-hormonal drugs. At the aromatase molecule, steroidal inhibitors like exemestane and formestane compete with the hormonal precursors for the substrate binding site and inactivate the enzyme irreversibly. An isopropanolic extract of the rootstock of black cohosh (iCR), which is a common comedication of aromatase inhibitors in breast cancer patients suffering from climacteric symptoms, contains triterpene glycosides and cinnamic acid esters, both of which possess structural similarities to steroids. We therefore tested a high dose of iCR, guaranteeing an effective uptake of 60 mg herbal substance per kg body weight and shown to influence rat bone and uterus, for putative interactions with two low dosing regimens of 3.5 mg or 5.0 mg formestane per animal and day. We chose a rat model of chemically induced breast cancer and evaluated tumor growth and serum estrogen levels. Compared to a tumor area of 1400 mm2 after 21 days of unopposed tumor growth, formestane treatment, irrespective of concomitant black cohosh application, significantly reduced neoplastic growth by 50%. Formestane also significantly reduced serum estrogen levels, an effect which was also not abolished by iCR. Therefore, in this experimental setting, when challenging two low doses of formestane with a high dose of iCR, our data do not raise concerns against combining aromatase inhibitors with black cohosh.

  16. Manipulation of broiler chickens sex differentiation by in ovo injection of aromatase inhibitors, and garlic and tomato extracts.

    PubMed

    Fazli, Nahid; Hassanabadi, Ahmad; Mottaghitalab, Majid; Hajati, Hosna

    2015-11-01

    The influence of in ovo administration of aromatase inhibitors, clomiphen citrate, tomoxifen, and garlic and tomato extracts on sex differentiation in broiler chickens were investigated in 2 experiments. Five hundred, and 1,000 fertile eggs from Ross 308 strain were used in experiments 1 and 2, respectively. In both experiments, eggs were divided into 5 groups: control group (DW, 0.1 mL/egg), tomoxifen (0.05 mg/egg), clomiphene citrate (0.05 mg/egg), garlic and tomato extracts (0.1 mL/egg). Eggs were sanitized and prepared for incubation in a regular automatic hatchery. Experimental preparations were injected into eggs at day 5 of the incubation period. Injection sites on the eggs were cleaned with 70% ethylic alcohol, bored by a needle, and aromatase inhibitors were injected into the white from the thin end of the eggs by insulin syringe and then sealed by melted paraffin. In experiment 1, hatched one-day-old chicks (mixed-sex) were raised till 42 days of age in 25 floor pens with a completely randomized design. Experiment 2 was designed to investigate the effects of sex and treatments on the feed-to-gain ratio of broiler chicks. In experiment 2, hatched one-day-old chicks were feather sexed and raised till 42 days of age in 50 floor pens. A completely randomized design with a 2 × 5 factorial arrangement of treatments (sex×treatment) was used. Gonads of the chicks were checked to determine their sex on day 42 by optic microscope to make sure feather sexing was correct. At the end of both experiments, on day 42, one bird from each pen was slaughtered for carcass analysis. In experiment 1, hatchability and the one-day-old weight of chicks showed no significant differences among treatments (P > 0.05). However, in ovo administration of garlic and tomato extracts caused the highest percentage of male chicks (P < 0.05). Also, the percentage of thighs and wings of the males were significantly higher than those of females (P < 0.05). In experiment 2, feed-to-gain ratio

  17. Anti-tumor efficacy of new 7α-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells.

    PubMed

    Amaral, Cristina; Varela, Carla L; Maurício, João; Sobral, Ana Filipa; Costa, Saul C; Roleira, Fernanda M F; Tavares-da-Silva, Elisiário J; Correia-da-Silva, Georgina; Teixeira, Natércia

    2017-04-07

    The majority of breast cancer cases are estrogen receptor positive (ER(+)). Although, third-generation aromatase inhibitors (AIs) are used as first-line treatment in post-menopausal women, they cause endocrine resistance and bone loss, which limits their success. Therefore, there is a demand to discover new potent molecules, with less toxicity that can circumvent these drawbacks. Our group has previously demonstrated that new 7α-substituted steroidal molecules, 7α-(2ξ,3ξ-epoxypropyl)androsta-1,4-diene-3,17-dione (3), 7α-allylandrost-4-ene-3,17-dione (6), 7α-allylandrost-4-en-17-one (9), 7α-allyl-3-oxoandrosta-1,4-dien-17β-ol (10) and 7α-allylandrosta-1,4-diene-3,17-dione (12) are potent AIs in placental microsomes. In this work, it was investigated their anti-aromatase activity and in vitro effects in sensitive and resistant breast cancer cells. All the steroids efficiently inhibit aromatase in breast cancer cells, allowing to establish new structure-activity relationships for this class of compounds. Moreover, the new AIs can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of AIs 3 and 12 on sensitive cells were dependent on aromatase inhibition and androgen receptor (AR), while for AI 9 and AI 10 were AR- and ER-dependent, respectively. In addition, it was shown that all the AIs can sensitize resistant cancer cells being their behavior similar to the sensitive cells. In summary, this study contributes to the understanding of the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. In addition, allowed the discovery of new potent 7α-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance.

  18. Predicting Adherence to Aromatase Inhibitor Therapy among Breast Cancer Survivors: An Application of the Protection Motivation Theory

    PubMed Central

    Karmakar, Monita; Pinto, Sharrel L; Jordan, Timothy R; Mohamed, Iman; Holiday-Goodman, Monica

    2017-01-01

    The purpose of this observational study was to determine if the Protection Motivation Theory could predict and explain adherence to aromatase inhibitor (AI) therapy among breast cancer survivors. Purposive sampling was used to identify 288 survivors who had been prescribed AI therapy. A valid and reliable survey was mailed to survivors. A total of 145 survivors completed the survey. The Morisky scale was used to measure adherence to AI. The survivors reported a mean score of 6.84 (±0.66) on the scale. Nearly 4 in 10 survivors (38%) were non-adherent. Adherence differed by age, marital status, insurance status, income, and presence of co-morbid conditions. Self-efficacy (r=0.485), protection motivation (r=0.310), and Response Efficacy (r=0.206) were positively and significantly correlated with adherence. Response Cost (r=-0.235) was negatively correlated with adherence. The coping appraisal constructs were statistically significant predictors medication adherence (β=0.437) with self-efficacy being the strongest significant predictor of adherence (β = 0.429). PMID:28469437

  19. The effect of exercise on body composition and bone mineral density in breast cancer survivors taking aromatase inhibitors.

    PubMed

    Thomas, Gwendolyn A; Cartmel, Brenda; Harrigan, Maura; Fiellin, Martha; Capozza, Scott; Zhou, Yang; Ercolano, Elizabeth; Gross, Cary P; Hershman, Dawn; Ligibel, Jennifer; Schmitz, Kathryn; Li, Fang-Yong; Sanft, Tara; Irwin, Melinda L

    2017-02-01

    This study examined the effect of 12 months of aerobic and resistance exercise versus usual care on changes in body composition in postmenopausal breast cancer survivors taking aromatase inhibitors (AIs). The Hormones and Physical Exercise study enrolled 121 breast cancer survivors and randomized them to either supervised twice-weekly resistance exercise training and 150 min/wk of aerobic exercise (N = 61) or a usual care (N = 60) group. Dual-energy X-ray absorptiometry scans were conducted at baseline, 6 months, and 12 months to assess changes in body mass index, percent body fat, lean body mass, and bone mineral density. At 12 months, the exercise group relative to the usual care group had a significant increase in lean body mass (0.32 vs. -0.88 kg, P = 0.03), a decrease in percent body fat (-1.4% vs. 0.48%, P = 0.03), and a decrease in body mass index (-0.73 vs. 0.17 kg/m(2) , P = 0.03). Change in bone mineral density was not significantly different between groups at 12 months (0.001 vs. -0.006 g/cm(2) , P = 0.37). A combined resistance and aerobic exercise intervention improved body composition in breast cancer survivors taking AIs. Exercise interventions may help to mitigate the negative side effects of AIs and improve health outcomes in breast cancer survivors. © 2016 The Obesity Society.

  20. Adverse Drug Event-based Stratification of Tumor Mutations: A Case Study of Breast Cancer Patients Receiving Aromatase Inhibitors.

    PubMed

    Wang, Chen; Zimmermann, Michael T; Prodduturi, Naresh; Chute, Christopher G; Jiang, Guoqian

    2014-01-01

    Adverse drug events (ADEs) are a critical factor for selecting cancer therapy options. The underlying molecular mechanisms of ADEs associated with cancer therapy drugs may overlap with their antineoplastic mechanisms; an aspect of toxicity. In the present study, we develop a novel knowledge-driven approach that provides an ADE-based stratification (ADEStrata) of tumor mutations. We demonstrate clinical utility of the ADEStrata approach through performing a case study of breast invasive carcinoma (BRCA) patients receiving aromatase inhibitors (AI) from The Cancer Genome Atlas (TCGA) (n=212), focusing on the musculoskeletal adverse events (MS-AEs). We prioritized somatic variants in a manner that is guided by MS-AEs codified as 6 Human Phenotype Ontology (HPO) terms. Pathway enrichment and hierarchical clustering of prioritized variants reveals clusters associated with overall survival. We demonstrated that the prediction of per-patient ADE propensity simultaneously identifies high-risk patients experiencing poor outcomes. In conclusion, the ADEStrata approach could produce clinically and biologically meaningful tumor subtypes that are potentially predictive of the drug response to the cancer therapy drugs.

  1. A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers

    PubMed Central

    McCann, Susan E.; Edge, Stephen B.; Hicks, David G.; Thompson, Lilian U.; Morrison, Carl D.; Fetterly, Gerald; Andrews, Christopher; Clark, Kim; Wilton, John; Kulkarni, Swati

    2014-01-01

    Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS) are not often described. We conducted a pilot 2×2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER+) breast cancer, to assess the effects of flaxseed and anastrozole, and possible interactions between them, on serum steroid hormone and tumor-related characteristics associated with long-term survival (Roswell Park Cancer Institute, 2007–2010). The effect of each treatment vs placebo on outcomes was determined by linear regression adjusting for pre-treatment measure, stage, and grade. Although not statistically significant, mean ERβ expression was approximately 40% lower from pre- to post-intervention in the FS+AI group only. We observed a statistically significant negative association (β±SE −0.3±0.1; p=0.03) for androstenedione in the FS+AI group vs placebo and for DHEA with AI treatment (β±SE −1.6±0.6; p=0.009). Enterolactone excretion was much lower in the FS+AI group compared to the FS group. Our results do not support strong effects of flaxseed on AI activity for selected breast tumor characteristics or serum steroid hormone levels, but suggest AI therapy might reduce the production of circulating mammalian lignans from flaxseed. PMID:24669750

  2. Adverse Drug Event-based Stratification of Tumor Mutations: A Case Study of Breast Cancer Patients Receiving Aromatase Inhibitors

    PubMed Central

    Wang, Chen; Zimmermann, Michael T.; Prodduturi, Naresh; Chute, Christopher G.; Jiang, Guoqian

    2014-01-01

    Adverse drug events (ADEs) are a critical factor for selecting cancer therapy options. The underlying molecular mechanisms of ADEs associated with cancer therapy drugs may overlap with their antineoplastic mechanisms; an aspect of toxicity. In the present study, we develop a novel knowledge-driven approach that provides an ADE-based stratification (ADEStrata) of tumor mutations. We demonstrate clinical utility of the ADEStrata approach through performing a case study of breast invasive carcinoma (BRCA) patients receiving aromatase inhibitors (AI) from The Cancer Genome Atlas (TCGA) (n=212), focusing on the musculoskeletal adverse events (MS-AEs). We prioritized somatic variants in a manner that is guided by MS-AEs codified as 6 Human Phenotype Ontology (HPO) terms. Pathway enrichment and hierarchical clustering of prioritized variants reveals clusters associated with overall survival. We demonstrated that the prediction of per-patient ADE propensity simultaneously identifies high-risk patients experiencing poor outcomes. In conclusion, the ADEStrata approach could produce clinically and biologically meaningful tumor subtypes that are potentially predictive of the drug response to the cancer therapy drugs. PMID:25954427

  3. Predicting Adherence to Aromatase Inhibitor Therapy among Breast Cancer Survivors: An Application of the Protection Motivation Theory.

    PubMed

    Karmakar, Monita; Pinto, Sharrel L; Jordan, Timothy R; Mohamed, Iman; Holiday-Goodman, Monica

    2017-01-01

    The purpose of this observational study was to determine if the Protection Motivation Theory could predict and explain adherence to aromatase inhibitor (AI) therapy among breast cancer survivors. Purposive sampling was used to identify 288 survivors who had been prescribed AI therapy. A valid and reliable survey was mailed to survivors. A total of 145 survivors completed the survey. The Morisky scale was used to measure adherence to AI. The survivors reported a mean score of 6.84 (±0.66) on the scale. Nearly 4 in 10 survivors (38%) were non-adherent. Adherence differed by age, marital status, insurance status, income, and presence of co-morbid conditions. Self-efficacy (r=0.485), protection motivation (r=0.310), and Response Efficacy (r=0.206) were positively and significantly correlated with adherence. Response Cost (r=-0.235) was negatively correlated with adherence. The coping appraisal constructs were statistically significant predictors medication adherence (β=0.437) with self-efficacy being the strongest significant predictor of adherence (β = 0.429).

  4. Zoledronic Acid for Treatment of Osteopenia and Osteoporosis in Women with Primary Breast Cancer Undergoing Adjuvant Aromatase Inhibitor Therapy1

    PubMed Central

    Hines, Stephanie L.; Sloan, Jeff A.; Atherton, Pamela J.; Perez, Edith A.; Dakhil, Shaker R.; Johnson, David B.; Reddy, Pavan S.; Dalton, Robert J.; Mattar, Bassam I.; Loprinzi, Charles L.

    2010-01-01

    Background Postmenopausal women with osteoporosis/osteopenia are at increased risk of fracture. Aromatase inhibitors further increase bone loss in these patients. This study evaluates whether zoledronic acid prevents the bone loss expected when these patients initiate letrozole. Patients and Methods Postmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a bone mineral density (BMD) T-score < −2.0 were given letrozole 2.5 mg/vitamin D 400 international units daily, calcium 500 mg twice daily, and 4 mg zoledronic acid every 6 months. The BMD was assessed at baseline and 1 year. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year. Results 46 patients completed 1 year of treatment. LS BMD increased by 2.66% (p=0.01), femoral neck (FN) by 4.81% (p=0.01), and any measured endpoint by 4.55% (p=0.0052). Conclusions Zoledronic acid prevents bone loss in postmenopausal women with osteoporosis/osteopenia starting letrozole and is associated with improvements in BMD. PMID:20079640

  5. [Effects of aromatase inhibitor on sexual differentiation of SDN-POA in rats].

    PubMed

    Ohe, E

    1994-03-01

    The sexually dimorphic nucleus of the preoptic area (SDN-POA) of male rats is larger than that of females, the difference being caused by the perinatal effect of estrogen converted from androgen. To investigate the role of estrogen formation in the SDN-POA during the critical period of this sexual differentiation, CGS16949A (0.5 mg/kg, sc) was injected into the mothers in the late gestational age(F) or into neonates for 14 days from birth(N). Animals were sacrificed on the 20th. day of gestation and 7 days after birth, and fetal and neonatal brain aromatase activities (AA) as well as serum levels of testosterone(T) and corticosterone(B) were measured. On the 30th day after birth, the offspring of treated mothers and neonatally treated rats were sacrificed and the cross-sectional areas of the SDN-POA were evaluated by image processor NEXUS 6800. In group F, CGS16949A markedly suppressed brain AA in vitro (fetal hypothalamus: IC50 1.4nM) and in vivo in both the hypothalamus and amygdala. However, the levels of T and B did not show any significant change in group F. The same depression of AA was also observed in group N on the 7th day after birth. In CGS-treated males in groups F and N, the SDN-POA area markedly decreased to that of control females. The area in males in group F was not significantly different from that in females. These results suggest that estrogen converted from androgen plays a dominant role in the development of sexual dimorphism of the SDN-POA, and that the brain AA in the pre- and postnatal period is important in this process.

  6. Determination and confirmation of selective estrogen receptor modulators (SERMs), anti-estrogens and aromatase inhibitors in bovine and porcine urine using UHPLC-MS/MS.

    PubMed

    Meijer, Thijs; Essers, Martien L; Kaklamanos, George; Sterk, Saskia S; van Ginkel, Leendert A

    2017-04-01

    Selective estrogen receptor modulators (SERMs), anti-estrogens and aromatase inhibitors are prohibited in human sports doping. However, they also present a risk of being used illegally in animal husbandry for fattening purposes. A method was developed and validated using UHPLC-MS/MS for the determination and confirmation of SERMs, anti-estrogens and aromatase inhibiters in bovine and porcine urine. This method was used in a survey of more than 200 bovine and porcine urine samples from Dutch farms. In 18 out of 103 porcine urine samples (17%) and two out of 114 bovine samples (2%) formestane, an aromatase inhibitor, was detected. None of the other compounds was detected. From human doping control it is known that formestane can, in some cases, be of natural origin. Analyses of reference samples from untreated bovine and porcine animals demonstrated the presence of formestane in bovine animals, but not yet in porcine animals. Future research will focus on whether the detected formestane in porcine and bovine urine is from endogenous or exogenous origin, using GC-c-IRMS.

  7. Transferrin-conjugated lipid-coated PLGA nanoparticles for targeted delivery of aromatase inhibitor 7α-APTADD to breast cancer cells

    PubMed Central

    Zheng, Yu; Yu, Bo; Weecharangsan, Wanlop; Piao, Longzhu; Darby, Michael; Mao, Yicheng; Koynova, Rumiana; Yang, Xiaojuan; Li, Hong; Xu, Songlin; Lee, L. James; Sugimoto, Yasuro; Brueggemeier, Robert W.; Lee, Robert J.

    2013-01-01

    Transferrin (Tf)-conjugated lipid-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles carrying the aromatase inhibitor, 7α-(4′-amino)phenylthio-1,4-androstadiene-3,17-dione (7α-APTADD), were synthesized by a solvent injection method. Formulation parameters including PLGA-to-lipid, egg PC-to-TPGS, and drug-to-PLGA ratios and aqueous-to-organic phase ratio at the point of synthesis were optimized to obtain nanoparticles with desired sizes and drug loading efficiency. The optimal formulation had a drug loading efficiency of 36.3±3.4%, mean diameter of 170.3±7.6 nm and zeta potential of −18.9±1.5 mV. The aromatase inhibition activity of the nanoparticles was evaluated in SKBR-3 breast cancer cells. IC50 value of the Tf-nanoparticles was ranging from 0.77 to 1.21 nM, and IC50 value of the nanoparticles was ranging from 1.90 to 3.41 nM (n = 3). The former is significantly lower than the latter (p < 0.05). These results suggested that the aromatase inhibition activity of the Tf-nanoparticles was enhanced relative to that of the non-targeted nanoparticles, which was attributable to Tf receptor (TfR) mediated uptake. In conclusion, Tf-conjugated lipid-coated PLGA nanoparticles are potential vehicles for improving the efficiency and specificity of therapeutic delivery of aromatase inhibitors. PMID:20156537

  8. Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters.

    PubMed

    Dias, J P; Shardell, M D; Carlson, O D; Melvin, D; Caturegli, G; Ferrucci, L; Chia, C W; Egan, J M; Basaria, S

    2017-01-01

    Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men ≥65 years, mean age 71 ± 3 years with serum total T < 350 ng/dL were randomized in a double-blind, placebo-controlled, parallel-group, proof-of-concept trial evaluating the effects of 5 g transdermal testosterone gel (TT) (n = 10), 1 mg anastrozole (n = 10) or placebo (n = 9) daily for 12 months. Homeostatic Model Assessment of insulin resistance (HOMAIR ) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12 months. After 12 months, absolute changes in HOMAIR in both treatment arms (TT group: -0.05 ± 0.21); (AI group: 0.15 ± 0.10) were similar to placebo (-0.11 ± 0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8 ± 0.9 mg/L, p = 0.02) and abdominal subcutaneous fat (-60.34 ± 3.19 cm(2) , p = 0.003) and leptin levels (-1.5 ± 1.2 ng/mL, p = 0.04) were significantly lower with AI. Mid-thigh subcutaneous fat was reduced in both treatment arms (TT group: -4.88 ± 1.24 cm(2) , p = 0.008); (AI group: -6.05 ± 0.87 cm(2) , p = 0.0002). In summary, in this proof-of-concept trial, changes in HOMAIR AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men.

  9. Aromatase expression in ovarian epithelial cancers.

    PubMed

    Cunat, S; Rabenoelina, F; Daurès, J-P; Katsaros, D; Sasano, H; Miller, W R; Maudelonde, T; Pujol, P

    2005-01-01

    Our study focused on aromatase cytochrome P450 (CYP19) expression in ovarian epithelial normal and cancer cells and tissues. Aromatase mRNA expression was analyzed by real-time PCR in ovarian epithelial cancer cell lines, in human ovarian surface epithelial (HOSE) cell primary cultures, and in ovarian tissue specimens (n=94), including normal ovaries, ovarian cysts and cancers. Aromatase mRNA was found to be expressed in HOSE cells, in BG1, PEO4 and PEO14, but not in SKOV3 and NIH:OVCAR-3 ovarian cancer cell lines. Correlation analysis of aromatase expression was performed according to clinical, histological and biological parameters. Aromatase expression in ovarian tissue specimens was higher in normal ovaries and cysts than in cancers (P<0.0001). Using laser capture microdissection in normal postmenopausal ovaries, aromatase was found to be predominantly expressed in epithelial cells as compared to stromal component. Using immunohistochemistry (IHC), aromatase was also detected in the epithelium component. There was an inverse correlation between aromatase and ERalpha expression in ovarian tissues (P<0.001, r=-0.34). In the cancer group, no significant differences in aromatase expression were observed according to tumor histotype, grade, stage and survival. Aromatase activity was evaluated in ovarian epithelial cancer (OEC) cell lines by the tritiated water assay and the effects of third-generation aromatase inhibitors (AIs) on aromatase activity and growth were studied. Letrozole and exemestane were able to completely inhibit aromatase activity in BG1 and PEO14 cell lines. Interestingly, both AI showed an antiproliferative effect on the estrogen responsive BG1 cell line co-expressing aromatase and ERalpha. Aromatase expression was found in ovarian epithelial normal tissues and in some ovarian epithelial cancer cells and tissues. This finding raises the possibility that some tumors may respond to estrogen and provides a basis for ascertaining an antimitogenic

  10. Synthesis and structure-activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors.

    PubMed

    Doiron, Jérémie; Soultan, Al Haliffa; Richard, Ryan; Touré, Mamadou Mansour; Picot, Nadia; Richard, Rémi; Cuperlović-Culf, Miroslava; Robichaud, Gilles A; Touaibia, Mohamed

    2011-09-01

    A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing a 1,2,5-triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC(50) = 4.64 μM), a letrozole 1 analogue bearing para-cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen.

  11. Persistent endocrine disruption effects in medaka fish with early life-stage exposure to a triazole-containing aromatase inhibitor (letrozole).

    PubMed

    Liao, Pei-Han; Chu, Szu-Hung; Tu, Tzu-Yi; Wang, Xiao-Huan; Lin, Angela Yu-Chen; Chen, Pei-Jen

    2014-07-30

    Letrozole (LET) is a triazole-containing drug that can inhibit the activity of cytochrome P450 aromatase. It is an environmentally emerging pollutant because of its broad use in medicine and frequent occurrence in aquifers receiving the effluent of municipal or hospital wastewater. However, the toxic impact of LET on fish populations remains unclear. We exposed medaka fish (Oryzias latipes) at an early stage of sexual development to a continuous chronic LET at environmentally relevant concentrations and assessed the endocrine disruption effects in adulthood and the next generation. LET exposure at an early life stage persistently altered phenotypic sex development and reproduction in adults and skewed the sex ratio in progeny. As well, LET exposure led to a gender-different endocrine disruption as seen by the interruption in gene expression responsible for estrogen synthesis and metabolism and fish reproduction. LET interfering with the aromatase system in early life stages of medaka can disrupt hormone homeostasis and reproduction. This potent aromatase inhibitor has potential ecotoxicological impact on fish populations in aquatic environments.

  12. The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer

    PubMed Central

    Fabian, C J

    2007-01-01

    The third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have largely replaced tamoxifen as the preferred treatment for hormone receptor – positive breast cancer in postmenopausal women. Approximately 185,000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AIs. In addition, AIs are currently being tested as primary prevention therapy in large randomised trials involving tens of thousands of women at increased risk for breast cancer. Given the volume of use, internists will increasingly see postmenopausal women who are taking or considering treatment with AIs. Physicians need to be able to: (i) briefly discuss the pros and cons of using a selective estrogen receptor modulator such as tamoxifen or raloxifene vs. an AI for risk reduction and (ii) recognise and manage AI-associated adverse events. The primary purpose of this review is to help internists with these two tasks. Review Criteria Expert opinion based on review of literature on relevant clinical trials. Message for the Clinic Both tamoxifen and AIs are effective for the adjuvant and neoadjuvant treatment of postmenopausal breast cancer; the optimal choice of drug is dependent on the characteristics of the patient and tumour. Adverse events with both drug classes are manageable. Adverse events associated with tamoxifen include increased risk of uterine cancers and thromboembolic events vs. an increased incidence of vaginal dryness, loss of libido, musculoskeletal pain and bone mineral density loss with AIs. Promising studies of AIs in the breast cancer prevention setting are ongoing. PMID:17892469

  13. Effects of the aromatase inhibitor fadrozole on plasma sex steroid secretion, spermatogenesis and epididymis morphology in the lizard, Podarcis sicula.

    PubMed

    Cardone, Anna; Comitato, Raffaella; Bellini, Luigi; Angelini, Francesco

    2002-09-01

    Recently, increasing importance has been attached to the role of estrogens and their receptors in male reproduction, since they have been found to be abundant in the male reproductive tract. In the lizard, Podarcis sicula, a seasonal breeder, estrogens seem to be involved in the regulation of testicular activity. Particularly, it has been hypothesized that the block of spermatogenesis and the complete regression of the epididymis and other secondary sexual characters (SSCs) in autumn might be due to high estrogen levels. To investigate the role of estrogens in the reproductive process of male lizards, we utilized Fadrozole ((AI) [4-(5,6,7,8-tetrahydroimidazole [1,5-a] pyridin-5-yl)-benzonitrile monohydrochloride] (CGS 16949A)), a nonsteroidal inhibitor of aromatase, the enzyme involved in the aromatization of androgens to estrogens, evaluating its effects on plasma sex-hormone release, spermatogenesis and epididymis morphology. For this purpose, adult male lizards, captured during the autumnal recrudescence, were intraperitoneally injected with 0.5 microg and 5 microg/g/body weight of AI for 15 and 30 days. In the animals treated with the higher AI dose, estrogen levels decreased if compared to the control groups, whereas androgen levels increased. Furthermore, histologic sections of testes and epididymes showed that the 30-day treatment with AI-induced spermatogenesis resumption with release of sperms into the large lumen of the seminiferous tubules, and the epididymes appeared more developed with moderately secreting columnar canal cells. Therefore, it is proposed that failure of spermatogenesis in autumn might be due to high estrogen levels.

  14. Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor

    PubMed Central

    Clatot, Florian; Perdrix, Anne; Augusto, Laetitia; Beaussire, Ludivine; Delacour, Julien; Calbrix, Céline; Sefrioui, David; Viailly, Pierre-Julien; Bubenheim, Michael; Moldovan, Cristian; Alexandru, Cristina; Tennevet, Isabelle; Rigal, Olivier; Guillemet, Cécile; Leheurteur, Marianne; Gouérant, Sophie; Petrau, Camille; Théry, Jean-Christophe; Picquenot, Jean-Michel; Veyret, Corinne; Frébourg, Thierry; Jardin, Fabrice

    2016-01-01

    Purpose To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment. Patients and methods ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas. Results Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome. Conclusion ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted. PMID:27801670

  15. Indications of clinical and genetic predictors for aromatase inhibitors related musculoskeletal adverse events in Chinese Han women with breast cancer.

    PubMed

    Wang, Jingxuan; Lu, Kangping; Song, Ying; Xie, Li; Zhao, Shu; Wang, Yunxuan; Sun, Wenzhou; Liu, Lei; Zhao, Hong; Tang, Dabei; Ma, Wenjie; Pan, Bo; Xuan, Qijia; Liu, Hang; Zhang, Qingyuan

    2013-01-01

    Women with breast cancer treated with aromatase inhibitors (AIs) may experience musculoskeletal symptoms that lead to discontinuation of effective therapy. The purpose of the current study is to evaluate the clinical and genetic predictors for AIs-related musculoskeletal adverse events(MS-AEs). We recruited 436 postmenopausal Chinese Han women receiving adjuvant AIs therapy for early-stage hormone-sensitive breast cancer. Patients completed a self-administered questionnaire assessing the presence of musculoskeletal symptoms that started or worsened after initiating AIs. 27 single nucleotide polymorphisms (SNP) of ESR1, ESR2 and PGR were analyzed by Sequenom MassARRAY assays and /or PCR-based TaqMan assays.Of the 436 enrolled women, 206 cases experienced musculoskeletal symptoms.Patients who received taxane chemotherapy were more than two times more likely than other patients to have AIs-related MS-AEs. Genetic assay had showed that only two ESR1 SNPs, rs2234693 and rs9340799 were associated with AIs-related MS-AEs.TT genotype and the T allele in rs2234693 was statistically significantly lower in AIs-Related MS-AEs group than controls (P = 0.001; P = 9.49E-7). The frequency of AA genotype and the A allele in rs9340799 was higher (P = 2.20E-5; P = 3.09E-4). Our results suggested that prior taxane-based chemotherapy was the clinical predictor, while rs2234693 and rs9340799 were the genetic predictors for AIs-related MS-AEs.

  16. Electroacupuncture for fatigue, sleep, and psychological distress in breast cancer patients with aromatase inhibitor-related arthralgia: a randomized trial.

    PubMed

    Mao, Jun J; Farrar, John T; Bruner, Deborah; Zee, Jarcy; Bowman, Marjorie; Seluzicki, Christina; DeMichele, Angela; Xie, Sharon X

    2014-12-01

    Although fatigue, sleep disturbance, depression, and anxiety are associated with pain in breast cancer patients, it is unknown whether acupuncture can decrease these comorbid symptoms in cancer patients with pain. The objective of this study was to evaluate the effect of electroacupuncture (EA) on fatigue, sleep, and psychological distress in breast cancer survivors who experience joint pain related to aromatase inhibitors (AIs). The authors performed a randomized controlled trial of an 8-week course of EA compared with a waitlist control (WLC) group and a sham acupuncture (SA) group in postmenopausal women with breast cancer who self-reported joint pain attributable to AIs. Fatigue, sleep disturbance, anxiety, and depression were measured using the Brief Fatigue Inventory (BFI), the Pittsburgh Sleep Quality Index (PSQI), and the Hospital Anxiety and Depression Scale (HADS). The effects of EA and SA versus WLC on these outcomes were evaluated using mixed-effects models. Of the 67 randomly assigned patients, baseline pain interference was associated with fatigue (Pearson correlation coefficient [r]=0.75; P < .001), sleep disturbance (r=0.38; P=.0026), and depression (r=0.58; P < .001). Compared with the WLC condition, EA produced significant improvements in fatigue (P=.0095), anxiety (P=.044), and depression (P=.015) and a nonsignificant improvement in sleep disturbance (P=.058) during the 12-week intervention and follow-up period. In contrast, SA did not produce significant reductions in fatigue or anxiety symptoms but did produce a significant improvement in depression compared with the WLC condition (P=.0088). Compared with usual care, EA produced significant improvements in fatigue, anxiety, and depression; whereas SA improved only depression in women experiencing AI-related arthralgia. © 2014 American Cancer Society.

  17. Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors.

    PubMed

    Kadakia, Kunal C; Kidwell, Kelley M; Seewald, Nicholas J; Snyder, Claire F; Storniolo, Anna Maria; Otte, Julie L; Flockhart, David A; Hayes, Daniel F; Stearns, Vered; Henry, N Lynn

    2017-07-01

    Aromatase inhibitors (AI), which decrease circulating estradiol concentrations in post-menopausal women, are associated with toxicities that limit adherence. Approximately one-third of patients will tolerate a different AI after not tolerating the first. We report the effect of crossover from exemestane to letrozole or vice versa on patient-reported outcomes (PROs) and whether the success of crossover is due to lack of estrogen suppression. Post-menopausal women enrolled on a prospective trial initiating AI therapy for early-stage breast cancer were randomized to exemestane or letrozole. Those that discontinued for intolerance were offered protocol-directed crossover to the other AI after a washout period. Changes in PROs, including pain [Visual Analog Scale (VAS)] and functional status [Health Assessment Questionnaire (HAQ)], were compared after 3 months on the first versus the second AI. Estradiol and drug concentrations were measured. Eighty-three patients participated in the crossover protocol, of whom 91.3% reported improvement in symptoms prior to starting the second AI. Functional status worsened less after 3 months with the second AI (HAQ mean change AI #1: 0.2 [SD 0.41] vs. AI #2: -0.05 [SD 0.36]; p = 0.001); change in pain scores was similar between the first and second AI (VAS mean change AI #1: 0.8 [SD 2.7] vs. AI #2: -0.2 [SD 2.8]; p = 0.19). No statistical differences in estradiol or drug concentrations were found between those that continued or discontinued AI after crossover. Although all AIs act via the same mechanism, a subset of patients intolerant to one AI report improved PROs with a different one. The mechanism of this tolerance remains unknown, but does not appear to be due to non-adherence to, or insufficient estrogen suppression by, the second AI.

  18. Modification of abdominal fat distribution after aromatase inhibitor therapy in breast cancer patients visualized using 3-D computed tomography volumetry.

    PubMed

    Battisti, Sofia; Guida, Francesco Maria; Coppa, Federica; Vaccaro, Donata M; Santini, Daniele; Tonini, Giuseppe; Zobel, Bruno B; Semelka, Richard C

    2014-10-01

    The purpose of this study was to describe modification of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) distributions in breast cancer patients after aromatase inhibitor (AI) therapy using computed tomography (CT) volumetric measurement of abdominal body fat distribution. Sixty-four consecutive patients who were receiving adjuvant AI therapy were included in this study. Patients were evaluated using CT before and after at least 6 months of AI therapy with imaging follow-up of 4.3 ± 2.2 years. Abdominal fat distribution was automatically calculated using a workstation that obtained total abdominal adipose tissue (TAAT) area (mm(3)). SAT was manually segmented and VAT was determined as TAAT - SAT. Percentages were calculated for change of TAAT, VAT, and SAT. VAT/SAT ratio was calculated. Percentage of TAAT after AI therapy was increased by a mean of 9.1% from baseline (16,280.3 ± 6953.3 mm(3)) to (17,763.6 ± 6850.8 mm(3)). Two groups of patients were observed; those with an increase in TAAT and those with a decrease. Modification of VAT/SAT ratio was observed (from 1.38 to 1.69) in all subjects, reflecting a relative increased volume of VAT (mean, 18%) and slight mean reduction of SAT (mean 1.9%). In our study, therapy with AI in breast cancer patients was accompanied with a change in fat distribution to relatively greater VAT/SAT ratio in patients, regardless of whether they gained or lost weight after therapy. Because this pattern of fat distribution is associated with metabolic disorders, attention must be paid to these clinical manifestations in patients during their follow-up management. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Aromatase inhibitors associated musculoskeletal disorders and bone fractures in postmenopausal breast cancer patients: a result from Chinese population.

    PubMed

    Xu, Lu; Wang, Jue; Xue, Dan-Dan; He, Wei

    2014-09-01

    As the prognosis of early breast cancer patients improves, the long-term safety of aromatase inhibitors (AIs) is increasingly important. In the present study, we retrospectively investigated the incidences of musculoskeletal disorders (MSDs) and bone fractures in a cohort of Chinese postmenopausal patients with breast cancer. Data of postmenopausal patients with breast cancer were collected. Among which, 70 patients received AIs therapy (median follow-up of 32.5 months), 52 patients received tamoxifen (TAM), and 89 patients received no endocrine therapy (NE). Baseline characteristics, incidence of MSDs and bone fractures were analyzed and compared. When compared with NE group (40.4 %, 36/89), more patients in AIs group developed MSDs (72.9 %, 51/70, adjusted odds ratio (AOR) = 3.30, 95 % confidence interval (CI) = 1.59-6.88, P = 0.001). But no difference was found between TAM group (36.5 %, 19/52, AOR = 0.70, 95 % CI = 0.32-1.52, P = 0.372) and NE group. About 39.7 months after initial AIs therapy, nine patients in AI group developed bone fractures in different sites, and the bone fracture rate was significantly increased (12.9 %, 9/70, adjusted hazard ratio (AHR) = 20.08, 95 % CI = 1.72-234.08, P = 0.017) in comparison with NE group (1.1 %, 1/89). Moreover, the bone fracture rate of TAM group was not different from NE group (1.9 %, 1/52, AHR = 2.64, 95 % CI = 0.14-48.73, P = 0.513). AIs therapy may induce increased rates of MSDs and bone fractures in Chinese population of postmenopausal breast cancer patients, whereas TAM therapy did not help reduce the incidences of MSDs and bone fractures.

  20. Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling.

    PubMed

    Chan, George Ho Man; Ho, Emmie Ngai Man; Leung, David Kwan Kon; Wong, Kin Sing; Wan, Terence See Ming

    2016-01-05

    The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups

  1. Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

    PubMed

    Hertz, Daniel L; Speth, Kelly A; Kidwell, Kelley M; Gersch, Christina L; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C; Hayes, Daniel F; Henry, N Lynn; Rae, James M

    2017-06-22

    The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

  2. Association between self-report adherence measures and oestrogen suppression among breast cancer survivors on aromatase inhibitors.

    PubMed

    Brier, Moriah J; Chambless, Dianne; Gross, Robert; Su, H Irene; DeMichele, Angela; Mao, Jun J

    2015-09-01

    Poor adherence to oral adjuvant hormonal therapy for breast cancer is a common problem, but little is known about the relationship between self-report adherence measures and hormonal suppression. We evaluated the relationship of three self-report measures of medication adherence and oestrogen among patients on aromatase inhibitors (AIs). We recruited 235 women with breast cancer who were prescribed AI therapy. Participants self-reported AI adherence by completing the following: (1) a single item asking whether they took an AI in the last month, (2) a modified Morisky Medication Adherence Scale-8 (MMAS-8) and (3) the Visual Analog Scale (VAS). Serum estrone and estradiol were analysed using organic solvent extraction and Celite column partition chromatography, followed by radioimmunoassay. Ten percent of participants reported they had not taken an AI in the last month and among this group, median estrone (33.2 pg/ml [interquartile range (IQR)=22.3]) and estradiol levels (7.2 pg/mL [IQR=3.3]) were significantly higher than those in participants who reported AI use (median estrone=11.5 pg/mL [IQR=4.9]; median estradiol=3.4 pg/mL [IQR=2.1]; p<0.001). This relationship held when controlling for race and AI drug type. A single-item monthly-recall adherence measure for AIs was associated with oestrogen serum levels. This suggests that patient-reported monthly adherence may be a useful measure to identify early non-adherence behaviour and guide interventions to improve patient adherence to hormonal treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast Cancer

    PubMed Central

    Henry, N. Lynn; Azzouz, Faouzi; Desta, Zereunesay; Li, Lang; Nguyen, Anne T.; Lemler, Suzanne; Hayden, Jill; Tarpinian, Karineh; Yakim, Elizabeth; Flockhart, David A.; Stearns, Vered; Hayes, Daniel F.; Storniolo, Anna Maria

    2012-01-01

    Purpose Aromatase inhibitors (AIs) are effective for treatment of hormone receptor–positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another. Patients and Methods Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period. Results Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months. Conclusion Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms. PMID:22331951

  4. Age-related differences in persistence in women with breast cancer treated with tamoxifen or aromatase inhibitors in Germany.

    PubMed

    Jacob, Louis; Hadji, Peyman; Kostev, Karel

    2016-05-01

    To study age-related persistence in postmenopausal women with endocrine-responsive breast cancer treated with tamoxifen (TAM) and aromatase inhibitors (AI). Data on 29,245 patients diagnosed with metastatic or non-metastatic breast cancer (BC) and initially treated with TAM or AI between 2004 and 2013 were included. The primary outcome measure was the age-dependent rate of discontinuation of endocrine treatment within 5years after initiation. Discontinuation of therapy was defined as a period of at least 90days without treatment. A multivariate Cox regression model was created to determine the influence of age on the risk of discontinuation. Health insurance type (private/statutory), type of care (gynecological/general), region (West/East Germany), concomitant diagnoses (depression, osteoporosis, and diabetes), and Charlson Comorbidity Score were included as covariates. The mean ages of the women in the <70 and ≥70 groups were 55.9 (SD: 9.7) and 77.4 (SD: 5.4) years, respectively. Within 5years after treatment initiation, 88.8% of women <70 of age and 82% of women ≥70 years of age had terminated treatment (p-value<0.001). Patients aged ≥70 exhibited a lower risk of treatment discontinuation than patients aged <70 (HR=0.75, 95% CI: 0.66-0.85). Furthermore, gynecological practices, disease management programs, and high Charlson scores increased persistence. Overall, the present study indicates that persistence rates are low in both women with BC aged <70 and those aged ≥70 years. We also found that younger women with BC are at a higher risk of treatment discontinuation than older women. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Induction of CYP1A and cyp2-mediated arachidonic acid epoxygenation and suppression of 20-hydroxyeicosatetraenoic acid by imidazole derivatives including the aromatase inhibitor vorozole.

    PubMed

    Diani-Moore, Silvia; Papachristou, Fotini; Labitzke, Erin; Rifkind, Arleen B

    2006-08-01

    Cytochrome P450 (P450) enzymes metabolize the membrane lipid arachidonic acid to stable biologically active epoxides [eicosatrienoic acids (EETs)] and 20-hydroxyeicosatetraenoic acid (20-HETE). These products have cardiovascular activity, primarily acting as vasodilators and vasoconstrictors, respectively. EET formation can be increased by the prototype CYP1A or CYP2 inducers, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or phenobarbital (PB), respectively. We report here that imidazole derivative drugs: the anthelminthics, albendazole and thiabendazole; the proton pump inhibitor, omeprazole; the thromboxane synthase inhibitor, benzylimidazole; and the aromatase (CYP19) inhibitor vorozole (R76713, racemate; and R83842, (+) enantiomer) increased hepatic microsomal EET formation in a chick embryo model. Albendazole increased EETs by transcriptional induction of CYP1A5 and the others by combined induction of CYP1A5 and CYP2H, the avian orthologs of mammalian CYP1A2 and CYP2B, respectively. All inducers increased formation of the four EET regioisomers, but TCDD and albendazole had preference for 5,6-EET and PB and omeprazole for 14,15-EET. Vorozole, benzylimidazole, and TCDD also suppressed 20-HETE formation. Vorozole was a remarkably effective and potent inducer of multiple hepatic P450s at a dose range which overlapped its inhibition of ovarian aromatase. Increased CYP1A activity in mouse Hepa 1-6 and human HepG2 cells by vorozole and other imidazole derivatives demonstrated applicability of the findings to mammalian cells. The findings suggest that changes in P450-dependent arachidonic acid metabolism may be a new source of side effects for drugs that induce CYP1A or CYP2. They demonstrate further that in vivo induction of multiple hepatic P450s produces additive increases in arachidonic acid epoxygenase activity and can occur concurrently with inhibition of ovarian aromatase activity.

  6. Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors.

    PubMed

    Flågeng, M Hauglid; Moi, L L Haugan; Dixon, J M; Geisler, J; Lien, E A; Miller, W R; Lønning, P E; Mellgren, G

    2009-10-20

    Acquired resistance to endocrine therapy in breast cancer is poorly understood. Characterisation of the molecular response to aromatase inhibitors in breast cancer tissue may provide important information regarding development of oestrogen hypersensitivity. We examined the expression levels of nuclear receptor co-regulators, the orphan nuclear receptor liver receptor homologue-1 and HER-2/neu growth factor receptor using real-time RT-PCR before and after 13-16 weeks of primary medical treatment with the aromatase inhibitors anastrozole or letrozole. mRNA expression of the steroid receptor co-activator 1 (SRC-1) and peroxisome-proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) was correlated (P=0.002), and both co-activators increased during treatment in the patient group as a whole (P=0.008 and P=0.032, respectively), as well as in the subgroup of patients achieving an objective treatment response (P=0.002 and P=0.006). Although we recorded no significant change in SRC-3/amplified in breast cancer 1 level, the expression correlated positively to the change of SRC-1 (P=0.002). Notably, we recorded an increase in HER-2/neu levels during therapy in the total patient group (18 out of 26; P=0.016), but in particular among responders (15 out of 21; P=0.008). Our results show an upregulation of co-activator mRNA and HER-2/neu during treatment with aromatase inhibitors. These mechanisms may represent an early adaption of the breast cancer cells to oestrogen deprivation in vivo.

  7. Design, synthesis, and evaluation of 4-(4'-aminobenzyl)-2-oxazolidinones as novel inhibitors of the cytochrome P-450 enzyme aromatase.

    PubMed

    Ahmed, Sabbir; Adat, Shaheen; Murrells, Annabel; Owen, Caroline P; Amanuel, Yonas

    2002-10-01

    The synthesis of a series of N-alkylated 4-(4(')aminobenzyl)-2-oxazolidinones is described using a synthetically useful scheme which avoids the use of phosgene-since the derivatization is undertaken with the oxazolidin-2-one ring intact. The compounds were tested for human placental aromatase (AR) inhibition in vitro, using [1beta,2beta-3H]androstenedione as substrate for the AR enzyme. The compounds were found, in general, to be more potent than the standard compound, aminoglutethimide (AG), and as such proved to be good lead compounds in the search for more specific AR inhibitors.

  8. [Combination of trastuzumab, aromatase inhibitor and anti-cancer drugs obtained a good prognosis for an inoperable stage III B breast cancer patient with giant skin ulceration].

    PubMed

    Takeda, Yasutaka; Tanaka, Noriyoshi; Konishi, Juichiro

    2012-04-01

    A 68-year-old woman who had an inoperable, ER-positive, PgR-positive and HER2-positive advanced breast cancer with giant skin ulceration has been treated with the combination of trastuzumab, aromatase inhibitor and anti-cancer drugs. She was thus well-controll for over 9 years. Trastuzumab was administered more than 400 times, but no cardiac toxicity has been observed. The synergistic efficacy of the combination of trastuzumab and anti-cancer drugs was already proven, but it has recently been reported that concurrent treatment of trastuzumab and endocrine therapy improves the prognoses of triple positive breast cancer patients.

  9. Modulation of Aromatase by Phytoestrogens

    PubMed Central

    Lephart, Edwin D.

    2015-01-01

    The aromatase enzyme catalyzes the conversion of androgens to estrogens in many human tissues. Estrogens are known to stimulate cellular proliferation associated with certain cancers and protect against adverse symptoms during the peri- and postmenopausal intervals. Phytoestrogens are a group of plant derived naturally occurring compounds that have chemical structures similar to estrogen. Since phytoestrogens are known to be constituents of animal/human food sources, these compounds have received increased research attention. Phytoestrogens may contribute to decreased cancer risk by the inhibition of aromatase enzyme activity and CYP19 gene expression in human tissues. This review covers (a) the aromatase enzyme (historical descriptions on function, activity, and gene characteristics), (b) phytoestrogens in their classifications and applications to human health, and (c) a chronological coverage of aromatase activity modulated by phytoestrogens from the early 1980s to 2015. In general, phytoestrogens act as aromatase inhibitors by (a) decreasing aromatase gene expression, (b) inhibiting the aromatase enzyme itself, or (c) in some cases acting at both levels of regulation. The findings presented herein are consistent with estrogen's impact on health and phytoestrogen's potential as anticancer treatments, but well-controlled, large-scale studies are warranted to determine the effectiveness of phytoestrogens on breast cancer and age-related diseases. PMID:26798508

  10. Natural compounds with aromatase inhibitory activity: an update.

    PubMed

    Balunas, Marcy J; Kinghorn, A Douglas

    2010-08-01

    Several synthetic aromatase inhibitors are currently in clinical use for the treatment of postmenopausal women with hormone-receptor positive breast cancer. However, these treatments may lead to untoward side effects and so the search for new aromatase inhibitors continues, especially those for which the activity is promoter-specific, targeting the breast-specific promoters I.3 and II. Recently, numerous natural compounds have been found to inhibit aromatase in noncellular, cellular, and IN VIVO studies. These investigations, covering the last two years, as well as additional studies that have focused on the evaluation of natural compounds as promoter-specific aromatase inhibitors or as aromatase inducers, are described in this review.

  11. Anti-aromatase chemicals in red wine.

    PubMed

    Eng, E T; Williams, D; Mandava, U; Kirma, N; Tekmal, R R; Chen, S

    2002-06-01

    Estrogen synthesized in situ plays a more important role in breast cancer cell proliferation than does circulating estrogen. Aromatase is the enzyme that converts androgen to estrogen and is expressed at a higher level in breast cancer tissue than in surrounding noncancer tissue. A promising route of chemoprevention against breast cancer may be through the suppression of in situ estrogen formation using aromatase inhibitors. A diet high in fruits and vegetables may reduce the incidence of breast cancer, because they contain phytochemicals that can act as aromatase inhibitors. In our previous studies, we found that grapes and wine contain potent phytochemicals that can inhibit aromatase. We show that red wine was more effective than white wine in suppressing aromatase activity. Interestingly, our results from white wine studies suggest a weak inductive effect of alcohol on aromatase activity. On the other hand, the potent effect of anti-aromatase chemicals in red wine overcomes the weak inductive effect of alcohol in wine. Several purification procedures were performed on whole red wine to separate active aromatase inhibitors from non-active compounds. These techniques included liquid-liquid extraction, silica gel chromatography, various solid phase extraction (SPE) columns, and high performance liquid chromatography. An active Pinot Noir red wine SPE C18 column fraction (20% acetonitrile:water) was more effective than complete Pinot Noir wine in suppressing aromatase assay. This red wine extract was further analyzed in a transgenic mouse model in which aromatase was over-expressed in mammary tissue. Our gavaged red wine extract completely abrogated aromatase-induced hyperplasia and other neoplastic changes in mammary tissue. These results suggest that red wine or red wine extract may be a chemopreventive diet supplement for postmenopausal women who have a high risk of breast cancer. Further research is underway to purify and characterize the active compounds in red

  12. Biological aromatization of delta4,6- and delta1,4,6-androgens and their 6-alkyl analogs, potent inhibitors of aromatase.

    PubMed

    Numazawa, M; Yoshimura, A

    1999-01-01

    Enzymic aromatization of delta6- and delta1,6-derivatives of the natural substrate androstenedione with human placental aromatase was first studied using gas-chromatography-mass spectrometry. The two steroids were aromatized with apparent Km and Vmax values of 62 nM and 32 pmol/min/mg protein for the delta6-steroid and 167 nM and 10 pmol/min/mg protein for the delta1,6-steroid, respectively. We next explored the aromatization of a series of 6-alkyl (methyl, ethyl, n-propyl, and n-pentyl)-substituted delta6-androstenediones and their delta1,6-analogs, potent competitive inhibitors of aromatase, to gain insight into the relationships between the inhibitory activity of the 6-alkyl-C19 steroids and their ability to serve as a substrate of aromatase. In a series of the delta1,6-androstenediones, all the 6-alkyl steroids were more efficient substrates than the parent delta1,6-steroid in which the aromatization rates of the alkyl steroids were about 2-fold that of the parent steroid, in contrast, all of the 6-alkyl-substituted delta6-androstenediones were converted into the corresponding 6-alkyl-delta6-estrogens with the rates of less than about a half that of the parent steroid. These results indicate that the 6-alkyl function decreases the aromatization rate of the delta6-steroid but enhances that of the delta1,6-steroid. The relative apparent Km values for the C19 steroids obtained in this study are different from the relative Ki values obtained previously, indicating that a good inhibitor is not essentially a good substrate in the 6-alkyl-substituted delta6- and delta1,6-androstenedione series.

  13. Suppression of aromatase activity in vitro by PCBs 28 and 105 and Aroclor 1221.

    PubMed

    Woodhouse, Amanda J; Cooke, Gerard M

    2004-08-30

    The effects of polychlorinated biphenyls (PCBs) on human cytochrome P450 aromatase activity in vitro were investigated using a commercially available microsomal fraction obtained from baculovirus infected insects that had been transfected with the human CYP19 gene and cytochrome P450 reductase. The assay measured the conversion of tritiated testosterone to estradiol in Tris buffer at pH 7.4. When aroclors, commercial preparations of PCBs, were added to aromatase assays at a 10 microM concentration, Aroclor 1221 caused a reduction in the aromatase activity, whereas other aroclors (1016, 1232, 1242, 1248, 1254, 1260, 5432, 5442 and 5460) were without effect. Further investigation of the effect of Aroclor 1221 on aromatase activity showed that the inhibition was dose dependent. When a reconstituted mixture (RM) of PCBs that represented the congeneric content of human milk was investigated, no inhibition of aromatase activity at the maximum treatment of 15.0 microM was observed. None of the congeners present in the reconstituted mixture, except PCB 28 and 105, affected P450 arom activity. PCB 28 showed a statistically significant inhibition of aromatase activity (P<0.05) at 1.5 and 15 microM and a significant inhibition of aromatase activity by PCB 105 was also observed, but only at 15 microM. In three separate kinetic analyses the Km(app) for aromatase was 64, 89 and 69 nM (mean 74 nM). In addition, PCB 28 resulted in an increase in the Km(app) without a significant effect on Vmax(app), suggesting competitive inhibition by this congener. This conclusion was supported by slope (Km(app)/Vmax(app) versus [inhibitor]) and intercept (1/Vmax(app) versus [inhibitor]) replots. The slope replots gave Ki(app) values for PCB 28 of 0.9, 1.3 and 2.0 microM (mean 1.4 microM), whereas intercept replots were almost horizontal. Thus, PCB 28 is a competitive inhibitor of aromatase with a Ki(app) value approximately 20-fold the Km(app) value. Based on these studies, we conclude that

  14. Aromatase Inhibition in a Transcriptional Network Context

    EPA Science Inventory

    A variety of chemicals in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. We examined the responses of female fathead minnow ovaries (FHM, Pimephales promelas) to a model aromatase inhibitor, fadrozole, using a transcriptional ne...

  15. Aromatase Inhibition in a Transcriptional Network Context

    EPA Science Inventory

    A variety of chemicals in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. We examined the responses of female fathead minnow ovaries (FHM, Pimephales promelas) to a model aromatase inhibitor, fadrozole, using a transcriptional ne...

  16. Preventive effect of zoledronic acid on aromatase inhibitor-associated bone loss for postmenopausal breast cancer patients receiving adjuvant letrozole

    PubMed Central

    Sun, Shengliang; Wang, Fuchao; Dou, Honglei; Zhang, Longqiang; Li, Jiwen

    2016-01-01

    Background This study aims to compare the efficacy and safety between zoledronic acid combined with calcium and calcium alone to prevent aromatase inhibitor-associated bone loss for postmenopausal breast cancer patients receiving adjuvant letrozole. Methods One hundred twenty patients were randomly divided into two groups, A and B. Patients in group A (n=60) received modified radical mastectomy or breast-conserving surgery + four cycles of AC followed by T regimen (optional) + radiotherapy (optional) + letrozole 2.5 mg daily + calcium 500 mg twice daily + vitamin D 400 international units daily +4 mg of zoledronic acid every 6 months, while patients in group B (n=60) were not given zoledronic acid and the rest of the treatments of group B were the same as group A. All the patients were followed up for 1 year. The primary endpoint was the intrapatient percentage change in lumbar spine (LS) bone mineral density (BMD) from baseline to month 12. Secondary endpoints included the percentage change in total hip (TH) and femoral neck (FN) BMD, the incidence of osteoporosis, the incidence of a clinically meaningful 5% decline in BMD at 1 year, change of serum N-telopeptide of type 1 collagen (NTX) and bone-specific alkaline phosphatase (BSAP) concentrations. Results Patients in group A had a statistically significant higher average change and average percent change in LS, FN, and TH than group B. Group A had a statistically significant lower incidence of a clinically meaningful loss of bone density at the LS, FN, or TH than Group B. The incidence of osteoporosis in group A was significantly lower than group B. The decreases in NTX and BSAP concentrations from baseline to month 12 in patients of group A were significant; in contrast, patients in group B were found to have increases in NTX and BSAP concentrations from baseline. The most common adverse reactions in patients are flu-like symptoms (38%), bone pain (28%), and joint pain (20%). Conclusion AI-associated bone loss

  17. Tai chi for well-being of breast cancer survivors with aromatase inhibitor-associated arthralgias: a feasibility study.

    PubMed

    Galantino, Mary Lou; Callens, Mary L; Cardena, Gregg J; Piela, Nicole L; Mao, Jun James

    2013-01-01

    Arthralgia is common and debilitating for a significant proportion of breast cancer survivors (BCSs) and leads to poor adherence to aromatase inhibitors (AIs). Despite increased recognition of the negative impact of arthralgia on function and the poor adherence that results, very few interventions have been developed to target this side effect. This study aimed to determine the feasibility of tai chi to improve well-being for women experiencing AI-associated arthralgias (AIAAs). The study was a pilot to (1) demonstrate the feasibility of recruitment and retention for a tai chi trial, (2) determine the safety of tai chi, and (3) identify the outcomes (function, pain, and quality of life[QOL]) that tai chi may impact. The study took place at the Gilda's Club South Jersey in Linwood, NJ, USA. Postmenopausal women with a history of stage I-III breast cancer reporting AIAA were enrolled. Group tai chi was practiced for 1 h 2 ×/wk for 8 wks. Functional outcomes included (1) sit-and-reach (SR), (2) functional reach (FR), (3) the Berg Balance Scale (BBS), and (4) timed up-and-go (TUG). The following patient-reported outcomes (PROs) were evaluated pre- and postintervention: (1) the Hospital Anxiety and Depression Scale (HADS), (2) the Functional Assessment of Cancer Therapy-Breast (FACT-B), (3) the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue), (4) the Brief Pain Inventory (BPI), (5) the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx), and (6) the Functional Assessment of Chronic Illness Therapy- Spiritual Well-being Scale (FACIT-Sp). Participants also recorded their tai chi experiences in a journal. For the 12 participants, adherence to the classes was 75%, with no adverse events reported. Participants experienced significant improvement from baseline to follow-up for the HADS anxiety (P = .003) and depression (P = .020) scales, the emotional well-being scale of the FACT-B (P = .027), the FACIT

  18. Inhibition of peripheral aromatization in baboons by an enzyme-activated aromatase inhibitor (MDL 18,962)

    SciTech Connect

    Longcope, C.; Femino, A.; Johnston, J.O.

    1988-05-01

    The peripheral aromatization ((rho)BM) of androstenedione (A) and testosterone (T) was measured before and after administration of the aromatase inhibitor 10-(2 propynyl)estr-4-ene-3,17-dione (MDL-18,962) to five mature female baboons, Papio annubis. The measurements were made by infusing (3H)androstenedione/(14C)estrone or (3H)testosterone/(14C)estradiol for 3.5 h and collecting blood samples during the infusions and all urine for 96 h from the start of the infusion. Blood samples were analyzed for radioactivity as infused and product steroids, and the data were used to calculate MCRs. An aliquot of the pooled urine was analyzed for the glucuronides of estrone and estradiol and used to calculate the (rho)BM. MDL-18,962 was administered as a pulse in polyethylene glycol-400 (1-5 ml) either iv or via gastric tube 30 min before administration of the radiolabeled steroids. Control studies were done with and without polyethylene glycol-400 administration. When MDL-18,962 was given iv at 4 mg/kg, the aromatization of A was decreased 91.8 +/- 0.9% from the control value of 1.23 +/- 0.13% to 0.11 +/- 0.01%. At the same dose, aromatization of T was decreased 82.0 +/- 7.1%, from a control value of 0.20 +/- 0.03% to 0.037 +/- 0.018%. When MDL-18,962 was given iv at doses of 0.4, 0.1, 0.04, and 0.01 mg/kg, the values for aromatization of A were 0.16 +/- 0.03%, 0.18 +/- 0.06%, 0.37 +/- 11%, and 0.65 +/- 0.09%, respectively. The administration of MDL-18,962 via gastric tube at 4 mg/kg as a pulse decreased the aromatization of A from 1.35 +/- 0.06% to 0.43 +/- 0.12%, an inhibition of 67.2 +/- 10.7%. When administered via gastric tube daily for 5 days at 4 mg/kg, the aromatization of A fell from 1.35 +/- 0.06% to 0.063 +/- 0.003%, an inhibition of 84.4 +/- 0.5%.

  19. Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism.

    PubMed

    Hanamura, Toru; Niwa, Toshifumi; Nishikawa, Sayo; Konno, Hiromi; Gohno, Tatsuyuki; Tazawa, Chika; Kobayashi, Yasuhito; Kurosumi, Masafumi; Takei, Hiroyuki; Yamaguchi, Yuri; Ito, Ken-Ichi; Hayashi, Shin-Ichi

    2013-06-01

    Aromatase inhibitors (AIs) have been reported to exert their antiproliferative effects in postmenopausal women with hormone receptor-positive breast cancer not only by reducing estrogen production but also by unmasking the inhibitory effects of androgens such as testosterone (TS) and dihydrotestosterone (DHT). However, the role of androgens in AI-resistance mechanisms is not sufficiently understood. 5α-Androstane-3β,17β-diol (3β-diol) generated from DHT by 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) shows androgenic and substantial estrogenic activities, representing a potential mechanism of AI resistance. Estrogen response element (ERE)-green fluorescent protein (GFP)-transfected MCF-7 breast cancer cells (E10 cells) were cultured for 3 months under steroid-depleted, TS-supplemented conditions. Among the surviving cells, two stable variants showing androgen metabolite-dependent ER activity were selected by monitoring GFP expression. We investigated the process of adaptation to androgen-abundant conditions and the role of androgens in AI-resistance mechanisms in these variant cell lines. The variant cell lines showed increased growth and induction of estrogen-responsive genes rather than androgen-responsive genes after stimulation with androgens or 3β-diol. Further analysis suggested that increased expression of HSD3B1 and reduced expression of androgen receptor (AR) promoted adaptation to androgen-abundant conditions, as indicated by the increased conversion of DHT into 3β-diol by HSD3B1 and AR signal reduction. Furthermore, in parental E10 cells, ectopic expression of HSD3B1 or inhibition of AR resulted in adaptation to androgen-abundant conditions. Coculture with stromal cells to mimic local estrogen production from androgens reduced cell sensitivity to AIs compared with parental E10 cells. These results suggest that increased expression of HSD3B1 and reduced expression of AR might reduce the sensitivity to AIs as demonstrated by enhanced androgen

  20. Synthesis and biochemical evaluation of novel inhibitors of aromatase (AR) using an enhanced representation of the active site of AR derived from the consideration of the reaction mechanism.

    PubMed

    Ahmed, S; Amanuel, Y

    2000-01-07

    A novel molecular modeling study, involving inhibitors bound to the iron of cytochrome P450 heme, is described for nonsteroidal inhibitors of aromatase (AR). Study of compounds such as aminoglutethimide (AG) suggests that it utilizes hydrogen bonding group(s) at the active site which would usually H-bond to the steroid C(17) carbonyl group. Interaction between AG's carbonyl groups and the area of the active site corresponding to the substrate C(3)==O group is not possible due to steric interaction. Possible reasons for the difference in activity of enantiomers of alternative inhibitors is also suggested, as well as the mode of action of the new AR inhibitor, Arimidex-whose inhibitory activity previously has not been rationalized. The present study proposes that it is able to use hydrogen bonding groups at the active site corresponding to the steroid C(17)==O and C(3)==O area, contradicting a previous study where it is postulated that azole-type compounds only use polar groups at the active site corresponding to the steroid D ring. Using the hypotheses of the modeling study, we designed and synthesized a number of novel (enantiomerically pure) inhibitors, which upon biochemical evaluation were found to be good inhibitors; the N-nonyl derivative of the S-enantiomer was found to possess 39% inhibition at 100 microM inhibitor concentration (using androstenedione as the substrate), under similar conditions, and AG possessed 20% inhibition. Copyright 2000 Academic Press.

  1. Brain and gonadal aromatase as potential targets of endocrine disrupting chemicals in a model species, the zebrafish (Danio rerio).

    PubMed

    Hinfray, N; Palluel, O; Turies, C; Cousin, C; Porcher, J M; Brion, F

    2006-08-01

    Many chemicals in the aquatic environment are able to adversely affect in vitro brain and ovarian aromatase expression/activity. However, it remains to be determined if these substances elicit in vivo effect in fish. With the view to further understanding possible effects of endocrine disrupting chemicals (EDCs) on aromatase function, we first developed methods to measure brain and ovarian aromatase expression/activity in a model species, the zebrafish, and assessed the effect of estradiol (E2) and androstatrienedione (ATD), a steroidal aromatase inhibitor. We showed that CYP19b gene was predominantly expressed in the brain whereas in the ovary CYP19a mRNA level was predominant. Moreover, aromatase activities (AA) were higher in brain than in ovary. In adult zebrafish, E2 treatment had no effect on aromatase expression/activity in brain, whereas at larval stage, E2 strongly triggered CYP19b expression. In the ovaries, E2 led to a complete inhibition of both CYP19a expression and AA. Exposure to ATD led to a total inhibition of both brain and ovarian AA but had no effect on CYP19 transcripts abundance. Together, these results provide relevant knowledge concerning the characterization of aromatase in the zebrafish, and reinforce the idea that brain and ovarian aromatase are promising markers of EDCs in fish and deserve further in vivo studies.

  2. Understanding the pathological manifestations of aromatase excess syndrome: lessons for clinical diagnosis

    PubMed Central

    Shozu, Makio; Fukami, Maki; Ogata, Tsutomu

    2014-01-01

    CYP19A1 Aromatase excess syndrome is characterized by pre- or peripubertal onset of gynecomastia due to estrogen excess because of a gain-of-function mutation in the aromatase gene (CYP19A1). Subchromosomal recombination events including duplication, deletion, and inversion has been identified. The latter two recombinations recruit novel promoters for CYP19A1 through a unique mechanism. Gynecomastia continues for life, and although the general condition is well preserved, it may cause psychological issues. Minor symptoms (variably advanced bone age and short adult height), if present, are exclusively because of estrogen excess. Serum estradiol levels are elevated in 48% of affected males, but are not necessarily useful for diagnosis. Molecular analysis of CYP19A1 mutations is mandatory to confirm aromatase excess syndrome diagnosis. Furthermore, the use of an aromatase inhibitor can ameliorate gynecomastia. PMID:25264451

  3. Letrozole, an aromatase inhibitor, reduces post-peak age-related regression of rooster reproductive performance.

    PubMed

    Ali, Emad Abdulgabbar; Zhandi, Mahdi; Towhidi, Armin; Zaghari, Mojtaba; Ansari, Mahdi; Najafi, Mojtaba; Deldar, Hamid

    2017-08-01

    This study was designed to evaluate orally administrated Letrozole (Lz) on reproductive performance, plasma testosterone and estradiol concentrations and relative abundance of mRNA of GnRH, FSH and LH in roosters. Ross 308 roosters (n=32) that were 40-weeks of age were individually housed and received a basal standard diet supplemented different amounts of capsulated Lz [0 (Lz-0), 0.5 (Lz-0.5), 1 (Lz-1) or 1.5 (Lz-1.5), mg Lz/bird/day] for 12 weeks. Sperm quality variables and plasma testosterone and estradiol concentrations were assessed from the first to the tenth week of the treatment period. Semen samples from the 11th to 12th week were used for artificial insemination and eggs were collected and allotted to assess fertility and hatchability rates. Relative abundance of hypothalamic and pituitary GnRH, LH and FSH mRNA was evaluated at the end of 12th week. The results indicated that total and forward sperm motility as well as egg hatchability rate were greater in the Lz-0.5 group. Greater sperm concentrations, ejaculate volume, sperm plasma membrane integrity, testis index and fertility rates were recorded for both Lz-0.5 and Lz-1 groups compared with the Lz-0 group (P<0.05). Body weight, percentage of sperm abnormalities, and sperm plasma membrane functionality were not affected by treatment. Testosterone and estradiol concentrations were negatively related with greater testosterone concentrations in the Lz-1.5 group which had lesser estradiol concentrations. Relative mRNA transcript abundance for GnRH, LH and FSH was Lz dose responsive being greater in the treated groups; however, this trend plateaued for GnRH and for the relative abundance of both LH and FSH mRNA was less in the Lz-1.5 group than the other treatment groups. It is concluded that Lz may be an effective treatment to improve age related post-peak reproductive performance of roosters. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. New cell culture model for aromatase inhibitor-resistant breast cancer shows sensitivity to fulvestrant treatment and cross-resistance between letrozole and exemestane

    PubMed Central

    HOLE, STINE; PEDERSEN, ASTRID M.; HANSEN, SUSANNE K.; LUNDQVIST, JOHAN; YDE, CHRISTINA W.; LYKKESFELDT, ANNE E.

    2015-01-01

    Aromatase inhibitor (AI) treatment is first-line systemic treatment for the majority of postmenopausal breast cancer patients with estrogen receptor (ER)-positive primary tumor. Although many patients benefit from treatment, some will develop resistance, and models mimicking acquired resistance will be valuable tools to unravel the resistance mechanisms and to find new treatments and biomarkers. Cell culture models for acquired resistance to the three clinically relevant AIs letrozole, anastrozole and exemestane were developed by selection and expansion of colonies of MCF-7 breast cancer cells surviving long-term AI treatment under conditions where endogenous aromatase-mediated conversion of androgen to estrogen was required for growth. Four cell lines resistant to each of the AIs were established and characterized. Maintenance of ER expression and function was a general finding, but ER loss was seen in one of twelve cell lines. HER receptor expression was increased, in particular EGFR expression in letrozole-resistant cell lines. The AI-resistant cell lines had acquired ability to grow without aromatase-mediated conversion of testosterone to estradiol, but upon withdrawal of AI treatment, testosterone induced minor growth stimulation. Letrozole, exemestane and tamoxifen were able to abrogate the testosterone stimulation but could not reduce growth to below the level in standard growth medium with AI, demonstrating cross-resistance between letrozole, exemestane and tamoxifen. In contrast, fulvestrant totally blocked growth of the AI resistant cell lines both after withdrawal of AI and with AI treatment. These data show that ER is the main driver of growth of the AI-resistant cell lines and indicate ligand-independent activation of ER. Fulvestrant is an efficient treatment option for these AI-resistant breast cancer cells, and the cell lines will be useful tools to disclose the underlying molecular mechanism for resistance to the different AIs. PMID:25625755

  5. New cell culture model for aromatase inhibitor-resistant breast cancer shows sensitivity to fulvestrant treatment and cross-resistance between letrozole and exemestane.

    PubMed

    Hole, Stine; Pedersen, Astrid M; Hansen, Susanne K; Lundqvist, Johan; Yde, Christina W; Lykkesfeldt, Anne E

    2015-04-01

    Aromatase inhibitor (AI) treatment is first-line systemic treatment for the majority of postmenopausal breast cancer patients with estrogen receptor (ER)-positive primary tumor. Although many patients benefit from treatment, some will develop resistance, and models mimicking acquired resistance will be valuable tools to unravel the resistance mechanisms and to find new treatments and biomarkers. Cell culture models for acquired resistance to the three clinically relevant AIs letrozole, anastrozole and exemestane were developed by selection and expansion of colonies of MCF-7 breast cancer cells surviving long-term AI treatment under conditions where endogenous aromatase-mediated conversion of androgen to estrogen was required for growth. Four cell lines resistant to each of the AIs were established and characterized. Maintenance of ER expression and function was a general finding, but ER loss was seen in one of twelve cell lines. HER receptor expression was increased, in particular EGFR expression in letrozole-resistant cell lines. The AI-resistant cell lines had acquired ability to grow without aromatase-mediated conversion of testosterone to estradiol, but upon withdrawal of AI treatment, testosterone induced minor growth stimulation. Letrozole, exemestane and tamoxifen were able to abrogate the testosterone stimulation but could not reduce growth to below the level in standard growth medium with AI, demonstrating cross-resistance between letrozole, exemestane and tamoxifen. In contrast, fulvestrant totally blocked growth of the AI resistant cell lines both after withdrawal of AI and with AI treatment. These data show that ER is the main driver of growth of the AI-resistant cell lines and indicate ligand-independent activation of ER. Fulvestrant is an efficient treatment option for these AI-resistant breast cancer cells, and the cell lines will be useful tools to disclose the underlying molecular mechanism for resistance to the different AIs.

  6. Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level.

    PubMed

    Balthazart, Jacques; Baillien, Michelle; Charlier, Thierry D; Cornil, Charlotte A; Ball, Gregory F

    2003-09-01

    Evidence has recently accumulated indicating that aromatase activity in the preoptic area is modulated in parallel by both slow (hours to days) genomic and rapid (minutes to hours) non-genomic mechanisms. We review here these two types of control mechanisms and their potential contribution to various aspects of brain physiology in quail. High levels of aromatase mRNA, protein and activity (AA) are present in the preoptic area of this species where the transcription of aromatase is controlled mainly by steroids. Estrogens acting in synergy with androgens play a key role in this control and both androgen and estrogen receptors (ER; alpha and beta subtypes) are present in the preoptic area even if they are not necessarily co-localized in the same cells as aromatase. Steroids have more pronounced effects on aromatase transcription in males than in females and this sex difference could be caused, in part, by a sexually differentiated expression of the steroid receptor coactivator 1 in this area. The changes in aromatase concentration presumably control seasonal variations as well as sex differences in brain estrogen production. Aromatase activity in hypothalamic homogenates is also rapidly (within minutes) down-regulated by exposure to conditions that enhance protein phosphorylation such as the presence of high concentrations of calcium, magnesium and ATP. Similarly, pharmacological manipulations such as treatment with thapsigargin or stimulation of various neurotransmitter receptors (alpha-amino-3-hydroxy-methyl-4-isoxazole propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA)) leading to enhanced intracellular calcium concentrations depress within minutes the aromatase activity measured in quail preoptic explants. The effects of receptor stimulation are presumably direct: electrophysiological data confirm the presence of these receptors in the membrane of aromatase-expressing cells. Inhibitors of protein kinases interfere with these processes and Western

  7. Randomized phase II placebo-controlled study to evaluate the efficacy of topical pure emu oil for joint pain related to adjuvant aromatase inhibitor use in postmenopausal women with early breast cancer: JUST (Joints Under Study).

    PubMed

    Chan, Arlene; De Boer, R; Gan, A; Willsher, P; Martin, R; Zissiadis, Y; Miller, K; Bauwens, A; Hastrich, D

    2017-07-09

    Aromatase inhibitors are standard of care in women with hormone receptor-positive early breast cancer. Published evidence demonstrates that adverse effects may have an impact on drug compliance, with arthralgias being one of the most commonly reported adverse effects. Eligible patients were postmenopausal women who had experienced arthralgia following initiation of an aromatase inhibitor. Patients who experienced arthralgias following a minimum of a 3-month treatment on the aromatase inhibitor were randomized to emu oil or placebo oil. The primary endpoint was to assess for a reduction in pain as measured by a visual analogue score after 8 weeks of treatment. Seventy-three patients comprised the intent-to-treat population, and there was no statistically significant benefit with use of EO. However, there was a statistically significant improvement in pain (visual analogue score was -1.28; p < 0.001) and Brief Pain Inventory severity score -0.88 (p < 0.001), as well as functional interference (Brief Pain Inventory interference -1.10 (p < 0.001) for the entire population following an 8-week administration of EO or placebo oil. Arthralgias, as a result of aromatase inhibitor use, may be ameliorated by the use of topical oil massaged onto the joint. Further research into interventions for this common side effect is needed.

  8. Depsidones, aromatase inhibitors and radical scavenging agents from the marine-derived fungus Aspergillus unguis CRI282-03.

    PubMed

    Sureram, Sanya; Wiyakrutta, Suthep; Ngamrojanavanich, Nattaya; Mahidol, Chulabhorn; Ruchirawat, Somsak; Kittakoop, Prasat

    2012-04-01

    Three new depsidones ( 1, 3, and 4), a new diaryl ether ( 5), and a new natural pyrone ( 9) (synthetically known), together with three known depsidones, nidulin ( 6), nornidulin ( 7), and 2-chlorounguinol ( 8), were isolated from the marine-derived fungus ASPERGILLUS UNGUIS CRI282-03. Aspergillusidone C ( 4) showed the most potent aromatase inhibitory activity with the IC (50) value of 0.74 µM, while depsidones 1, 3, 6- 8 inhibited aromatase with IC (50) values of 1.2-11.2 µM. It was found that the structural feature of depsidones, not their corresponding diaryl ether derivatives (e.g. 5), was important for aromatase inhibitory activity. Aspergillusidones A ( 1) and B ( 3) showed radical scavenging activity in the XXO assay with IC (50) values of 16.0 and < 15.6 µM, respectively. Compounds 1 and 3- 7 were mostly inactive or showed only weak cytotoxic activity against HuCCA-1, HepG2, A549, and MOLT-3 cancer cell lines.

  9. Novel aromatase inhibitors selection using induced fit docking and extra precision methods: Potential clinical use in ER-alpha-positive breast cancer

    PubMed Central

    Kumavath, Ranjith; Azad, Manan; Devarapalli, Pratap; Tiwari, Sandeep; Kar, Shreya; Barh, Debmalya; Azevedo, Vasco; Kumar, Alan Prem

    2016-01-01

    Aromatase (CYP19A1) the key enzyme of estrogen biosynthesis, is often deregulated in breast cancer patients. It catalyzes the conversion of androgen to estrogen, thus responsible for production of estrogen in human body. However, it causes over-production of estrogen which eventually leads to proliferation of breast cancer cells. Identification of new small molecule inhibitors targeted against CYP19A1 therefore, facilitates to increase drug sensitivity of cancer cells. In this scenario, the present study aims to identify new molecules which could block or suppress the activity of aromatase enzyme by molecular docking studies using Schrödinger-Maestro v9.3. In this study we used in silico approach by modeling CYP19A1 protein the strcture was subjected to protein preparation wizard; to add hydrogen and optimize the protonation states of Thr310 and Ser478 and Asp309 residues. Active site of the CYP19A1 protein was identified using SiteMap tool of Scchrodinger package. We further carried out docking studies by means of Glid, with various ligands. Based on glid score, potential ligands were screeened and their interaction with CYP19A1 was identified. The best hits were further screened for Lipinski’s rule for drug-likeliness and bioactivity scoring properties. Thus, we report two rubivivaxin and rhodethrin compounds that have successfully satisfied all in silico parameters, necessitating further in vitro and in vivo studies. PMID:28293075

  10. In vivo visualization of aromatase in animals and humans

    PubMed Central

    Biegon, Anat

    2015-01-01

    Aromatase catalyzes the last and obligatory step in the biosynthesis of estrogens across species. In vivo visualization of aromatase can be performed using positron emission tomography (PET) with radiolabeled aromatase inhibitors such as [11C]vorozole. PET studies in rats, monkeys and healthy human subjects demonstrate widespread but heterogeneous aromatase availability in brain and body, which appears to be regulated in a species, sex and region-specific manner. Thus, aromatase availability is high in brain amygdala and in ovaries of all species examined to date, with males demonstrating higher levels than females in all comparable organs. However, the highest concentrations of aromatase in the human brain are found in specific nuclei of the thalamus while the highest levels in rats and monkeys are found in the amygdala. Regional brain aromatase availability is increased by androgens and inhibited by nicotine. Future studies may improve diagnosis and treatment in brain disorders and cancers overexpressing aromatase. PMID:26456904

  11. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    SciTech Connect

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie

    2013-10-15

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [{sup 3}H]{sub 2}O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks

  12. Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors.

    PubMed

    Lézé, Marie-Pierre; Palusczak, Anja; Hartmann, Rolf W; Le Borgne, Marc

    2008-08-15

    Two new series of benzonitrile derivatives on position 6 or 4 of indole ring were successfully synthesized via a Leimgruber-Batcho reaction. All the compounds were evaluated in vitro on the inhibition of aromatase (CYP19) and 17alpha-hydroxylase-C17,20-lyase (CYP17). The racemate, 4-[(1H-imidazol-1-yl)(1H-indol-4-yl)methyl]benzonitrile 9, showed high level of inhibitory activity towards CYP19 (IC(50)=11.5 nM).

  13. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity.

    PubMed

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie

    2013-10-15

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [(3)H](2)O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks. © 2013

  14. ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole.

    PubMed

    Smollich, Martin; Götte, Martin; Fischgräbe, Jeanett; Macedo, Luciana F; Brodie, Angela; Chen, Shiuan; Radke, Isabel; Kiesel, Ludwig; Wülfing, Pia

    2010-09-01

    Endothelin-1 (ET-1) and endothelin A receptor (ETAR) contribute to the development and progression of breast carcinomas by modulating cell proliferation, angiogenesis, and anti-apoptosis. We investigated antitumoral effects of the specific ETAR antagonist ZD4054 in breast cancer cells and xenografts, and assessed antitumoral efficacy of the combinations of ZD4054 with aromatase inhibitors and fulvestrant. Gene expression changes were assessed by quantitative real-time PCR. Cell proliferation was measured using alamarBlue; migration and invasion assays were performed using modified Boyden chambers. Evaluating the antitumoral efficacy of ZD4054 in vivo, different breast cancer models were employed using nude mice xenografts. ZD4054 reduced ET-1 and ETAR expression in MCF-7, MDA-MB-231, and MDA-MB-468 breast cancer cells in a concentration-dependent manner. ZD4054 inhibited invasion by up to 37.1% (P = 0.022). Combinations of ZD4054 with either anastrozole or letrozole produced significant reductions in migration of aromatase-overexpressing MCF-7aro cells (P < 0.05). Combination of ZD4054 with fulvestrant reduced MCF-7 cell migration and invasion by 36.0% (P = 0.027) and 56.7% (P < 0.001), respectively, with effects significantly exceeding those seen with either compound alone. Regarding tumor volume reduction in vivo, ZD4054 (10 mg/kg) was equipotent to fulvestrant (200 mg/kg) and exhibited additive effects with anastrozole (0.5 mg/kg). These data are the first indicating that selective ETAR antagonism by ZD4054 displays antitumoral activity on breast cancer cells in vitro and in vivo. Our data strongly support a rationale for the clinical use of ZD4054 in combination with endocrine therapies.

  15. Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules.

    PubMed

    Ghorab, Mostafa M; Alsaid, Mansour S; Samir, Nermin; Abdel-Latif, Ghada A; Soliman, Aiten M; Ragab, Fatma A; Abou El Ella, Dalal A

    2017-07-07

    Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 μM) than that of the reference drug (doxorubicin, IC50 = 9.8 μM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 μM and 6.7 μM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10(-4) folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Effect of the aromatase inhibitor CGS-16949A on pregnancy and secretion of progesterone, estradiol-17beta, prostaglandins E and F2alpha (PGE; PGF2alpha) and pregnancy specific protein B (PSPB) in 90-day ovariectomized pregnant ewes.

    PubMed

    Weems, Y S; Bridges, P J; LeaMaster, B R; Sasser, R G; Ching, L; Weems, C W

    2001-09-01

    The aromatase inhibitor CGS-16949A was used to determine whether CGS-16949A altered secretion of progesterone, estradiol-17beta, PGE (PGE1 + PGE2), PGF2alpha and PSPB. Ninety day pregnant ewes were ovariectomized and received vehicle, PGF2alpha, CGS-16949A or PGF2alpha+CGS-16949A. None of the ewes treated with PGF2alpha, CGS-16949A or PGF2alpha+CGS-16949A aborted (P > or = 0.05) during the 108-h experimental period. Treatment with CGS-16949A lowered (P < or = 0.05) progesterone in jugular venous plasma but concentrations of progesterone were not affected (P > or = 0.05) by treatment with PGF2alpha. Concentrations of estradiol-17beta and PSPB in jugular venous plasma and PGE in inferior vena cava plasma were decreased (P < or = 0.05) by treatment with CGS-16949A. Concentrations of PGF2alpha in inferior vena cava plasma were not affected (P > or = 0.05) by treatment with CGS-16949A. Decreases in estradiol-17beta occurred before decreases in PSPB, which was then followed by decreases in PGE (P < or = 0.05). It is concluded that these data support the hypothesis that estradiol-17beta regulates placental secretion of PSPB; PSPB regulates placental secretion of PGE; and PGE regulates placental secretion of progesterone during mid-pregnancy in ewes.

  17. Clotrimazole exposure modulates aromatase activity in gonads and brain during gonadal differentiation in Xenopus tropicalis frogs.

    PubMed

    Gyllenhammar, Irina; Eriksson, Hanna; Söderqvist, Anneli; Lindberg, Richard H; Fick, Jerker; Berg, Cecilia

    2009-01-31

    Clotrimazole is a pharmaceutical used for treatment of fungal infections. It has been found in surface waters outside municipal wastewater treatment plants but data are scarce regarding its effects on aquatic organisms. It is known that clotrimazole and other imidazole fungicides are inhibitors of the enzyme aromatase (CYP 19). Aromatase converts androgens into estrogens and is suggested to be involved in the sex differentiation in amphibians. The aim of the present study was to evaluate effects of larval exposure to clotrimazole on aromatase activity in brain and gonads, and on gonadal differentiation in Xenopus tropicalis frogs. Another purpose was to determine if larval exposure to ethynylestradiol (EE(2)), at a concentration known to cause male-to-female sex reversal, affects aromatase activity in brain and gonads during gonadal differentiation. Tadpoles were exposed from shortly after hatching (Nieuwkoop and Faber developmental stages 47-48) until complete metamorphosis (NF stage 66) to 6, 41, and 375 nM clotrimazole or 100 nM (nominal) EE(2). Aromatase activity was measured in the brain and gonad/kidney complex of tadpoles during gonadal differentiation (NF stage 56) and, in the clotrimazole experiment, also at metamorphosis. In clotrimazole-exposed tadpoles gonadal aromatase activity increased over exposure time in the 41 and 375 nM groups but did not differ significantly from the control group. Gonadal aromatase activity was increased in both sexes exposed to 41 and 375 nM clotrimazole at metamorphosis. Brain aromatase activity was decreased in tadpoles (NF stage 56) exposed to 375 nM clotrimazole, but at metamorphosis no differences were seen between groups or between sexes. No effects of clotrimazole on sex ratio or gonadal histology were noted at completed metamorphosis. EE(2)-exposed tadpoles had a slightly decreased gonadal aromatase activity, though not significantly different from control group, and there was no effect of EE(2) on brain aromatase

  18. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19).

    PubMed

    Guo, Jiajia; Yuan, Yun; Lu, Danfeng; Du, Baowen; Xiong, Liang; Shi, Jiangong; Yang, Lijuan; Liu, Wanli; Yuan, Xiaohong; Zhang, Guolin; Wang, Fei

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds-trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)-were found to potently inhibit estrogen biosynthesis (IC50: 1μM and 0.5μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers.

  19. Aromatase and breast cancer.

    PubMed

    Brodie, A; Sabnis, G; Jelovac, D

    2006-12-01

    Several aromatase inhibitors and also new antiestrogens are now available for treating breast cancer. We have developed a model to compare the antitumor efficacy of these agents and to explore strategies for their optimal use. Results from the model have been predictive of clinical outcome. In this model, tumors are grown in ovariectomized, immunodeficient mice from MCF-7 human breast cancer cells transfected with the aromatase gene (MCF-7Ca). The possibility that blockade of estrogen action and estrogen synthesis may be synergistic was explored by treating mice with the aromatase inhibitor letrozole and the antiestrogen tamoxifen alone and in combination. The results indicated that letrozole alone was better than all other treatments. In addition, when tamoxifen treatment was no longer effective, tumor growth was significantly reduced in mice switched to letrozole treatment. However, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors eventually adapt and grow during letrozole treatment, we determined the expression of signaling proteins in tumors during the course of letrozole treatment compared to the tumors of control mice. Tumors initially up-regulated the ER while responding to treatment, but subsequently receptor levels decreased in tumors unresponsive to letrozole. Also, Her-2 and adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the MAPK cascade (p-Raf, p-Mekl/2, and p-MAPK), but not in the Pl3/Akt pathway, were increased in tumors no longer responsive to letrozole. To investigate whether sensitivity to letrozole could be regained, cells were isolated from the letrozole resistant tumors (LTLT) and treated with inhibitors of the MAPKinase pathway (PD98059 and UO126). These compounds reduced MAPK activity and increased ER expression. EGFR/Her-2 inhibitors, gefitinib and AEE78S although not effective in the parental MCF-70a cells, restored the sensitivity of LTLT cells to

  20. Randomized Controlled Trial of a Home-Based Walking Program to Reduce Moderate to Severe Aromatase Inhibitor-Associated Arthralgia in Breast Cancer Survivors.

    PubMed

    Nyrop, Kirsten A; Callahan, Leigh F; Cleveland, Rebecca J; Arbeeva, Liubov L; Hackney, Betsy S; Muss, Hyman B

    2017-10-01

    In postmenopausal women diagnosed with breast cancer (BC), most BC tumors are hormone receptor positive and guidelines recommend adjuvant endocrine therapy that includes an aromatase inhibitor (AI). This study investigates the impact of a 6-week, home-based, self-directed walking program on the commonly reported side effect of AI-associated arthralgia (AIAA). In this phase II trial, consented BC patients were randomized to walking Intervention (n = 31) or Wait List Control (WLC; n = 31). Eligibility criteria included: stage 0-III BC, on AI for at least 4 weeks, ≥3 on a 5-point scale inquiring about joint symptom intensity "at its worst," and exercising ≤150 minutes per week. Outcomes were self-reported joint symptoms and psychosocial measures. Analyses comparing Intervention and WLC groups were conducted on an intention-to-treat basis to assess intervention impact at 6 weeks (postintervention) and at 6-months follow-up. Adjusted means were calculated to assess differences in two groups. In our final sample (n = 62), mean age was 64 years, 74% were white, and 63% had a body mass index of 30 or higher. At postintervention, Intervention group participants reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living (ADL), and less perceived helplessness in managing joint symptoms. At 6-months follow-up (postwalking period in both Intervention and WLC), walking minutes per week had decreased significantly; however, improvements in stiffness and difficulty with ADLs were maintained. This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA. Breast cancer survivors whose adjuvant endocrine treatment includes an aromatase inhibitor (AI) often experience the side effect of AI-associated arthralgia (AIAA). This study investigates the impact of a 6-week, home-based, self-directed walking program in the management

  1. Vaginal Testosterone Cream vs Estradiol Vaginal Ring for Vaginal Dryness or Decreased Libido in Women Receiving Aromatase Inhibitors for Early-Stage Breast Cancer: A Randomized Clinical Trial.

    PubMed

    Melisko, Michelle E; Goldman, Mindy E; Hwang, Jimmy; De Luca, Amy; Fang, Sally; Esserman, Laura J; Chien, Amy J; Park, John W; Rugo, Hope S

    2017-03-01

    Aromatase inhibitors (AI) are associated with significant urogenital atrophy, affecting quality of life and drug compliance. To evaluate safety of intravaginal testosterone cream (IVT) or an estradiol-releasing vaginal ring (7.5 μg/d) in patients with early-stage breast cancer (BC) receiving an AI. Intervention was considered unsafe if more than 25% of patients had persistent elevation in estradiol (E2), defined as E2 greater than 10 pg/mL (to convert to pmol/L, multiply by 3.671) and at least 10 pg/mL above baseline after treatment initiation on 2 consecutive tests at least 2 weeks apart. Postmenopausal (PM) women with hormone receptor (HR)-positive stage I to III BC taking AIs with self-reported vaginal dryness, dyspareunia, or decreased libido were randomized to 12 weeks of IVT or an estradiol vaginal ring. Estradiol was measured at baseline and weeks 4 and 12 using a commercially available liquid chromatography and tandem mass spectrometry assay; follicle-stimulating hormone levels were measured at baseline and week 4. Gynecologic examinations and sexual quality-of-life questionnaires were completed at baseline and week 12. This randomized noncomparative design allowed safety evaluation of 2 interventions concurrently in the same population of patients, reducing the possibility of E2 assay variability over time and between the 2 interventions. The primary objective of this trial was to evaluate safety of IVT or an estradiol vaginal ring in patients with early-stage BC receiving an AI; secondary objectives included evaluation of adverse events, changes in sexual quality of life using the Cancer Rehabilitation Evaluation System sexuality subscales, changes in vaginal atrophy using a validated 4-point scale, and comparison of E2 levels. Overall, 76 women signed consent (mean [range] age, 56 [37-78] years), 75 started treatment, and 69 completed 12 weeks of treatment. Mean (range) baseline E2 was 20 (<2 to 127) pg/mL. At baseline, E2 was above the postmenopausal

  2. Defining the Biological Domain of Applicability of Adverse Outcome Pathways Across Diverse Species: The Estrogen Receptor/Aromatase Case Study

    EPA Science Inventory

    Aromatase inhibitors (e.g. fadrozole, prochloraz) and estrogen receptor antagonists (e.g. tamoxifen) reduce the circulating concentration of 17β-estradiol, leading to reproductive dysfunction in affected organisms. While these toxic effects are well-characterized in fish and...

  3. Defining the Biological Domain of Applicability of Adverse Outcome Pathways Across Diverse Species: The Estrogen Receptor/Aromatase Case Study

    EPA Science Inventory

    Aromatase inhibitors (e.g. fadrozole, prochloraz) and estrogen receptor antagonists (e.g. tamoxifen) reduce the circulating concentration of 17β-estradiol, leading to reproductive dysfunction in affected organisms. While these toxic effects are well-characterized in fish and...

  4. Phase II study assessing lapatinib added to letrozole in patients with progressive disease under aromatase inhibitor in metastatic breast cancer-Study BES 06.

    PubMed

    Villanueva, C; Romieu, G; Salvat, J; Chaigneau, L; Merrouche, Y; N'guyen, T; Vuillemin, A Thiery; Demarchi, M; Dobi, E; Pivot, Xavier

    2013-06-01

    This trial evaluated the effect of adding lapatinib to letrozole after clinical resistance to aromatase inhibitor (IA) treatment in hormone receptor-positive metastatic breast cancer. Postmenopausal women received daily letrozole plus lapatinib (1,500 mg). The primary end point was objective rate response (ORR) at week 12. Secondary objectives included time to response, duration of response, clinical benefit (CB), progression-free survival (PFS), overall survival, and safety. Twenty-four human epidermal growth factor receptor 2 (HER2)-negative patients were included with secondary resistance to IA. ORR at 12 weeks was 4 % (95 % confidence interval (CI), 0.7-20). Stable and progression diseases were reported in 25 % (95 % CI, 12-45) and 71 % (95 % CI, 51-85) of cases, respectively. At 24 weeks, the ORR increased to 8 %. CB was 21 % (95 % CI, 9-40). At a median follow-up of 27 months, median PFS was 3.4 months (95 % CI, 2.8-5.4). Grade 3 or 4 adverse events were rarely reported. No clinical cardiac toxicity was observed. Lapatinib was discontinued in two patients due to severe diarrhea. This trial was prematurely closed due to low recruitment. These preliminary results suggest that the addition of lapatinib to letrozole has a favorable safety profile and could overcome tumoral resistance to letrozole among HER2-negative tumors.

  5. Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: a prospective study

    PubMed Central

    Iwase, H; Yamamoto, Y; Yamamoto-Ibusuki, M; Murakami, K-I; Okumura, Y; Tomita, S; Inao, T; Honda, Y; Omoto, Y; Iyama, K-I

    2013-01-01

    Background: Oestrogens usually stimulate the progression of oestrogen receptor (ER)-positive breast cancer. Paradoxically, high-dose oestrogens suppress the growth of these tumours in certain circumstances. Methods: We prospectively examined the efficacy and safety of ethinylestradiol treatment (3 mg per day oral) in postmenopausal patients with advanced or recurrent ER-positive breast cancer who had previously received endocrine therapies, especially those with resistance to aromatase inhibitors. Results: Eighteen patients were enrolled with the median age of 63 years and the mean observation time of 9.2 months. Three cases withdrew within 1 week due to oestrogen flare reactions with nausea, fatigue and muscle-skeletal pain. The response rate was 50% (9 out of 18), and the clinical benefit rate was 56% (10 out of 18). The stable disease (<6 months) was 17% (3 out of 18) and another 2 cases were judged as progressive disease. Time-to-treatment failure including 2 on treatment was a median of 5.6 months (range 0.1 to 14.5+). Although vaginal bleeding or endometrial thickening was observed in patients receiving long-term treatment, there were no severe adverse events, such as deep venous thrombosis or other malignancies. Conclusion: Although the mechanism of this treatment has not been fully understood, our data may contribute to change the common view of late-stage endocrine therapy. PMID:24002591

  6. Aromatase inhibitors with or without luteinizing hormone-releasing hormone agonist for metastatic male breast cancer: report of four cases and review of the literature.

    PubMed

    Kuba, Sayaka; Ishida, Mayumi; Oikawa, Masahiro; Nakamura, Yoshiaki; Yamanouchi, Kosho; Tokunaga, Eriko; Taguchi, Kenichi; Esaki, Taito; Eguchi, Susumu; Ohno, Shinji

    2016-11-01

    The roles of aromatase inhibitors (AIs) and luteinizing hormone-releasing hormone (LH-RH) agonists in the management of male breast cancer remain uncertain, with no reports in Japanese men. We report four Japanese male patients with metastatic breast cancer treated with AIs with or without an LH-RH agonist, and consider the relationship between treatment effect and estradiol (E2) concentration. Three patients were initially treated with AI alone after selective estrogen receptor modulators (SERMs), and one received AIs plus an LH-RH agonist after a SERM. Two patients treated with an AI alone responded, one patient with E2 levels below the lower assay limit and the other with levels above the limit. The other treated with an AI alone experienced progression regardless of the E2 levels below the lower assay limit, however, responded after the addition of an LH-RH agonist. E2 concentrations were related to the efficacy of treatment in one patient. The patient initially treated with an AI plus an LH-RH agonist also responded. No grade 3 or 4 adverse events were observed in any of the patients treated with AIs with or without an LH-RH agonist. AIs with or without an LH-RH agonist offer an effective treatment option for hormone receptor-positive metastatic male breast cancer.

  7. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios.

    PubMed

    Gregoriou, Odysseas; Bakas, Panagiotis; Grigoriadis, Charalampos; Creatsa, Maria; Hassiakos, Dimitrios; Creatsas, Georgios

    2012-07-01

    To compare the effects of 2.5 mg letrozole with those of 1 mg anastrazole daily on the hormonal and semen profiles of a subset of infertile men with low T/E(2) ratios. Prospective, nonrandomized study. Reproductive medicine clinic. The study group consisted of 29 infertile men with a low serum T/E(2) ratio (<10). Patients were divided into two groups. Group A included 15 patients treated with 2.5 mg letrozole orally once daily for 6 months, and Group B consisted of 14 patients treated with 1 mg anastrazole orally every day for 6 months. Hormonal evaluation included measurement of serum FSH, LH, PRL, T, and E(2). In all sperm analyses pretreatment and posttreatment total motile sperm counts (ejaculate volume × concentration × motile fraction) were evaluated. The use of aromatase inhibitors (either letrozole or anastrazole) in cases of infertile men with low T/E(2) ratios improved both hormonal and semen parameters. This study suggests that some men with severe oligospermia, low T levels, and normal gonadotropin concentration may have a treatable endocrinopathy. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  8. The Androgen Metabolite 5α-androstane-3β,17β-diol (3βAdiol) Induces Breast Cancer Growth via Estrogen Receptor: Implications for Aromatase Inhibitor Resistance

    PubMed Central

    Sikora, Matthew J.; Cordero, Kevin E.; Larios, Jose M.; Johnson, Michael D.; Lippman, Marc E.; Rae, James M.

    2009-01-01

    The aromatase inhibitors (AIs) are used to treat estrogen receptor-positive (ER+) breast tumors in post-menopausal women, and function by blocking the conversion of adrenal androgens to estrogens by the enzyme CYP19 aromatase. Breast cancer patients receiving AI therapy have circulating estrogen levels below the level of detection; however, androgen concentrations remain unchanged. We were interested in studying the effects of androgens on breast cancer cell proliferation under profound estrogen-deprived conditions. Using in vitro models of estrogen-dependent breast cancer cell growth we show that the androgens testosterone and 5α-dihydrotestosterone induce the growth of MCF-7, T47D and BT-474 cells in the absence of estrogen. Furthermore, we demonstrate that under profound estrogen-deprived conditions these breast cancer cells up-regulate steroidogenic enzymes that can metabolize androgens to estrogens. Lastly, we found that the downstream metabolite of 5α-dihydrotestosterone, 5α-androstane-3β,17β-diol (3βAdiol), is estrogenic in breast cancer cells, and induces growth and ER-signaling via activation of ERα. In conclusion, our results show that breast cancer cells deprived of estrogen up-regulate steroidogenic enzymes and metabolize androgens to estrogen-like steroids. The generation of estrogen-like steroids represents a potential mechanism of resistance to aromatase inhibitors. PMID:18521740

  9. Neuroprotective Actions of Brain Aromatase

    PubMed Central

    Saldanha, Colin J.; Duncan, Kelli A.; Walters, Bradley J.

    2009-01-01

    The steroidal regulation of vertebrate neuroanatomy and neurophysiology includes a seemingly unending list of brain areas, cellular structures and behaviors modulated by these hormones. Estrogens, in particular have emerged as potent neuromodulators, exerting a range of effects including neuroprotection and perhaps neural repair. In songbirds and mammals, the brain itself appears to be the site of injury-induced estrogen synthesis via the rapid transcription and translation of aromatase (estrogen synthase) in astroglia. This induction seems to occur regardless of the nature and location of primary brain damage. The induced expression of aromatase apparently elevates local estrogen levels enough to interfere with apoptotic pathways, thereby decreasing secondary degeneration and ultimately lessening the extent of damage. There is even evidence suggesting that aromatization may affect injury-induced cytogenesis. Thus, aromatization in the brain appears to confer neuroprotection by an array of mechanisms that involve the deceleration and acceleration of degeneration and repair respectively. We are only beginning to understand the factors responsible for the injury-induced transcription of aromatase in astroglia. In contrast, much of the manner in which local and circulating estrogens may achieve their neuroprotective effects has been elucidated. However, gaps in our knowledge include issues about the cell-specific regulation of aromatase expression, steroidal influences of aromatization distinct from estrogen formation, and questions about the role of constitutive aromatase in neuroprotection. Here we describe the considerable consensus and some interesting differences in knowledge gained from studies conducted on diverse animal models, experimental paradigms and preparations towards understanding the neuroprotective actions of brain aromatase. PMID:19450619

  10. Natural Product Compounds with Aromatase Inhibitory Activity: An Update

    PubMed Central

    Balunas, Marcy J.; Kinghorn, A. Douglas

    2010-01-01

    Several synthetic aromatase inhibitors are currently in clinical use for the treatment of postmenopausal women with hormone-receptor positive breast cancer. However, these treatments may lead to untoward side effects and so a search for new aromatase inhibitors continues, especially those for which the activity is promoter-specific, targeting the breast-specific promoters I.3 and II. Recently, numerous natural product compounds have been found to inhibit aromatase in non-cellular, cellular, and in vivo studies. These investigations, covering the last two years, as well as additional studies that have focused on the evaluation of natural product compounds as promoter-specific aromatase inhibitors or as aromatase inducers, are described in this review. PMID:20635310

  11. Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells.

    PubMed

    Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O'Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H M

    2017-03-07

    Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer.

  12. Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation.

    PubMed

    Trösken, Eva R; Fischer, Kathrin; Völkel, Wolfgang; Lutz, Werner K

    2006-02-15

    Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14alpha-demethylase (CYP51). Azoles are also used for the treatment of estrogen-dependent diseases, e.g. in breast cancer therapy. Inhibition of CYP19 (aromatase) is the working principle for tumor therapy, but is an unwanted side effect of azoles used as fungicides or antifungal drugs. The inhibition of recombinant human CYP19 by 21 azoles in use for the three different purposes was investigated using the natural substrate testosterone. Estradiol product formation was measured by a newly developed and fully validated analytical method based on liquid chromatography-tandem mass spectrometry utilizing photospray ionization (APPI). Potency of enzyme inhibition was expressed in terms of IC50 concentrations. The two cytostatic drugs fadrozole and letrozole were the most potent inhibitors. However, azoles used as fungicides, e.g. prochloraz, or as antifungal drugs, e.g. bifonazole, were almost as potent inhibitors of aromatase as the drugs used in tumor therapy. Comparison of plasma concentrations that may be reached in antifungal therapy do not allow for large safety factors for bifonazole and miconazole. The IC50 values were compared to data obtained with other substrates, such as the pseudo-substrate dibenzylfluorescein (DBF). A high correlation was found, indicating that the fluorescence assay with DBF can well be used for potency ranking and screening of chemicals for aromatase inhibition. The data for antifungal drugs show that side effects on steroid hormone synthesis in humans due to inhibition of aromatase should be considered.

  13. Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

    PubMed Central

    Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O’Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H.M

    2017-01-01

    Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer. PMID:28178667

  14. Aromatase overexpression induces malignant changes in estrogen receptor α negative MCF-10A cells.

    PubMed

    Wang, J; Gildea, J J; Yue, W

    2013-10-31

    Estrogen is a risk factor of breast cancer. Elevated expression of aromatase (estrogen synthase) in breast tissues increases local estradiol concentrations and is associated with breast cancer development, but the causal relationship between aromatase and breast cancer has not been identified. Accumulating data suggest that both estrogen receptor (ER)-dependent and -independent effects are involved in estrogen carcinogenesis. We established a model by expressing aromatase in ERα- MCF-10A human breast epithelial cells to investigate ERα-independent effects of estrogen in the process of malignant transformation. Overexpression of aromatase significantly increased anchorage-independent growth. Parental- or vector-expressing MCF-10A cells did not form colonies under the same conditions. The anchorage-independent growth of MCF-10A(arom) cells can be completely abolished by pre-treatment with the aromatase inhibitor, letrozole. Neither MCF-10A(arom) nor MCF-10A(vector) cells grown in monolayer were affected by short-term exposure to estradiol. Enhanced motility is another characteristic of cellular transformation. Motility of MCF-10A(arom) cells was increased, which could be inhibited by letrozole. Increases in stem cell population in breast cancer tissues are associated with tumor recurrence and metastasis. CD44(high)/CD24(low) is a stem cell marker. We found that CD24 mRNA levels were reduced in MCF-10A(arom) cells compared with those in parental- and vector-transfected cells. By examining individual clones of MCF-10A(arom) with various aromatase activities, we found that the CD24 mRNA levels were inversely correlated with aromatase activity. The ability of MCF-10A(arom) cells to form mammospheres in the absence of serum was increased. Our results suggest that overexpression of aromatase in MCF-10A cells causes malignant transformation. Estrogen metabolite-mediated genotoxicity and induction of a stem cell/progenitor cell population are possible mechanisms. These

  15. Testosterone-derived estradiol production by male endothelium is robust and dependent on p450 aromatase via estrogen receptor alpha.

    PubMed

    Villablanca, Amparo C; Tetali, Sarada; Altman, Robin; Ng, Kenneth F; Rutledge, John C

    2013-12-01

    Vascular endothelium expresses both the estrogen receptors (ERs) α and β, and ERα mediates development of early atherosclerosis in male mice. This process is thought to be testosterone-dependent. We hypothesized that male murine aortic endothelium produces robust levels of estradiol by aromatase conversion of testosterone, and that regulation of this process is mediated by the presence of ERs, primarily ERα. Aortic endothelium was isolated from ERα knockout (ERα -/-) and wild-type (ERα +/+) male mice and treated with testosterone or the 5α reduction product dihydrotestosterone (DHT), with or without the P450 aromatase inhibitor anastrazole, or a non-specific estrogen receptor antagonist. Aromatase gene expression and estradiol production were assayed. Treatment with testosterone, but not DHT, caused increased aromatase expression and estradiol production in ERα +/+ endothelium that was attenuated by disruption of ERα in the ERα -/- group. Anastrazole inhibition of aromatase reduced testosterone-induced aromatase expression and estradiol levels in both ERα -/- and ERα +/+ endothelium. Antagonism of both ERs decreased testosterone-induced aromatase expression in both wild-type and knockout groups. The effects of the receptor antagonist on estradiol production differed between the two groups, however, with a reduction in estradiol release from the ERα +/+ cells and complete abolition of estradiol release from the ERα -/- cells. Thus, estradiol production in vascular endothelium from male mice is robust, depends on the aromatic conversion of testosterone and requires functional ERα to achieve maximal levels of estradiol generation. Local vascular production of aromatase-mediated estradiol in response to circulating testosterone may affect ERα-dependent mechanisms to increase susceptibility to early atheroma formation in male mice. This pathway may have important therapeutic relevance for reducing the risk of atherosclerotic cardiovascular disease in

  16. Aromatase and leiomyoma of the uterus.

    PubMed

    Shozu, Makio; Murakami, Kouich; Inoue, Masaki

    2004-02-01

    In leiomyoma of the uterus, both aromatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type I are overexpressed compared with myometrium. This suggests that leiomyoma cells convert circulating androstenedione into estrone (via aromatase), then into the active form of estrogen, estradiol (via 17beta-HSD type I). In vitro experiments and several clinical findings support the notion that in situ estrogen plays a role in leiomyoma growth under hypoestrogenemic conditions, such as natural menopause and therapy with gonadotropin-releasing hormone (GnRH) agonists. GnRH agonists abolish estrogen production both in situ in leiomyoma and in the ovary, leading to quick and profound regression of the leiomyoma. Aromatase inhibitors also inhibit estrogen synthesis in both leiomyoma and the ovary and may be used therapeutically. Certain doses of competitive aromatase inhibitors would completely inhibit estrogen production in leiomyoma, whereas ovarian production of estrogen would continue at reduced levels. This may lead to advantageous therapeutic conditions in which leiomyoma regresses without adverse symptoms related to estrogen depletion because levels of ovarian estrogen would be insufficient to support leiomyoma growth but sufficient to prevent symptoms associated with deficiency. This article discusses the potential uses of aromatase inhibitors.

  17. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-11C]Vorozole

    SciTech Connect

    Biegon, A.; Biegon, A.; Kim, S.W.; Alexoff, D.; Millard, J.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J.

    2010-10-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-{sup 11}C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V{sub T}) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from {approx}70% blocking in thalamus andpreoptic area to {approx}10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  18. Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole

    PubMed Central

    Biegon, Anat; Kim, Sung Won; Alexoff, David L.; Jayne, Millard; Carter, Pauline; Hubbard, Barbara; King, Payton; Logan, Jean; Muench, Lisa; Pareto, Deborah; Schlyer, David; Shea, Colleen; Telang, Frank; Wang, Gene-Jack; Xu, Youwen; Fowler, Joanna S.

    2010-01-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-11C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, 3 men and 3 women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90 min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (VT) values in both men and women followed the rank order: thalamus>amygdala=preoptic area>medulla(inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region dependent; ranging from ~70% blocking in thalamus and preoptic area to ~10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the non-invasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain. PMID:20842717

  19. The Effect of COX-2 Inhibitors on the Aromatase Gene (CYP19) Expression in Human Breast Cancer

    DTIC Science & Technology

    2006-12-01

    sulfa ” allergy. Drug Safety 2001; 24 (4), 239-247. 21. Patterson R, Bello A, Lefkowith J: Immunologic tolerability profile of celecoxib... drug is it is associated with less side effects than non- steroidal inflammatory drugs (NSAIDs), particularly gastroduodenal ulcers. Randomized...IIIB disease. 3.8 A woman who has received a COX-2 inhibitor, or NSAID within 7 days of study drug . 3.9 A women who is taking fluconazole, or

  20. Assessing fracture risk in early stage breast cancer patients treated with aromatase-inhibitors: An enhanced screening approach incorporating trabecular bone score.

    PubMed

    Mariotti, Veronica; Page, David B; Davydov, Oksana; Hans, Didier; Hudis, Clifford A; Patil, Sujata; Kunte, Siddharth; Girotra, Monica; Farooki, Azeez; Fornier, Monica N

    2017-06-01

    Aromatase-inhibitors (AIs) are commonly used for treatment of patients with hormone-receptor positive breast carcinoma, and are known to induce bone density loss and increase the risk of fractures. The current standard-of-care screening tool for fracture risk is bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). The fracture risk assessment tool (FRAX®) may be used in conjunction with BMD to identify additional osteopenic patients at risk of fracture who may benefit from a bone-modifying agent (BMA). The trabecular bone score (TBS), a novel method of measuring bone microarchitecture by DXA, has been shown to be an independent indicator of increased fracture risk. We report how the addition of TBS and FRAX®, respectively, to BMD contribute to identification of elevated fracture risk (EFR) in postmenopausal breast cancer patients treated with AIs. 100 patients with early stage hormone-positive breast cancer treated with AIs, no prior BMAs, and with serial DXAs were identified. BMD and TBS were measured from DXA images before and following initiation of AIs, and FRAX® scores were calculated from review of clinical records. EFR was defined as either: BMD ≤-2.5 or BMD between -2.5 and -1 plus either increased risk by FRAX® or degraded microstructure by TBS. At baseline, BMD alone identified 4% of patients with EFR. The addition of FRAX® increased detection to 13%, whereas the combination of BMD, FRAX® and TBS identified 20% of patients with EFR. Following AIs, changes in TBS were independent of changes in BMD. On follow-up DXA, BMD alone detected an additional 1 patient at EFR (1%), whereas BMD+ FRAX® identified 3 additional patients (3%), and BMD+FRAX®+TBS identified 7 additional patients (7%). The combination of FRAX®, TBS, and BMD maximized the identification of patients with EFR. TBS is a novel assessment that enhances the detection of patients who may benefit from BMAs.

  1. Randomized Multicenter Placebo-Controlled Trial of Omega-3 Fatty Acids for the Control of Aromatase Inhibitor-Induced Musculoskeletal Pain: SWOG S0927.

    PubMed

    Hershman, Dawn L; Unger, Joseph M; Crew, Katherine D; Awad, Danielle; Dakhil, Shaker R; Gralow, Julie; Greenlee, Heather; Lew, Danika L; Minasian, Lori M; Till, Cathee; Wade, James L; Meyskens, Frank L; Moinpour, Carol M

    2015-06-10

    Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Omega-3 fatty acids (O3-FAs) can be effective in decreasing arthralgia resulting from rheumatologic conditions and reducing serum triglycerides. Women with early-stage breast cancer receiving an AI who had a worst joint pain/stiffness score ≥ 5 of 10 using the Brief Pain Inventory-Short Form (BPI-SF) were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. Clinically significant change was defined as ≥ 2-point drop from baseline. Patients also completed quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Symptoms) and additional pain/stiffness assessments at baseline and weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis. Among 262 patients registered, 249 were evaluable, with 122 women in the O3-FA arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein. We found a substantial (> 50%) and sustained improvement in AI arthralgia for both O3-FAs and placebo but found no meaningful difference between the groups. © 2015 by American Society of Clinical Oncology.

  2. A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI.

    PubMed

    Lintermans, A; Van Asten, K; Wildiers, H; Laenen, A; Paridaens, R; Weltens, C; Verhaeghe, J; Vanderschueren, D; Smeets, A; Van Limbergen, E; Leunen, K; Christiaens, M R; Neven, P

    2014-07-01

    Aromatase inhibitor (AI) therapy for estrogen receptor-positive breast cancer is known to induce or enhance musculoskeletal problems. We have previously reported that loss of grip strength is more pronounced in AI-users with extremes in BMI. We here report results from a larger prospective study. Postmenopausal early breast cancer patients scheduled to start AI or tamoxifen therapy were recruited. A functional assessment grip strength test was performed at baseline, 3, 6, and 12 months of therapy. BMI was assessed, and a rheumatologic questionnaire was completed at each visit. 188 patients on an AI and 104 patients on tamoxifen were enrolled. 74 % of AI-users reported new/worsened musculoskeletal complaints compared with 37 % in the tamoxifen group. This was translated in a larger grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints (p = 0.0002). 15 % of AI-users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction versus adherent patients (p = 0.0107). Young age (p = 0.0135), taxane-based chemotherapy (p = 0.0223), and baseline VAS score >4 (p = 0.0155) were predictors for AI-related musculoskeletal pain. In addition, a quadratic trend of BMI with grip strength change (p = 0.0090) and probability of discontinuation was observed (p = 0.0424). Musculoskeletal events were a substantial problem in AI-treated patients and an important reason for treatment discontinuation. The decrease in grip strength was larger in AI- than in tamoxifen-users, with a more pronounced change in symptomatic patients. The inverse relationship between BMI extremes and grip strength change was confirmed in this large group of AI-patients.

  3. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up.

    PubMed

    Majithia, Neil; Atherton, Pamela J; Lafky, Jacqueline M; Wagner-Johnston, Nina; Olson, Janet; Dakhil, Shaker R; Perez, Edith A; Loprinzi, Charles L; Hines, Stephanie L

    2016-03-01

    This study was designed to explore whether zoledronic acid could prevent expected loss of bone mineral density (BMD) in postmenopausal women with pre-existing osteopenia or osteoporosis who were initiating adjuvant letrozole therapy for primary breast cancer. Between June 2006 and July 2007, 60 postmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a BMD T-score ≤-2.0 were enrolled. Participants received letrozole 2.5 mg and vitamin D 400 IU daily, calcium 500 mg twice daily, and zoledronic acid 4 mg every 6 months for a maximum of 5 years or until disease progression. BMD at the lumbar spine and femoral neck was recorded at the start of the study and annually for 5 years. Patients were evaluated for fractures every 6 months for the duration of the trial. After 5 years, mean BMD increased significantly by 11.6% (p = 0.01) at the lumbar spine and by 8.8% (p = 0.01) at combined sites. Femoral neck BMD increased by 4.2%, although this was not significant (p = 0.23). At the end of the trial, BMDs were consistent with osteoporosis in 7 % and osteopenia in 36% of the patients. A total of six fractures were reported after 417 individual assessments. Zoledronic acid appears to prevent further bone loss in postmenopausal breast cancer patients with osteopenia and osteoporosis starting treatment with letrozole. These findings were maintained at 5 years and support concurrent initiation of bisphosphonate and aromatase inhibitor therapy in this high-risk population.

  4. Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells.

    PubMed

    Chen, Zhike; Wang, Yuanzhong; Warden, Charles; Chen, Shiuan

    2015-05-01

    Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant clinical problem for a considerable number of patients. The oncogenic transcription factor c-MYC (hereafter referred to as MYC), which regulates glutamine metabolism in cancer cells, has been linked to endocrine resistance. We were interested in whether MYC-mediated glutamine metabolism is also associated with aromatase inhibitor (AI) resistant breast cancer. We studied the expression and regulation of MYC and the effects of inhibition of MYC expression in both AI sensitive and resistant breast cancer cells. Considering the role of MYC in glutamine metabolism, we evaluated the contribution of glutamine to the proliferation of AI sensitive and resistant cells, and performed RNA-sequencing to investigate mechanisms of MYC-mediated glutamine utilization in AI resistance. We found that glutamine metabolism was independent of estrogen but still required estrogen receptor (ER) in AI resistant breast cancer cells. The expression of MYC oncogene was up-regulated through the cross-talk between ER and human epidermal growth factor receptor 2 (HER2) in AI resistant breast cancer cells. Moreover, the glutamine transporter solute carrier family (SLC) 1A5 was significantly up-regulated in AI resistant breast cancer cells. ER down-regulator fulvestrant inhibited MYC, SLC1A5, glutaminase (GLS) and glutamine consumption in AI resistant breast cancer cells. Inhibition of MYC, SLC1A5 and GLS decreased AI resistant breast cancer cell proliferation. Our study has uncovered that MYC expression is up-regulated by the cross-talk between ER and HER2 in AI resistant breast cancer cells. MYC-mediated glutamine metabolism is associated with AI resistance of breast cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. The effects of aromatase and 5 alpha-reductase inhibitors, antiandrogen, and sex steroids on Bidder's organs development and gonadal differentiation in Bufo bufo tadpoles.

    PubMed

    Petrini, S; Zaccanti, F

    1998-02-15

    Embryos of toads (Bufo bufo) were treated with aromatase (4-OHA) and 5 alpha-reductase (17 beta C) inhibitors, antiandrogen (CPA), estradiol-17 beta, testosterone, and 5 alpha-dihydrotestosterone in order to study the role played by sex steroids in the development and sex differentiation of gonads. Test compounds were administered to tadpoles in water and morphometric and cytometric analyses were carried out on histological sections of the cephalic Bidder's organ (a rudimentary ovary) and of the gonadal region. In Bidder's organs, the number and size of oogonia and oocytes were modified by the treatments. However, the female commitment of the Bidder's organ occurs independently from steroid treatments that lead to an acceleration or slackening of the processes of proliferation and differentiation of oogonia. 4-OHA and androgens caused various degrees of inhibition of ovarian differentiation, with gonads maintaining an undifferentiated condition. Estrogen provoked a shift of the sex ratio towards the female sex, yet slackened gonadal growth. 17 beta C accelerated ovarian differentiation in females while CPA enhanced gonadal differentiation in both sexes by promoting the germ and somatic cell proliferation. We suggest that sex hormones may have a local regulatory role in gonadal differentiation during early developmental stages. Furthermore, the strong tendency of Bidderian germ cells to develop in the oogenetic way regardless of sex genotype and steroid treatments, and the quantitative sex differences found in the control Bidder's organs and gonads, suggest that other factors (such as intracellular mechanisms) may be involved in the initial steps of the process of germ cell differentiation.

  6. Bone health and adherence to vitamin D and calcium therapy in early breast cancer patients on endocrine therapy with aromatase inhibitors.

    PubMed

    Bošković, Lidija; Gašparić, Maja; Petković, Marija; Gugić, Damir; Lovasić, Ingrid Belac; Soldić, Željko; Miše, Branka Petrić; Dabelić, Nina; Vazdar, Ljubica; Vrdoljak, Eduard

    2017-02-01

    Randomized trials involving aromatase inhibitors (AIs) in the adjuvant treatment of breast cancer patients have reported increased osteoporosis risk. Bone loss can be reduced with appropriate life style, vitamin D and calcium supplements, and with bisphosphonate therapy. The aim of this analysis was to investigate adherence to vitamin D and calcium in postmenopausal breast cancer patients receiving adjuvant non-steroidal AIs, and oncologists' adherence to the bone health guidelines. This prospective study included 438 newly diagnosed patients and those who have already been receiving non-steroidal AIs for up to 3.5 years. Median endocrine therapy duration before recruitment in the study was 10.5 months (interquartile 4.8-26.6). Densitometry was performed on 142 patients (32.4%) before initiation of endocrine therapy, and on additional 38 (8.6%) patients at second study visit. Densitometry was not performed on 258 (59%) patients. Vitamin D and calcium were prescribed to 329/438 (75.1%) patients at some point during the study. Patients who took more than 80% of the prescribed dose were considered adherent. Self-reported adherence was 88.4%. Osteoporosis was diagnosed in 24 patients (5.5%) of the total study population, bearing in mind that 258/438 (59%) patients did not have densitometry. Bisphosphonates were prescribed to 54/438 (12.3%) patients, whilst only 19 (35.2%) of those had osteoporosis. In this analysis, lack of oncologists' adherence to the bone health guidelines was observed. In addition, a significant proportion of the patients did not adhere to the vitamin D and calcium. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Effects of 17α-Methyltestosterone and Aromatase Inhibitor Letrozole on Sex Reversal, Gonadal Structure, and Growth in Yellow Catfish Pelteobagrus fulvidraco.

    PubMed

    Shen, Zhi-Gang; Fan, Qi-Xue; Yang, Wei; Zhang, Yun-Long; Wang, Han-Ping

    2015-04-01

    Monosex populations are in demand in many fish species with sexual dimorphism, e.g., better growth performance, higher gonad value, superior ornamental value. From the point of view of research, a monosex population is one of the best materials for investigating sex-determining mechanisms, sex differentiation, and sex-linked markers. Sex reversal of females (phenotypic reversal from XX female to XX male) is the first step in all-female production in species with an XX/XY system for sex determination. In the present study, masculinization of yellow catfish, a species with XX/XY sex determination, was investigated by oral administration of various doses of 17α-methyltestosterone (MT) or an aromatase inhibitor (AI) letrozole (LZ); effects on survival, growth performance, sex ratio, and changes in gonadal structure were evaluated. Three doses (20, 50, and 100 mg kg(-1) diet) of oral MT or LZ were administered to fry from 10 days post-hatching (DPH) to 59 DPH. Oral administration of MT at all doses did not significantly change the ratio of males (45.8%, 33.3%, and 50.0% respectively) compared to the control group (37.5%), while yielding intersex fish at all doses (4.2% to 8.3%). Oral administration of LZ produced a significantly higher proportion of males in all doses (75.5%, 83.3%, and 75.0%, respectively). Additionally, the lowest dose of LZ improved the growth of treated fish compared to the control, and all doses of LZ enhanced spermatogenesis in treated males.

  8. Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer survivors: the Hormones and Physical Exercise (HOPE) study.

    PubMed

    Arem, Hannah; Sorkin, Mia; Cartmel, Brenda; Fiellin, Martha; Capozza, Scott; Harrigan, Maura; Ercolano, Elizabeth; Zhou, Yang; Sanft, Tara; Gross, Cary; Schmitz, Kathryn; Neogi, Tuhina; Hershman, Dawn; Ligibel, Jennifer; Irwin, Melinda L

    2016-08-01

    Up to 50 % of postmenopausal breast cancer survivors taking aromatase inhibitors (AIs) experience AI-associated arthralgias, or joint pain, which causes many to stop taking AIs and may inhibit exercise, despite known health benefits. We thus evaluated exercise adherence and factors associated with better exercise adherence in breast cancer survivors experiencing AI-induced arthralgia in the (HOPE) year long randomized controlled trial. We included 61 HOPE women randomized to exercise (150 min/week of moderate-intensity aerobic exercise and twice-weekly supervised strength training). Our main outcomes were aerobic exercise measured with daily activity logs, attendance at supervised exercise sessions, and changes in cardiorespiratory fitness, measured maximal oxygen consumption (VO2max). We examined means and standard deviations (SDs) for exercise adherence by demographic and medical characteristics and used the t test for mean differences. We also examined predictors of adherence using linear regression. On average, at the end of the year long trial, women reported 119 (SD 78) min/week of moderate-intensity aerobic exercise and participated in 70 % of supervised exercise training sessions. After adjustment for other factors that influence adherence, at 6 months postrandomization, only baseline VO2max was associated with higher aerobic exercise levels and at 12 months, only older age predicted better supervised exercise training attendance. Breast cancer survivors taking AIs and experiencing arthralgia are able to initiate and maintain a year long exercise program, regardless of other factors that influence activity levels. Breast cancer survivors can exercise at levels that have been shown to improve AI-associated arthralgia.

  9. Involvement of pituitary gonadotropins, gonadal steroids and breeding season in sex change of protogynous dusky grouper, Epinephelus marginatus (Teleostei: Serranidae), induced by a non-steroidal aromatase inhibitor.

    PubMed

    Garcia, Carlos Eduardo de O; Araújo, Bruno C; Mello, Paulo H; Narcizo, Amanda de M; Rodrigues-Filho, Jandyr A; Medrado, Andreone T; Zampieri, Ricardo A; Floeter-Winter, Lucile M; Moreira, Renata Guimarães

    2013-10-01

    Two experiments were performed using the aromatase inhibitor (AI) letrozole (100mg/kg) to promote sex change, from female-to-male, in protogynous dusky grouper. One experiment was performed during the breeding season (spring) and the other at the end of the breeding season (summer). During the spring, AI promoted sex change after 9 weeks and the sperm produced was able to fertilize grouper oocytes. During the summer, the sex change was incomplete; intersex individuals were present and sperm was not released by any of the animals. Sex changed gonads had a lamellar architecture; cysts of spermatocytes and spermatozoa in the lumen of the germinal compartment. In the spring, after 4 weeks, 11ketotestosterone (11KT) levels were higher in the AI than in control fish, and after 9 weeks, coincident with semen release, testosterone levels increased in the AI group, while 11KT returned to the initial levels. Estradiol (E2) levels remained unchanged during the experimental period. Instead of decreasing throughout the period, as in control group, 17 α-OH progesterone levels did not change in the AI-treated fish, resulting in higher values after 9 weeks when compared with control fish. fshβ and lhβ gene expression in the AI animals were lower compared with control fish after 9 weeks. The use of AI was effective to obtain functional males during the breeding season. The increase in androgens, modulated by gonadotropins, triggered the sex change, enabling the development of male germ cells, whereas a decrease in E2 levels was not required to change sex in dusky grouper. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Effects of transdermal testosterone gel or an aromatase inhibitor on serum concentration and pulsatility of growth hormone in older men with age-related low testosterone.

    PubMed

    Dias, Jenny Pena; Veldhuis, Johannes D; Carlson, Olga; Shardell, Michelle; Chia, Chee W; Melvin, Denise; Egan, Josephine M; Basaria, Shehzad

    2017-04-01

    Growth hormone is the major regulator of growth and body composition. Pulsatile GH secretion declines exponentially with age. Testosterone replacement is being increasingly offered to older men with age-related low testosterone. Testosterone administration has been shown to stimulate GH secretion. However, little is known about the effect of testosterone aromatization to estradiol on GH pulsatility and its impact on IGF-1 in older men. This randomized controlled proof-of-concept trial investigated the relative effects of testosterone and estradiol on GH pulsatility and IGF-1 in older men with low testosterone. Thirty-seven men, ≥65years with total testosterone <350ng/dL were randomized to 5g transdermal testosterone gel (TT), 1mg oral aromatase inhibitor (AI) or placebo daily for 12months. Primary outcome was deconvolution and approximate entropy analyses of pulsatile including basal and entropic modes of secretion performed at baseline and 3months. Secondary outcomes included IGF-1 evaluated at baseline, 3 and 6months. At 3months, mean GH and in IGF-1 were similar between the three groups. At 6months, IGF-1 significantly increased by Δ 15.3±10.3ng/ml in the TT-group compared to placebo (P=0.03). Both intervention groups significantly increased GH pulse frequency (TT-group, P=0.04; AI-group, P=0.05) compared to placebo. The GH secretory-burst mode (duration) significantly decreased in the TT-group (P=0.0018) compared to placebo while it remained unchanged in the AI-group (P=0.059). In older men, testosterone increases GH pulse frequency while the aromatization to estradiol is involved in the rise of IGF-1 levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Outcome analysis of aromatase inhibitor therapy to increase adult height in males with predicted short adult stature and/or rapid pubertal progress: a retrospective chart review.

    PubMed

    Shams, Kim; Cameo, Tamara; Fennoy, Ilene; Hassoun, Abeer A; Lerner, Shulamit E; Aranoff, Gaya S; Sopher, Aviva B; Yang, Christine; McMahon, Donald J; Oberfield, Sharon E

    2014-07-01

    Aromatase inhibitors (AIs) have been used off-label to increase adult height in short adolescent males. Studies have shown that AIs increase the predicted adult height (PAH) while delaying bone age (BA) maturation. We sought to determine whether AI therapy increases PAH in boys with short stature or rapid pubertal progression, and to evaluate any untoward effects. The charts of 27 boys with BA ≥ 13 and short stature [height ≥ 2 standard deviation (SD) below the mean or ≥ 2 SD below mid-parental target height (MPTH)] or rapid pubertal progress, treated with anastrozole were reviewed. Outcome measures included anthropomorphic, hormonal, and metabolic data. The AI therapy averaged 21 months (range 14-30 months) for all, with Rx group 1 receiving <18 months therapy (n=7) and Rx group 2 receiving 18-30 months therapy (n=20). Post-therapy, in Rx group 1 and all subjects, there was no significant change in the PAH, height SDS, or BA/chronological age (CA). In Rx group 2, there was a small, nonsignificant increase in PAH, no change in height SDS, and a small decrease in BA/CA. Post-therapy PAH was different from MPTH in all and in both Rx groups 1 and 2, p<0.02. Eight of them achieved near-final height, averaging 6.73 ± 1.40 cm less than MPTH and 1.91 ± 0.86 cm less than the pre-therapy PAH. Post-therapy, the initially decreased estradiol did not persist but mildly increased testosterone and decreased high-density lipoprotein were noted, as was an increase in hematocrit, and decrease in growth velocity. We suggest that although bone age progression may be slightly delayed with longer duration of therapy, an overall short-term AI therapy does not lead to a final height that is greater than the predicted pre-therapy height.

  12. Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo.

    PubMed

    Wright, Laura E; Harhash, Ahmed A; Kozlow, Wende M; Waning, David L; Regan, Jenna N; She, Yun; John, Sutha K; Murthy, Sreemala; Niewolna, Maryla; Marks, Andrew R; Mohammad, Khalid S; Guise, Theresa A

    2017-01-31

    Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.

  13. Cost-effectiveness of dual-energy X-ray absorptiometry plus antiresorptive treatment in Australian women with breast cancer who receive aromatase inhibitors.

    PubMed

    Sowa, P Marcin; Downes, Martin J; Gordon, Louisa G

    2017-03-01

    Postmenopausal women with breast cancer on aromatase inhibitor (AI) treatment are at increased risk of bone mineral density loss, which may lead to minimal trauma fractures. We examined the cost-effectiveness of dual energy X-ray absorptiometry (DXA) with antiresorptive (AR) therapy compared with fracture risk assessment, lifestyle advice, and vitamin supplementation. We used a hypothetical Markov cohort model of lifetime duration for 60-year-old women with early stage breast cancer receiving AIs. The data to inform the model came from medical literature, epidemiological reports, and costing data sets. Two eligibility scenarios for AR therapy were considered: (A) osteoporosis and (B) osteopenia or osteoporosis. The main outcomes were incremental cost per quality-adjusted life years gained and cumulative fractures per 1000 women, calculated relative to the comparator. Key aspects of the model were explored in sensitivity analyses. Due to relatively low effectiveness gains, the outcomes were primarily driven by the costs. The incremental cost per quality-adjusted life year gained was A$47,556 and A$253,000 for scenarios A and B, respectively. The numbers of fractures avoided were 56 and 77 per 1000 women, respectively. The results were most sensitive to the initial probability of osteoporosis, baseline risk of fracture, and cohort starting age. Compared with risk assessment and lifestyle advice only, a DXA scan followed by an AR treatment is potentially cost-effective for women aged 60 and over undergoing AI therapy for early breast cancer. However, the number of fractures averted through this intervention is small.

  14. Aromatase inhibitor associated arthralgia: the importance of oncology provider-patient communication about side effects and potential management through physical activity.

    PubMed

    Nyrop, Kirsten A; Callahan, Leigh F; Rini, Christine; Altpeter, Mary; Hackney, Betsy; DePue, Amy; Wilson, Anne; Schechter, Arielle; Muss, Hyman B

    2016-06-01

    Breast cancer survivors on aromatase inhibitors (AI) often experience side effects of joint pain, stiffness, or achiness (arthralgia). This study presents findings from a qualitative study of survivors on an AI regarding their knowledge of potential joint pain side effects and how both AI side effects and their management through moderate physical activity could be discussed during routine visits with their oncology provider. Qualitative data from semi-structured interviews were content analyzed for emergent themes. Descriptive statistics summarize sample characteristics. Our sample included 36 survivors, mean age of 67 (range 46-87); 86 % Caucasian and 70 % had education beyond high school. AI experience are as follows: 64 % anastrozole/Arimidex, 48 % letrozole/Femara, and 31 % exemestane/Aromasin. Participants expressed interest in having more information about potential joint pain side effects when the AI was prescribed so they could understand their joint symptoms when they appeared or intensified. They were relieved to learn that their joint symptoms were not unusual or "in their head." Participants would have been especially motivated to try walking as a way to manage their joint pain if physical activity had been recommended by their oncologist. Breast cancer survivors who are prescribed an AI as part of their adjuvant treatment want ongoing communication with their oncology provider about the potential for joint pain side effects and how these symptoms may be managed through regular physical activity. The prescription of an AI presents a "teachable moment" for oncologists to recommend and encourage their patients to engage in regular physical activity.

  15. The role of cyclooxygenase-2-dependent signaling via cyclic AMP response element activation on aromatase up-regulation by o,p'-DDT in human breast cancer cells.

    PubMed

    Han, Eun Hee; Kim, Hyung Gyun; Hwang, Yong Pil; Choi, Jae Ho; Im, Ji Hye; Park, Bonghwan; Yang, Ji Hye; Jeong, Tae Cheon; Jeong, Hye Gwang

    2010-10-20

    o,p'-Dichlorodiphenyltrichloroethane (o,p'-DDT) is a DDT isomer and xenoestrogen that can induce inflammation and cancer. However, the effect of o,p'-DDT on aromatase is unclear. Thus, we investigated the effects of o,p'-DDT on aromatase expression in human breast cancer cells. We also examined whether cyclooxygenase-2 (COX-2) is involved in o,p'-DDT-mediated aromatase expression. Treatment with o,p'-DDT-induced aromatase protein expression in MCF-7 and MDA-MB-231 human breast cancer cells; enhancing aromatase gene expression, and enzyme and promoter activity. Treatment with ICI 182.780, a estrogen receptor antagonist, did not affect the inductive effects of o,p'-DDT on aromatase expression. In addition, o,p'-DDT increased COX-2 protein levels markedly, increased COX-2 mRNA expression and promoter activity, enhanced the production of prostaglandin E(2) (PGE(2)), induced cyclic AMP response element (CRE) activation, and cAMP levels and binding of CREB. o,p'-DDT also increased the phosphorylation of PKA, Akt, ERK, and JNK in their signaling pathways in MCF-7 and MDA-MB-231 cells. Finally, o,p'-DDT induction of aromatase was inhibited by various inhibitors [COX-2 (by NS-398), PKA (H-89), PI3-K/Akt (LY 294002), EP2 (AH6809), and EP4 receptor (AH23848)]. Together, these results suggest that o,p'-DDT increases aromatase, and that o,p'-DDT-induced aromatase is correlated with COX-2 up-regulation, mediated via the CRE activation and PKA and PI3-kinase/Akt signaling pathways in breast cancer cells.

  16. Aromatase Activity and Bone Loss in Men

    PubMed Central

    Merlotti, Daniela; Gennari, Luigi; Stolakis, Konstantinos; Nuti, Ranuccio

    2011-01-01

    Aromatase is a specific component of the cytochrome P450 enzyme system responsible for the transformation of androgen precursors into estrogens. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is, expressed in ovary and testis, but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The activity of aromatase regulates the concentrations of estrogens with endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen in men. Clinical and experimental evidences clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, the attainment of peak bone mass, pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity may significantly affect bone loss and fracture risk in men. PMID:21772971

  17. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    SciTech Connect

    Guo, Jiajia; Yuan, Yun; Lu, Danfeng; Du, Baowen; Xiong, Liang; Shi, Jiangong; Yang, Lijuan; Liu, Wanli; Yuan, Xiaohong; Zhang, Guolin; Wang, Fei

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC{sub 50}: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They

  18. Flavonoid inhibition of aromatase enzyme activity in human preadipocytes.

    PubMed

    Campbell, D R; Kurzer, M S

    1993-09-01

    Eleven flavonoid compounds were compared with aminoglutethimide (AG), a pharmaceutical aromatase inhibitor, for their abilities to inhibit aromatase enzyme activity in a human preadipocyte cell culture system. Flavonoids exerting no effect on aromatase activity were catechin, daidzein, equol, genistein, beta-naphthoflavone (BNF), quercetin and rutin. The synthetic flavonoid, alpha-naphthoflavone (ANF), was the most potent aromatase inhibitor, with an I50 value of 0.5 microM. Three naturally-occurring flavonoids, chrysin, flavone, and genistein 4'-methyl ether (Biochanin A) showed I50 values of 4.6, 68, and 113 microM, respectively, while AG showed an I50 value of 7.4 microM. Kinetic analyses showed that both AG and the flavonoids acted as competitive inhibitors of aromatase. The Ki values, indicating the effectiveness of inhibition, were 0.2, 2.4, 2.4, 22, and 49 microM, for ANF, AG, chrysin, flavone, and Biochanin A, respectively. Chrysin, the most potent of the naturally-occurring flavonoids, was similar in potency and effectiveness to AG, a pharmaceutical aromatase inhibitor used clinically in cases of estrogen-dependent carcinoma. These data suggest that flavonoid inhibition of peripheral aromatase activity may contribute to the observed cancer-preventive hormonal effects of plant-based diets.

  19. Effects of organochlorine compounds on cytochrome P450 aromatase activity in an immortal sea turtle cell line.

    PubMed

    Keller, Jennifer M; McClellan-Green, Patricia

    2004-01-01

    Many classes of environmental contaminants affect the reproductive function of animals through interactions with the endocrine system. The primary components affected by endocrine active compounds (EACs) are the steroid receptors and the enzymes responsible for steroidogenesis. This study sought to develop an in vitro model for assessing EAC effects in sea turtles by examining their ability to alter cytochrome P450 aromatase (CYP19) activity. Aromatase is the enzyme responsible for the conversion of testosterone to estradiol. This enzyme is critical in the sexual differentiation of reptiles which demonstrate temperature-dependent sex determination. An immortal testis cell line GST-TS from a green sea turtle was grown in culture at 30 degrees C in RPMI 1640 media. The cells were exposed to three known aromatase inducers; dexamethasone (Dex), 8Br-cyclic AMP, or human chronic gonadotropin (HCG) and one aromatase inhibitor 4-androstenol-dione (4-OHA). In addition, the GST-TS cells were exposed to 0.1-30 microM atrazine and 3-100 microM 4,4'-DDE. The inducing compounds that have been shown to increase aromatase activity in other systems failed to induce aromatase activity in the GST-TS cells, yet exposure to the inhibiting compound, 4-OHA, did result in a significant reduction. Atrazine (0.1, 1.0 and 10 microM) significantly induced aromatase activity following a 24 h exposure, and 4,4'-DDE inhibited the activity but only at cytotoxic concentrations (100 microM). Based on these results, this in vitro model can be useful in examining the endocrine effects of EACs in sea turtles.

  20. Adaptive Response in Female Fathead Minnows Exposed to an Aromatase Inhibitor: Computational Modeling of the Hypothalamic-Pituitary-Gonadal Axis

    EPA Science Inventory

    Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course ...

  1. Adaptive Response in Female Fathead Minnows Exposed to an Aromatase Inhibitor: Computational Modeling of the Hypothalamic-Pituitary-Gonadal Axis

    EPA Science Inventory

    Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course ...

  2. Promoter-specific effects of metformin on aromatase transcript expression.

    PubMed

    Samarajeewa, Nirukshi U; Ham, Seungmin; Yang, Fangyuan; Simpson, Evan R; Brown, Kristy A

    2011-07-01

    Phase III aromatase inhibitors (AIs) are proving successful in the treatment of hormone-dependent postmenopausal breast cancer. Side-effects associated with total body aromatase inhibition have prompted new research into the development of breast-specific AIs. The identification of tissue- and disease-specific usage of aromatase promoters has made the inhibition of aromatase at the transcriptional level an interesting approach. We have previously demonstrated that AMPK-activating drugs, including metformin, were potent inhibitors of aromatase expression in primary human breast adipose stromal cells (hASCs). This study examines the promoter-specific effects of metformin on inhibiting aromatase expression in hASCs. Tumour-associated promoters PII/PI.3 were activated using forskolin (FSK)/phorbol ester (PMA), whereas normal adipose associated promoter PI.4 was activated using dexamethasone (DEX)/tumour necrosis factor-α (TNFα). Results demonstrate that metformin significantly decreased the FSK/PMA-, but not the DEX/TNFα-mediated expression of total aromatase at concentrations of 10, 20, and 50 μM (P ≤ 0.05). Using PCR to amplify promoter-specific transcripts of aromatase, it appears that the inhibition of the FSK/PMA-mediated expression of aromatase is due to decreases in PII/PI.3-specific transcripts, whereas no effect of metformin is observed on any promoter-specific transcript, including PI.4, in DEX/TNFα-treated hASCs. This report therefore supports the hypothesis that metformin would act as a breast-specific inhibitor of aromatase expression in the context of postmenopausal breast cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Discovery of a new class of cinnamyl-triazole as potent and selective inhibitors of aromatase (cytochrome P450 19A1).

    PubMed

    McNulty, James; Keskar, Kunal; Crankshaw, Denis J; Holloway, Alison C

    2014-09-15

    Synthesis of a novel class of natural product inspired cinnamyl-containing 1,4,5-triazole and the potent inhibition of human aromatase (CYP 450 19A1) by select members is described. Structure-activity data generated provides insights into the requirements for potency particularly the inclusion of an aryl bromide or chloride residue as a keto-bioisostere.

  4. Genistein induces breast cancer-associated aromatase and stimulates estrogen-dependent tumor cell growth in in vitro breast cancer model.

    PubMed

    van Duursen, M B M; Nijmeijer, S M; de Morree, E S; de Jong, P Chr; van den Berg, M

    2011-11-18

    In breast cancer, the interaction between estrogen-producing breast adipose fibroblasts (BAFs) and estrogen-dependent epithelial tumor cells is pivotal. Local estrogen production is catalyzed by aromatase, which is differentially regulated in disease-free and tumorigenic breast tissue. The use of aromatase inhibitors to block local estrogen production has proven effective in treatment of estrogen-dependent breast cancer. However, a major problem during breast cancer treatment is the sudden onset of menopause and many women seek for alternative medicines, such as the soy isoflavone genistein. In this study, we show that genistein can induce estrogen-dependent MCF-7 tumor cell growth and increase breast cancer-associated aromatase expression and activity in vitro. We have previously developed an in vitro breast cancer model where the positive feedback loop between primary BAFs and estrogen-dependent MCF-7 tumor cells is operational, thereby representing a more natural in vitro model for breast cancer. In this model, genistein could negate the growth inhibitory action of the aromatase inhibitor fadrozole at physiologically relevant concentrations. These data suggest that soy-based supplements might affect the efficacy of breast cancer treatment with aromatase inhibitors. Considering the high number of breast cancer patients using soy supplements to treat menopausal symptoms, the increasing risk for adverse interactions with breast cancer treatment is of major concern and should be considered with care.

  5. Bone health assessment by quantitative ultrasound and dual-energy x-ray absorptiometry in postmenopausal women with breast cancer receiving aromatase inhibitors.

    PubMed

    Catalano, Antonino; Morabito, Nunziata; Agostino, Rita Maria; Basile, Giorgio; Gaudio, Agostino; Atteritano, Marco; Natale, Giuseppe; Xourafa, Anastasia; Morini, Elisabetta; Adamo, Vincenzo; Lasco, Antonino

    2017-01-01

    Phalangeal quantitative ultrasound (QUS) measurements provide surrogate information on bone quality. The aim of the present study was to assess bone status by phalangeal QUS and by dual-energy x-ray absorptiometry (DXA), and to evaluate bone turnover in breast cancer (BC) women receiving aromatase inhibitors (AIs). Sixty postmenopausal BC women and 42 matched controls were recruited (mean age 61.64 ± 8.33 y). Amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), Ultrasound Bone Profile Index, as QUS parameters, L1-L4 and femoral neck BMD by DXA were assessed at baseline and after 18 months; serum bone-specific alkaline phosphatase (BSAP) and C-telopeptide of type 1 collagen were measured at baseline, 9 and 18 months. FRAX (without BMD) derived 10-years probability of major fractures and hip fractures were significantly associated with AD-SoS (r = -0.381, P = < 0.001 and r = -0.370, P < 0.001, respectively), Ultrasound Bone Profile Index (r = -0.434, P ≤ 0.001 and r = -0.409, P = < 0.001, respectively), BTT (r = -0.309, P = 0.002 and r = -0.340, P = 0.001, respectively). The median percent changes of AD-SoS (-3.71 [-5.38 to 0.11] vs -0.7 [-4.15 to 0.83], P = 0.02 respectively), BTT (-8.4 [-14.91 to -3.53] vs -1 [-5.72 to 3.75], P < 0.001 respectively) were significantly different between AIs users and controls. The same trend was observed for DXA measurements. BSAP and C-telopeptide of type 1 collagen significantly changed in AIs users. AD-SoS was associated with change of BMD at lumbar spine (β, 0.16; SE, 0.08; P = 0.04) and change of BSAP (β, -0.04; SE, 0.02; P = 0.04). Phalangeal QUS appeared a useful tool to evaluate bone quality in BC women on AIs.

  6. A Simulation Study to Compare the Treatment Effect of Tamoxifen by CYP2D6 Genotypes and Third-Generation Aromatase Inhibitors.

    PubMed

    Park, Gwan Cheol; Jung, Jin-A; Bae, Kyun-Seop; Lim, Hyeong-Seok

    2017-09-01

    Some prospective, randomized clinical trials, including ATAC and BIG 1-98, demonstrated superior treatment effect of third-generation aromatase inhibitors (AIs) versus tamoxifen in postoperative therapy for patients with breast cancer. In retrospective genotyping analyses of the 2 studies using tumor samples, no difference in the treatment effect of tamoxifen was observed by CYP2D6 genotypes. However, those analyses did not consider loss of heterozygosity that could have occurred when genotyping using tumor tissue. The present simulation study aimed to comparatively evaluate the treatment effect of tamoxifen versus AIs of anastrozole and letrozole by CYP2D6 genotypes. A meta-analysis was conducted to estimate disease-free survival (DFS) hazard ratios of CYP2D6 genotypes representing extensive metabolizers (EMs), HRW/W,TAM , versus intermediate metabolizers (IMs)/poor metabolizers (PMs), HRV/W,TAM , using previous study results in which genotypes were determined using blood samples. Based on known allele frequencies, the CYP2D6 genotype distribution of participants in ATAC and BIG 1-98 trials were simulated. Subsequently, DFS HRs of AIs versus tamoxifen by CYP2D6 genotypes (HRAI/TAM,W for EMs, HRAI/TAM,V for IMs/PMs) were estimated via regression analyses using NONMEM, based on the simulated genotype distributions, HRV/W,TAM , and HRs, of AIs versus tamoxifen (HRAI/TAM ) reported in the ATAC and BIG 1-98 trials. Median HRAI/TAM,V (95% prediction interval [PI]) was 0.43 (0.23-0.79) and 0.40 (0.22-0.73) for the ATAC and BIG 1-98 trials, respectively. However, the corresponding HRAI/TAM,W values were 0.97 (0.84-1.11) and 0.91 (0.77-1.08), respectively. These results suggest that in patients with the CYP2D6 genotype representing EMs, the treatment effect of tamoxifen is comparable to that of AIs. © 2017, The American College of Clinical Pharmacology.

  7. Modelling inhibition of avian aromatase by azole pesticides

    PubMed Central

    Saxena, A.K.; Devillers, J.; Bhunia, S.S.; Bro, E.

    2015-01-01

    The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase. PMID

  8. Modelling inhibition of avian aromatase by azole pesticides.

    PubMed

    Saxena, A K; Devillers, J; Bhunia, S S; Bro, E

    2015-01-01

    The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase.

  9. Aromatase regulates aggression in the African cichlid fish Astatotilapia burtoni.

    PubMed

    Huffman, Lin S; O'Connell, Lauren A; Hofmann, Hans A

    2013-03-15

    The roles of estrogen and androgens in male social behavior are well studied, but little is known about how these hormones contribute to behavior in a social hierarchy. Here we test the role of aromatase, the enzyme that converts testosterone into estradiol, in mediating aggression and reproductive behavior in male Astatotilapia burtoni, an African cichlid fish that displays remarkable plasticity in social behavior. We first measured aromatase expression in subordinate and dominant males in brain regions that regulate social behavior and found that subordinate males have higher aromatase expression than dominant males in the magnocellular and gigantocellular regions of the preoptic area. Next, we functionally tested the role of aromatase in regulating behavior by intraperitoneally injecting dominant males with either saline or fadrozole (FAD), an aromatase inhibitor, and found that FAD treatment decreases aggressive, but not reproductive, behaviors compared to saline controls. To determine the underlying physiological and molecular consequences of FAD treatment, we measured estradiol and testosterone levels from plasma and brain aromatase expression in FAD and saline treated dominant males. We found that estradiol levels decreased and testosterone levels increased in response to FAD treatment. Moreover, FAD treated males had increased aromatase expression in the gigantocellular portion of the POA, possibly a compensatory response. Overall, our results suggest aromatase is a key enzyme that promotes aggression in A. burtoni males through actions in the preoptic area.

  10. Expression of the K303R Estrogen Receptor α Breast Cancer Mutation Induces Resistance to an Aromatase Inhibitor via Addiction to the PI3K/Akt Kinase Pathway

    PubMed Central

    Barone, Ines; Cui, Yukun; Herynk, Matthew H; Corona-Rodriguez, Arnoldo; Giordano, Cinzia; Selever, Jennifer; Beyer, Amanda; Andò, Sebastiano; Fuqua, Suzanne A. W.

    2009-01-01

    Aromatase inhibitors (AIs) are rapidly becoming the first choice for hormonal treatment of estrogen receptor alpha (ERα)-positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ERα in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ERα mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione (AD), with or without the AI anastrozole (Ana). We found that Ana decreased AD-stimulated growth of WT cells, while K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B (PKB)/Akt survival pathways. Inhibition of the selective “addiction” to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ERα mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy. PMID:19487288

  11. Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved

    PubMed Central

    Lønning, Per Eystein; Eikesdal, Hans Petter

    2013-01-01

    Following their successful implementation for the treatment of metastatic breast cancer, the ‘third-generation’ aromatase inhibitors (anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancers. These drugs are characterized by potent aromatase inhibition, causing >98% inhibition of estrogen synthesis in vivo. A recent meta-analysis found no difference in anti-tumor efficacy between these three compounds. As of today, aromatase inhibitor monotherapy and sequential treatment using tamoxifen followed by an aromatase inhibitor for a total of 5 years are considered equipotent treatment options. However, current trials are addressing the potential benefit of extending treatment duration beyond 5 years. Regarding side effects, aromatase inhibitors are not found associated with enhanced risk of cardiovascular disease, and enhanced bone loss is prevented by adding bisphosphonates in concert for those at danger of developing osteoporosis. However, arthralgia and carpal tunnel syndrome preclude drug administration among a few patients. While recent findings have questioned the use of aromatase inhibitors among overweight and, in particular, obese patients, this problem seems to focus on premenopausal patients treated with an aromatase inhibitor and an LH-RH analog in concert, questioning the efficacy of LH-RH analogs rather than aromatase inhibitors among overweight patients. Finally, recent findings revealing a benefit from adding the mTOR inhibitor everolimus to endocrine treatment indicate targeted therapy against defined growth factor pathways to be a way forward, by reversing acquired resistance to endocrine therapy. PMID:23625614

  12. Combining computational and biochemical studies for a rationale on the anti-aromatase activity of natural polyphenols.

    PubMed

    Neves, Marco A C; Dinis, Teresa C P; Colombo, Giorgio; Sá e Melo, M Luisa

    2007-12-01

    Aromatase, an enzyme of the cytochrome P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer. The anti-aromatase activity of a set of natural polyphenolic compounds was evaluated in vitro. Strong aromatase inhibitors including flavones, flavanones, resveratrol, and oleuropein, with activities comparable to that of the reference anti-aromatase drug aminoglutethimide, were identified. Through the application of molecular modeling techniques based on grid-independent descriptors and molecular interaction fields, the major physicochemical features associated with inhibitory activity were disclosed, and a putative virtual active site of aromatase was proposed. Docking of the inhibitors into a 3D homology model structure of the enzyme defined a common binding mode for the small molecules under investigation. The good correlation between computational and biological results provides the first rationalization of the anti-aromatase activity of polyphenolic compounds. Moreover, the information generated in this approach should be further exploited for the design of new aromatase inhibitors.

  13. Proton pump inhibitors affect the gut microbiome

    PubMed Central

    Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Tigchelaar, Ettje F; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

    2016-01-01

    Background and aims Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. Methods The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. Results 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10−38). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. Conclusions The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs. PMID:26657899

  14. Effect of sildenafil on human aromatase activity: From in vitro structural analysis to catalysis and inhibition in cells.

    PubMed

    Baravalle, Roberta; Valetti, Francesca; Catucci, Gianluca; Gambarotta, Giovanna; Chiesa, Mario; Maurelli, Sara; Giamello, Elio; Barone, Ines; Catalano, Stefania; Andò, Sebastiano; Di Nardo, Giovanna; Gilardi, Gianfranco

    2017-01-01

    Aromatase catalyses the conversion of androgens into estrogens and is a well-known target for breast cancer therapy. As it has been suggested that its activity is affected by inhibitors of phosphodiesterase-5, this work investigates the potential interaction of sildenafil with aromatase. This is carried out both at molecular level through structural and kinetics assays applied to the purified enzyme, and at cellular level using neuronal and breast cancer cell lines. Sildenafil is found to bind to aromatase with a KD of 0.58±0.05μM acting as a partial and mixed inhibitor with a maximal inhibition of 35±2%. Hyperfine sublevel correlation spectroscopy and docking studies show that sildenafil binds to the heme iron via its 6th axial water ligand. These results also provide information on the starting molecular scaffold for the development of new generations of drugs designed to inhibit aromatase as well as phosphodiesterase-5, a new emerging target for breast cancer therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Preparation of a novel antiserum to aromatase with high affinity and specificity: Its clinicopathological significance on breast cancer tissue.

    PubMed

    Kanomata, Naoki; Matsuura, Shiro; Nomura, Tsunehisa; Kurebayashi, Junichi; Mori, Taisuke; Kitawaki, Jo; Moriya, Takuya

    2017-01-01

    Aromatase inhibitors have been widely used for the endocrine treatment of estrogen-dependent breast cancer in postmenopausal patients. However, clinicopathological studies of aromatase have been limited due to unsatisfactory specificity and/or restricted availability of anti-aromatase antibodies. Here, we have generated a polyclonal antiserum with high affinity and specificity for human aromatase using a monoclonal antibody tagged immunoaffinity chromatography on an industrial production scale. Our preliminary immunohistochemical analysis of 221 invasive breast cancer cases indicated that 87.3% (193/221) had at least 5% aromatase positive cells. The histoscore for aromatase was inversely correlated with pT (p = 0.019), pN (p = 0.001), stage (p < 0.001), histologic grade (p = 0.003), lymphatic infiltration (p < 0.001), venous infiltration (p < 0.001), and Ki-67 index (p < 0.001). However, cancer aromatase expression was independent of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 statuses. This antiserum will be applicable to clinicopathological examination of aromatase in addition to ER and PgR for an appropriate use of aromatase inhibitor on the treatment of breast cancer. Further studies on the relationship between Aromatase inhibitors have been widely used for the endocrine treatment of estrogen-dependent breast cancer in postmenopausal patients. However, clinicopathological studies of aromatase have been limited due to unsatisfactory specificity and/or restricted availability of anti-aromatase antibodies. Here, we have generated a polyclonal antiserum with high affinity and specificity for human aromatase using a monoclonal antibody tagged immunoaffinity chromatography on an industrial production scale. Our preliminary immunohistochemical analysis of 221 invasive breast cancer cases indicated that 87.3% (193/221) had at least 5% aromatase positive cells. The histoscore for aromatase was inversely correlated

  16. Analogue based drug design, synthesis, molecular docking and anticancer evaluation of novel chromene sulfonamide hybrids as aromatase inhibitors and apoptosis enhancers.

    PubMed

    Ghorab, Mostafa M; Alsaid, Mansour S; Al-Ansary, Ghada H; Abdel-Latif, Ghada A; Abou El Ella, Dalal A

    2016-11-29

    Twenty novel chromene derivatives carrying different sulfonamide moieties (3-22) were designed and synthesized. All the newly prepared compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (T47D). Most of the synthesized compounds showed good to moderate activity (IC50 = 8.8-108.9 μM), where compound 16 (IC50 = 8.8 μM) exhibited higher activity compared to doxorubicin (IC50 = 9.8 μM). In order to determine the mechanism of the anticancer activity in T47D cells, the effect of the most potent compounds (5-8, 11-14, and 16-18) on the aromatase activity was tested. Most of the selected compounds showed significant inhibitory effect on the aromatase activity, with compound 18 showing IC50 = 4.66 μM. Furthermore, apoptosis studies were conducted on two of the most potent compounds (8 & 16) to estimate the proapoptotic potential of our compounds. Both induced the levels of active caspase 3, caspase 8 and caspase 9. Moreover, they surprisingly boosted the Bax/Bcl2 ratio 5936 & 33,000 folds, respectively compared to the control. Moreover, they showed mild cytotoxic effect (IC50 = 183.8 μM & 172.04 μM, respectively) in normal breast cells 184A1. Finally, a molecular docking study was performed to investigate the probable interaction with the aromatase enzyme. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Aromatase excess in cancers of breast, endometrium and ovary.

    PubMed

    Bulun, Serdar E; Chen, Dong; Lu, Meiling; Zhao, Hong; Cheng, Youhong; Demura, Masashi; Yilmaz, Bertan; Martin, Regina; Utsunomiya, Hiroki; Thung, Steven; Su, Emily; Marsh, Erica; Hakim, Amy; Yin, Ping; Ishikawa, Hiroshi; Amin, Sanober; Imir, Gonca; Gurates, Bilgin; Attar, Erkut; Reierstad, Scott; Innes, Joy; Lin, Zhihong

    2007-01-01

    Pathogenesis and growth of three common women's cancers (breast, endometrium and ovary) are linked to estrogen. A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less clear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kb regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. In cancers of breast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter I.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE(2) via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE(2) secreted by malignant epithelial cells, PKC is also activated, and this potentiates cAMP-PKA-dependent induction of aromatase. Thus, inflammatory substances such as PGE(2) may play important roles in inducing local production of estrogen that promotes tumor growth.

  18. The effect of opiates on the activity of human placental aromatase/CYP19.

    PubMed

    Zharikova, Olga L; Deshmukh, Sujal V; Kumar, Meena; Vargas, Ricardo; Nanovskaya, Tatiana N; Hankins, Gary D V; Ahmed, Mahmoud S

    2007-01-15

    Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates L-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E(2) and E(3) formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E(3) formation was more pronounced than that on E(2) due to the lower affinity of 16-OHT than testosterone to aromatase. The K(i) values for the opiates that inhibited E(3) formation were sufentanil, 7 +/- 1 microM; LAAM, 13 +/- 8 microM; fentanyl, 25 +/- 5 microM; oxycodone, 92 +/- 22 microM; codeine, 218 +/- 69 microM; (+)-pentazocine, 225 +/- 73 microM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E(3) formation by 124-160% of control but had no effect on E(2) formation. Moreover, oxycodone and codeine did not inhibit E(2) formation and the IC(50) values for fentanyl, sufentanil, and (+)-pentazocine were >1000 microM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time.

  19. Aromatase inhibition by bioavailable methylated flavones.

    PubMed

    Ta, Nga; Walle, Thomas

    2007-10-01

    Previous studies have shown chrysin, 7-hydroxyflavone and 7,4'-dihydroxyflavone to be the most potent flavonoid inhibitors of aromatase. However, very poor oral bioavailability is a major limitation for the successful use of dietary flavonoids as chemopreventive agents. We have recently shown that methylated flavones, including 5,7-dimethoxyflavone, 7-methoxyflavone and 7,4'-dimethoxyflavone, are much more resistant to metabolism than their unmethylated analogs and have much higher intestinal absorption. In this study, we examined these fully methylated flavones as potential aromatase inhibitors for the prevention and/or treatment of hormone-dependent cancers. Whereas 5,7-dimethoxyflavone had poor effect compared to its unmethylated analog chrysin, 7-methoxyflavone and 7,4'-dimethoxyflavone were almost equipotent to their unmethylated analogs with IC(50) values of 2-9 microM. Thus, some fully methylated flavones appear to have great potential as cancer chemopreventive/chemotherapeutic agents.

  20. Aromatase inhibition by bioavailable methylated flavones

    PubMed Central

    Ta, Nga; Walle, Thomas

    2007-01-01

    Previous studies have shown chrysin, 7-hydroxyflavone and 7,4′-dihydroxyflavone to be the most potent flavonoid inhibitors of aromatase. However, very poor oral bioavailability is a major limitation for the successful use of dietary flavonoids as chemopreventive agents. We have recently shown that methylated flavones, including 5,7-dimethoxyflavone, 7-methoxyflavone and 7,4′-dimethoxyflavone, are much more resistant to metabolism than their unmethylated analogs and have much higher intestinal absorption. In this study, we examined these fully methylated flavones as potential aromatase inhibitors for the prevention and/or treatment of hormone-dependent cancers. Whereas 5,7-dimethoxyflavone had poor effect compared to its unmethylated analog chrysin, 7-methoxyflavone and 7,4′-dimethoxyflavone were almost equipotent to their unmethylated analogs with IC50 values of 2 to 9 μM. Thus, some fully methylated flavones appear to have great potential as cancer chemopreventive/chemotherapeutic agents. PMID:17624765

  1. Potential utility of natural products as regulators of breast cancer-associated aromatase promoters

    PubMed Central

    2011-01-01

    Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7) aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs) are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for specific hormone

  2. Potential utility of natural products as regulators of breast cancer-associated aromatase promoters.

    PubMed

    Khan, Shabana I; Zhao, Jianping; Khan, Ikhlas A; Walker, Larry A; Dasmahapatra, Asok K

    2011-06-21

    Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7) aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs) are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for specific hormone

  3. The control of preoptic aromatase activity by afferent inputs in Japanese quail.

    PubMed

    Absil, P; Baillien, M; Ball, G F; Panzica, G C; Balthazart, J

    2001-11-01

    This review summarizes current knowledge on the mechanisms that control aromatase activity in the quail preoptic area, a brain region that plays a key role in the control of reproduction. Aromatase and aromatase mRNA synthesis in the preoptic area are enhanced by testosterone and its metabolite estradiol, but estradiol receptors of the alpha subtype are not regularly colocalized with aromatase. Estradiol receptors of the beta subtype are present in the preoptic area but it is not yet known whether these receptors are colocalized with aromatase. The regulation by estrogen of aromatase activity may be, in part, trans-synaptically mediated, in a manner that is reminiscent of the ways in which steroids control the activity of gonadotropic hormone releasing hormone neurons. Aromatase-immunoreactive neurons are surrounded by dense networks of vasotocin-immunoreactive and tyrosine hydroxylase-immunoreactive fibers and punctate structures. These inputs are in part steroid-sensitive and could therefore mediate the effects of steroids on aromatase activity. In vivo pharmacological experiments indicate that catecholaminergic depletions significantly affect aromatase activity presumably by modulating aromatase transcription. In addition, in vitro studies on brain homogenates or on preoptic-hypothalamic explants show that aromatase activity can be rapidly modulated by a variety of dopaminergic compounds. These effects do not appear to be mediated by the membrane dopamine receptors and could involve changes in the phosphorylation state of the enzyme. Together, these results provide converging evidence for a direct control of aromatase activity by catecholamines consistent with the anatomical data indicating the presence of a catecholaminergic innervation of aromatase cells. These dopamine-induced changes in aromatase activity are observed after several hours or days and presumably result from changes in aromatase transcription but rapid non-genomic controls have also been

  4. Synthesis and aromatase inhibitory activity of novel pyridine-containing isoflavones.

    PubMed

    Kim, Young-Woo; Hackett, John C; Brueggemeier, Robert W

    2004-07-29

    Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone-dependent breast cancer. As a result, a number of synthetic steroidal or nonsteroidal aromatase inhibitors have been successfully developed. In addition, there are several classes of natural products that exert potent activities in aromatase inhibition, with the flavonoids being most prominent. Previous studies have exploited flavone and flavanone scaffolds for the development of new aromatase inhibitors. In this paper, we describe the design, synthesis, and biological evaluation of a novel series of 2-(4'-pyridylmethyl)thioisoflavones as the first example of synthetic isoflavone-based aromatase inhibitors.

  5. Protease Inhibitors Do Not Affect Antibody Responses to Pneumococcal Vaccination.

    PubMed

    De La Rosa, Indhira; Munjal, Iona M; Rodriguez-Barradas, Maria; Yu, Xiaoying; Pirofski, Liise-Anne; Mendoza, Daniel

    2016-06-01

    HIV(+) subjects on optimal antiretroviral therapy have persistently impaired antibody responses to pneumococcal vaccination. We explored the possibility that this effect may be due to HIV protease inhibitors (PIs). We found that in humans and mice, PIs do not affect antibody production in response to pneumococcal vaccination. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  6. Impact of Aromatase protein variants and drug interactions in breast cancer: a molecular docking approach.

    PubMed

    Setti, Aravind; Venugopal Rao, V; Priyamvada Devi, A; Pawar, Smita C; Naresh, B; Kalyan, C S V V

    2012-08-01

    Breast cancer is a frequently reported cancer in women all over the world. Several methods available to cure the breast cancer based on stage. This study focused on chemoprevention drugs of Aromatase, a potential target in breast cancer. Natural variants of Aromatase are very common; they have been collected and modeled, optimized the energy of mutated Aromatase protein. Reversible (Anastrozole) and irreversible (Exemestane) Aromatase inhibitors are selected and performed molecular docking studies of each drug against each variant to see the binding affinity impact on protein variant and drugs. In this comparative study, Anastrozole, a cumene derivative showed more binding affinity and Diethylstilbestrol showed weak binding affinity against among all drugs. The comparative molecular docking revealed that the binding affinity between drug and Aromatase protein variant is imprecise but fairly close; therefore the protein variants of Aromatase can be conceived to be equal for chemoprevention of breast cancer therapy.

  7. Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities

    PubMed Central

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; Flockhart, David A.; Cushman, Mark

    2015-01-01

    Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer. PMID:25751283

  8. White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation.

    PubMed

    Grube, B J; Eng, E T; Kao, Y C; Kwon, A; Chen, S

    2001-12-01

    Estrogen is a major factor in the development of breast cancer. In situ estrogen production by aromatase/estrogen synthetase in breast cancer plays a dominant role in tumor proliferation. Because natural compounds such as flavones and isoflavones have been shown to be inhibitors of aromatase, it is thought that vegetables that contain these phytochemicals can inhibit aromatase activity and suppress breast cancer cell proliferation. Heat-stable extracts were prepared from vegetables and screened for their ability to inhibit aromatase activity in a human placental microsome assay. The white button mushroom (species Agaricus bisporus) suppressed aromatase activity dose dependently. Enzyme kinetics demonstrated mixed inhibition, suggesting the presence of multiple inhibitors or more than one inhibitory mechanism. "In cell" aromatase activity and cell proliferation were measured using MCF-7aro, an aromatase-transfected breast cancer cell line. Phytochemicals in the mushroom aqueous extract inhibited aromatase activity and proliferation of MCF-7aro cells. These results suggest that diets high in mushrooms may modulate the aromatase activity and function in chemoprevention in postmenopausal women by reducing the in situ production of estrogen.

  9. Effect Of Microgravity On Aromatase Expression In Sertoli Cells.

    PubMed

    Cirelli, Elisa; De Domenico, Emanuela; Botti, Flavia; Massoud, Renato; Geremia, Raffaele; Grimaldi, Paola

    2017-06-14

    Cytochrome P450-aromatase catalyzes estrogen biosynthesis from C19 steroids. In the testis, Sertoli cells express P450-aromatase and represent the primary source of estrogen during prepuberal age. This study focused on the effect of simulated microgravity (SM) on aromatase expression in primary mouse Sertoli cells. When cultured in Rotary Cell Culture System (RCCS), Sertoli cells, formed multicellular three dimensional spheroids (3D). Biological properties were first analyzed in terms of viability, cell cycle, expression of cytoskeletal components and growth factors in comparison to Sertoli cells cultured in spheroids at unit gravity (G). SM did not affect cell viability and proliferation, nor expression of the main cytoskeleton proteins and of growth factors like Kit Ligand (KL) and glial derived neurotrophic factor (GDNF). On the other hand, SM caused a strong increase in P450 aromatase mRNA and protein expression. Interestingly, P450-aromatase was no more inducible by 8-Br-cAMP. The presence of a functional aromatase was confirmed by enrichment of 17β-estradiol released in the medium by androgen precursors. We concluded that SM causes a significant upregulation of aromatase gene expression in Sertoli cells, leading to a consequent increase in 17β-estradiol secretion. High level of 17β-estradiol in the testis could have potentially adverse effects on male fertility and testicular cancer.

  10. Exploring new chemical functionalities to improve aromatase inhibition of steroids.

    PubMed

    Varela, Carla L; Amaral, Cristina; Correia-da-Silva, Georgina; Costa, Saul C; Carvalho, Rui A; Costa, Giosuè; Alcaro, Stefano; Teixeira, Natércia A A; Tavares-da-Silva, Elisiário J; Roleira, Fernanda M F

    2016-06-15

    In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure-activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one (5) (IC50=0.11μM), and the Δ(9-11) double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50=0.25μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors.

  11. Effects of flavonoids on aromatase activity, an in vitro study.

    PubMed

    Pelissero, C; Lenczowski, M J; Chinzi, D; Davail-Cuisset, B; Sumpter, J P; Fostier, A

    1996-02-01

    In the study, the inhibitory effect of flavonoids, including isoflavonic phytoestrogens, on the ovarian aromatase enzyme complex from the rainbow trout, Oncorhynchus mykiss, was assessed in vitro. Some of the compounds tested on fish were also tested on human placental aromatase activity as a comparison between the two sources of enzyme. It was found that flavone, dl-aminoglutethimide, apigenin, quercetin, 7,4'- dihydroxyflavone, alpha-naphthoflavone and equol were potent inhibitors of the ovarian aromatase activity in rainbow trout. Relative potencies (RP) of these compounds compared to flavone (assigned an effect of 1) were, respectively, 19.0, 8.7, 5.3, 3.7, 3.2 and 0.9. Two other phytoestrogens, namely biochanin A and genistein, slightly inhibited aromatase activity. Finally, 7-hydroxyflavone, formononetin, daidzein, coumestrol, chrysin, flavanone and estradiol-17beta did not inhibit ovarian aromatase activity at doses up to 1000 microM. Experiments on human placental aromatase showed inhibitory effects of dl-aminoglutethimide, flavone, flavanone and equol with RP values of 2.8. 1, 1.5 and 0.4, respectively. These results are in accordance with previous studies. The influence of the experimental procedure on IC50 values and RP is discussed.

  12. Use of MR-based trabecular bone microstructure analysis at the distal radius for osteoporosis diagnostics: a study in post-menopausal women with breast cancer and treated with aromatase inhibitor

    PubMed Central

    Baum, Thomas; Karampinos, Dimitrios C.; Seifert-Klauss, Vanadin; Pencheva, Tsvetelina D.; Jungmann, Pia M.; Rummeny, Ernst J.; Müller, Dirk; Bauer, Jan S.

    2016-01-01

    Summary Purpose Treatment with aromatase inhibitor (AI) is recommended for post-menopausal women with hormone-receptor positive breast cancer. However, AI therapy is known to induce bone loss leading to osteoporosis with an increased risk for fragility fractures. The purpose of this study was to investigate whether changes of magnetic resonance (MR)-based trabecular bone microstructure parameters as advanced imaging biomarker can already be detected in subjects with AI intake but still without evidence for osteoporosis according to dual energy X-ray absorptiometry (DXA)-based bone mineral density (BMD) measurements as current clinical gold standard. Methods Twenty-one postmenopausal women (62±6 years of age) with hormone-receptor positive breast cancer, ongoing treatment with aromatase inhibitor for 23±15 months, and no evidence for osteoporosis (current DXA T-score greater than −2.5) were recruited for this study. Eight young, healthy women (24±2 years of age) were included as controls. All subjects underwent 3 Tesla magnetic resonance imaging (MRI) of the distal radius to assess the trabecular bone microstructure. Results Trabecular bone microstructure parameters were not significantly (p>0.05) different between subjects with AI intake and controls, including apparent bone fraction (0.42±0.03 vs. 0.42±0.05), trabecular number (1.95±0.10 mm−1 vs 1.89±0.15 mm−1), trabecular separation (0.30±0.03 mm vs 0.31±0.06 mm), trabecular thickness (0.21±0.01 mm vs 0.22±0.02 mm), and fractal dimension (1.70±0.02 vs. 1.70±0.03). Conclusion These findings suggest that the initial deterioration of trabecular bone microstructure as measured by MRI and BMD loss as measured by DXA occur not sequentially but rather simultaneously. Thus, the use of MR-based trabecular bone microstructure assessment is limited as early diagnostic biomarker in this clinical setting. PMID:27252740

  13. Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer

    PubMed Central

    2013-01-01

    Background After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Methods Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. Results When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. Conclusions TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. Trial registration number UMIN000001841 PMID:23679192

  14. Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis.

    PubMed

    Fleeman, N; Bagust, A; Boland, A; Dickson, R; Dundar, Y; Moonan, M; Oyee, J; Blundell, M; Davis, H; Armstrong, A; Thorp, N

    2011-01-01

    Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer. To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib (LAP) in combination with an aromatase inhibitor (AI) and trastuzumab (TRA) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive (HER2+) mBC. Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI. A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken. Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant

  15. Vitamin D analog EB1089 inhibits aromatase expression by dissociation of comodulator WSTF from the CYP19A1 promoter-a new regulatory pathway for aromatase.

    PubMed

    Lundqvist, Johan; Hansen, Susanne Kofoed; Lykkesfeldt, Anne E

    2013-01-01

    The enzyme aromatase, encoded by the CYP19A1 gene, catalyzes the production of estrogens and inhibition of aromatase has therefore become one of the key strategies in breast cancer treatment. We have studied the effects of the vitamin D analog EB1089 on aromatase gene expression and enzyme activity in breast cancer cells. We found that EB1089 was able to decrease the gene expression and enzyme activity as well as inhibit aromatase-dependent cell growth. Furthermore, a low dose of EB1089 combined with low doses of clinically used aromatase inhibitors such as anastrozole, letrozole and exemestane were able to effectively inhibit aromatase-dependent growth of breast cancer cells. The molecular mechanism for this effect of EB1089 on the aromatase gene expression was investigated and we found that it is mediated by the vitamin D receptor (VDR), vitamin D receptor interacting repressor (VDIR) and Williams syndrome transcription factor (WSTF). ChIP and Re-ChIP assays revealed that EB1089 mediates dissociation of WSTF from the CYP19A1 promoter and thereby decreases the gene expression. Regulation of aromatase via WSTF has not been reported previously. Furthermore, gene silencing of WSTF results in decreased gene expression of CYP19A1 and aromatase activity, showing that WSTF is an interesting drug target for development of new anti-cancer drugs. In summary, we report that the vitamin D analog EB1089 is able to decrease the gene expression and enzyme activity of aromatase via a novel regulatory pathway for aromatase and suggest that EB1089 may be a new treatment option for estrogen dependent breast cancer. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Molecular mechanisms of aromatase inhibition by new A, D-ring modified steroids.

    PubMed

    Cepa, Margarida; Correia-da-Silva, Georgina; Tavares da Silva, Elisiário J; Roleira, Fernanda M F; Hong, Yanyan; Chen, Shiuan; Teixeira, Natércia A

    2008-09-01

    A recent approach for treatment and prevention of estrogen-dependent breast cancer focuses on the inhibition of aromatase, the enzyme that catalyzes the final step of estrogen biosynthesis. Some synthetic steroids, such as formestane and exemestane, resembling the natural enzyme substrate androstenedione, revealed to be potent and useful aromatase inhibitors (AIs) and were approved for the treatment of estrogen-dependent breast cancer in postmenopausal women. Recently, we found that five newly synthesized steroids with chemical features in the A- and D-rings considered important for drug-receptor interaction efficiently inhibit aromatase derived from human placental microsomes. In this work, these steroids showed a similar pattern of anti-aromatase activity in several aromatase-expressing cell lines. 5alpha-androst-3-en-17-one and 3alpha,4alpha-epoxy-5alpha-androstan-17-one were revealed to be the most potent inhibitors. These compounds induced a time-dependent inhibition of aromatase, showing to be irreversible AIs. The specific interactions of these compounds with aromatase active sites were further demonstrated by site-directed mutagenesis studies and evaluated by computer-aided molecular modeling. Both compounds were able to suppress hormone-dependent proliferation of MCF-7aro cells in a dose-dependent manner. These findings are important for the elucidation of a structure-activity relationship on aromatase, which may help in the development of new AIs.

  17. A comparison of the effect of short-term aromatase inhibitor (letrozole) and GnRH agonist (triptorelin) versus case control on pregnancy rate and symptom and sign recurrence after laparoscopic treatment of endometriosis.

    PubMed

    Alborzi, Saeed; Hamedi, Bahareh; Omidvar, Azizeh; Dehbashi, Sedigheh; Alborzi, Soroosh; Alborzi, Mehrnoosh

    2011-07-01

    To compare the role of an aromatase inhibitor (letrozole) with a GnRH agonist (triptorelin) versus case control on the pregnancy rate and recurrence of symptoms and signs in patients with endometriosis. In a prospective randomized clinical trial, after treatment of 144 infertile women in their reproductive age by laparoscopy (whose endometriosis was confirmed by prior laparoscopy), they were divided into 3 groups: group 1 (47 cases) who received letrozole for 2 months, group 2 (40 patients) who were prescribed triptorelin for 2 months and group 3 who were 57 patients in the control group and did not receive any medication. We followed up each group at least for 12 months after their restoration of regular cycle. Pregnancy rate was 23.4% in group 1, 27.5% in group 2, and 28.1% in group 3. The results did not show significant differences among the 3 groups. Recurrence rate of endometriosis was 6.4% in group 1, 5% group 2 and 5.3% in group 3, which was not statistically significantly different as well. Pregnancy rate and endometriosis recurrence rate are comparable among the 3 groups.

  18. Reduced methadone clearance during aromatase inhibition.

    PubMed

    Lu, Wenjie Jessie; Thong, Nancy; Flockhart, David A

    2012-08-01

    Methadone is increasingly used in pain management and is a cornerstone in the treatment of opiate withdrawal. It is subject to highly variable clearance among patients. The complete metabolic disposition of methadone is likely to involve a number of enzymes, including specifically CYP2B6. Previous studies in vitro suggest that metabolism by aromatase may also contribute. Single-dose methadone pharmacokinetics (2 mg, intravenous) were studied in 15 healthy postmenopausal women in the presence and absence of a potent aromatase inhibitor, letrozole. A sequential design was used, involving a control period followed by treatment with letrozole (2.5 mg/d, 11 days), in which each subject served as her own control. On average, letrozole treatment reduced methadone systemic clearance by 22% (P = 0.001), increased methadone AUC by 23% (P = 0.007), and increased elimination half-life by 21% (P = 0.042). The plasma parent-to-metabolite ratio also increased (P = 0.009), and there was a linear relationship (R2 = 0.74) between change in this plasma ratio and change in methadone AUC0-∞. In contrast, there was no such association with change in apparent urinary methadone clearance. Letrozole did not change methadone distribution half-life or its volume of distribution. Overall, these data demonstrate a significant decrease in methadone clearance during coadministration of letrozole, consistent with decreased metabolism brought about by aromatase inhibition. An involvement of aromatase in the disposition of methadone may help explain the difficulty in methadone dosing and suggests a broader role for this catalyst of endogenous steroid metabolism in xenobiotic drug disposition.

  19. Caught in a Network: Recovery from Aromatase Inhibition

    EPA Science Inventory

    Fadrozole is an inhibitor of aromatase, an enzyme critical to estrogen synthesis. We exposed female fathead minnows (Pimephales promelas, FHM) to 0 or 30 ug/L fadrozole for 8 days, and fish were then held in clean water for 8 extra days. We analyzed ex vivo steroid production, pl...

  20. Caught in a Network: Recovery from Aromatase Inhibition

    EPA Science Inventory

    Fadrozole is an inhibitor of aromatase, an enzyme critical to estrogen synthesis. We exposed female fathead minnows (Pimephales promelas, FHM) to 0 or 30 ug/L fadrozole for 8 days, and fish were then held in clean water for 8 extra days. We analyzed ex vivo steroid production, pl...

  1. Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition.

    PubMed

    Dean, Afshan; Nilsen, Margaret; Loughlin, Lynn; Salt, Ian P; MacLean, Margaret R

    2016-08-01

    Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1 Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase.

  2. History of aromatase: saga of an important biological mediator and therapeutic target.

    PubMed

    Santen, R J; Brodie, H; Simpson, E R; Siiteri, P K; Brodie, A

    2009-06-01

    Aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. Initial studies of its enzymatic activity and function took place in an environment focused on estrogen as a component of the birth control pill. At an early stage, investigators recognized that inhibition of this enzyme could have major practical applications for treatment of hormone-dependent breast cancer, alterations of ovarian and endometrial function, and treatment of benign disorders such as gynecomastia. Two general approaches ultimately led to the development of potent and selective aromatase inhibitors. One targeted the enzyme using analogs of natural steroidal substrates to work out the relationships between structure and function. The other approach initially sought to block adrenal function as a treatment for breast cancer but led to the serendipitous finding that a nonsteroidal P450 steroidogenesis inhibitor, aminoglutethimide, served as a potent but nonselective aromatase inhibitor. Proof of the therapeutic concept of aromatase inhibition involved a variety of studies with aminoglutethimide and the selective steroidal inhibitor, formestane. The requirement for even more potent and selective inhibitors led to intensive molecular studies to identify the structure of aromatase, to development of high-sensitivity estrogen assays, and to "mega" clinical trials of the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which are now in clinical use in breast cancer. During these studies, unexpected findings led investigators to appreciate the important role of estrogens in males as well as in females and in multiple organs, particularly the bone and brain. These studies identified the important regulatory properties of aromatase acting in an autocrine, paracrine, intracrine, neurocrine, and juxtacrine fashion and the organ-specific enhancers and promoters controlling its transcription. The saga of these studies of aromatase and the ultimate

  3. Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens.

    PubMed

    Neves, Marco A C; Dinis, Teresa C P; Colombo, Giorgio; Luisa Sá E Melo, M

    2008-05-01

    High levels of endogenous estrogens are associated with increased risks of breast cancer. Estrogen levels are mainly increased by the activity of the aromatase enzyme and reduced by oxidative/conjugative metabolic pathways. In this paper, we demonstrate for the first time that catechol estrogen metabolites are potent aromatase inhibitors, thus establishing a link between aromatase activity and the processes involved in estrogen metabolism. In particular, the anti-aromatase activity of a set of natural hydroxyl and methoxyl estrogen metabolites was investigated using biochemical methods and subsequently compared with the anti-aromatase potency of estradiol and two reference aromatase inhibitors. Catechol estrogens proved to be strong inhibitors with an anti-aromatase potency two orders of magnitude higher than estradiol. A competitive inhibition mechanism was found for the most potent molecule, 2-hydroxyestradiol (2-OHE(2)) and a rational model identifying the interaction determinants of the metabolites with the enzyme is proposed based on ab initio quantum-mechanical calculations. A strong relationship between activity and electrostatic properties was found for catechol estrogens. Moreover, our results suggest that natural catechol estrogens may be involved in the control mechanisms of estrogen production.

  4. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    SciTech Connect

    Biegon, A.; Biegon, A.; Kim, S.-W.; Logan, J.; Hooker, J.M.; Muench, L.; Fowler, J.S.

    2010-01-12

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor [{sup 11}C]vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in [{sup 11}C]vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  5. Molecular pharmacology of aromatase and its regulation by endogenous and exogenous agents.

    PubMed

    Brueggemeier, R W; Richards, J A; Joomprabutra, S; Bhat, A S; Whetstone, J L

    2001-12-01

    focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aromatase inhibitors.

  6. Dual Protonophore–Chitinase Inhibitors Dramatically Affect O. volvulus Molting

    PubMed Central

    2015-01-01

    The L3-stage-specific chitinase OvCHT1 has been implicated in the development of Onchocerca volvulus, the causative agent of onchocerciasis. Closantel, a known anthelmintic drug, was previously discovered as a potent and specific OvCHT1 inhibitor. As closantel is also a known protonophore, we performed a simple scaffold modulation to map out the structural features that are relevant for its individual or dual biochemical roles. Furthermore, we present that either OvCHT1 inhibition or protonophoric activity was capable of affecting O. volvulus L3 molting and that the presence of both activities in a single molecule yielded more potent inhibition of the nematode’s developmental process. PMID:24918716

  7. Dual protonophore-chitinase inhibitors dramatically affect O. volvulus molting.

    PubMed

    Gooyit, Major; Tricoche, Nancy; Lustigman, Sara; Janda, Kim D

    2014-07-10

    The L3-stage-specific chitinase OvCHT1 has been implicated in the development of Onchocerca volvulus, the causative agent of onchocerciasis. Closantel, a known anthelmintic drug, was previously discovered as a potent and specific OvCHT1 inhibitor. As closantel is also a known protonophore, we performed a simple scaffold modulation to map out the structural features that are relevant for its individual or dual biochemical roles. Furthermore, we present that either OvCHT1 inhibition or protonophoric activity was capable of affecting O. volvulus L3 molting and that the presence of both activities in a single molecule yielded more potent inhibition of the nematode's developmental process.

  8. Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo - Meta-analyses on efficacy and adverse events based on randomized clinical trials.

    PubMed

    Rydén, Lisa; Heibert Arnlind, Marianne; Vitols, Sigurd; Höistad, Malin; Ahlgren, Johan

    2016-04-01

    Tamoxifen (TAM) and aromatase inhibitors (AI) are adjuvant therapy options for postmenopausal women with estrogen receptor positive (ER+) breast cancer. This systematic review of seven randomized controlled studies comparing TAM and AI, and one study comparing extended therapy with an AI with placebo after about 5 years of tamoxifen, aims to assess long-term clinical efficacy and adverse events. The literature review was performed according to the principles of the Cochrane Collaboration. The search included common databases up to 2013-01-14. Studies of high or moderate quality were used for grading of evidence. Revman™ software was utilized for meta-analyses of published data. Disease free survival (DFS) and overall survival (OS) were improved with AI monotherapy compared to TAM with high and moderate quality of evidence respectively. Sequenced therapy with AI → TAM (or vice versa) improved DFS compared with TAM with moderate quality of evidence, but did not improve OS (low quality of evidence). However, if only studies on sequenced AI therapy with randomization before endocrine therapy were considered, no improvement of DFS could be found. Fractures are more frequently associated with AI whereas the risk of endometrial cancer and venous thromboembolism are higher with TAM. For cardiovascular events no difference was found between AI (mono- or sequenced therapy) and TAM, whereas sequenced therapy compared with AI had lower risk of cardiovascular events (moderate level of evidence). AIs are superior to TAM as adjuvant hormonal therapy for postmenopausal ER-positive breast cancer. TAM can be considered for individual patients due to the different toxicity profile compared with AI. Cardiovascular events related to AI treatment deserve further attention.

  9. Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor(®)) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study.

    PubMed

    Donders, Gilbert; Neven, Patrick; Moegele, Maximilian; Lintermans, Anneleen; Bellen, Gert; Prasauskas, Valdas; Grob, Philipp; Ortmann, Olaf; Buchholz, Stefan

    2014-06-01

    Phase I pharmacokinetic (PK) study assessed circulating estrogens in breast cancer (BC) patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacillus combination vaginal tablets (Gynoflor(®)). 16 women on NSAI with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor(®) for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks. Primary outcomes were serum concentrations and PK of E3, estradiol (E2), and estrone (E1) using highly sensitive gas chromatography-mass spectrometry. Secondary outcomes were clinical measures for efficacy and side effects; microscopic changes in vaginal epithelium and microflora; and changes in serum FSH, LH, and sex hormone-binding globulin. Compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2-3 h post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed. The low-dose 0.03 mg E3 and Lactobacillus acidophilus vaginal tablets application in postmenopausal BC patients during AI treatment suffering from vaginal atrophy lead to small and transient increases in serum E3, but not E1 or E2, and therefore can be considered as safe and efficacious for treatment of atrophic vaginitis in BC patients taking NSAIs.

  10. Immediate Administration of Zoledronic Acid Reduces Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women With Early Breast Cancer: 12-month analysis of the E-ZO-FAST trial.

    PubMed

    Llombart, Antonio; Frassoldati, Antonio; Paija, Outi; Sleeboom, Harm Peter; Jerusalem, Guy; Mebis, Jeroen; Deleu, Ines; Miller, Joel; Schenk, Nora; Neven, Patrick

    2012-02-01

    Letrozole is a proven and effective adjuvant therapy in postmenopausal women with hormone receptor-positive (HR(+)) early breast cancer (EBC). As with other aromatase inhibitors (AIs), long-term letrozole administration is associated with decreased bone mineral density (BMD) and increased fracture risk. This study compared potential bone-protecting effects of immediate vs. delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. Patients with HR(+) EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years) were randomized to immediate ZOL treatment (immediate ZOL) or delayed ZOL treatment (delayed ZOL) (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for a BMD T-score that decreased to < -2.0 (lumbar spine [LS] or total hip [TH]) or for fracture. The primary endpoint was percentage change in the LS BMD at month 12. Patients were stratified by established or recent postmenopausal status, baseline T-scores, and adjuvant chemotherapy history. At 12 months, the LS BMD increased in the immediate ZOL group (+2.72%) but decreased in the delayed ZOL group (-2.71%); the absolute difference between groups was significant (5.43%; P < .0001). Across all subgroups, patients receiving immediate ZOL had significantly increased LS and TH BMD vs. those who received delayed ZOL (P < .0001). Differences in fracture incidence or disease recurrence could not be ascertained because of early data cutoff and low incidence of events. Adverse events were generally mild, transient, and consistent with the known safety profiles of both agents. Immediate ZOL administration effectively prevented BMD loss and increased BMD in postmenopausal women with HR(+) EBC receiving adjuvant letrozole, regardless of BMD status at baseline. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Patient Reported Outcomes in Women with Breast Cancer Enrolled in A Dual-Center Double Blind Randomized Controlled Trial Assessing the Effect of Acupuncture in Reducing Aromatase Inhibitor-induced Musculoskeletal Symptoms

    PubMed Central

    Bao, Ting; Cai, Ling; Snyder, Claire; Betts, Kelly; Tarpinian, Karineh; Gould, Jeff; Jeter, Stacie; Medeiros, Michelle; Chumsri, Saranya; Bardia, Aditya; Tan, Ming; Singh, Harvinder; Tkaczuk, Katherin HR; Stearns, Vered

    2013-01-01

    Background Aromatase Inhibitors (AIs) have been associated with decrements in patient-reported outcomes (PROs). Objectives To assess if real acupuncture (RA) compared to sham acupuncture (SA) improves PROs in breast cancer patients taking adjuvant AI. Methods Postmenopausal women with a stage 0-III breast cancer on AI with treatment-associated musculoskeletal symptoms were randomized to 8 weekly RA vs SA in a dual-center randomized controlled trial. National Surgical Adjuvant Breast and Bowel Project (NSABP) menopausal symptoms questionnaire, Center for Epidemiological Studies Depression (CESD), Hospital Anxiety and Depression Scale (HADS), Pittsburgh Sleep Quality Index (PSQI), Hot Flash Daily Diary, Hot Flash Related Daily Interference Scale (HFRDI) and EuroQol survey were used to assess PROs at baseline, 4, 8, and 12 weeks. Results The intention-to-treat analysis included 23 RA and 24 SA patients. There were no significant differences in baseline characteristics between groups. Compared to baseline, scores of RA patients improved significantly at week 8 on CESD (p=0.022), hot flash severity (p=0.006), hot flash frequency (p=0.011), HFRDI (p=0.014) and NSABP menopausal symptoms (p=0.022); scores of SA patients improved significantly on EuroQol (p=0.022), HFRDI (p=0.043) and NSABP menopausal symptoms (p=0.005). Post hoc analysis indicated that African American (AA) patients (n=9) benefited more from RA than SA when compared to non-AA patients (n=38) in reducing hot flash severity (p<0.001) and frequency (p<0.001) scores. Conclusion RA and SA were both associated with improvement in PROs in breast cancer patients taking AIs. We detected no significant difference between arms. Racial difference in response to acupuncture warrants further study. PMID:24375332

  12. Cotargeting of CYP-19 (aromatase) and emerging, pivotal signalling pathways in metastatic breast cancer

    PubMed Central

    Daldorff, Stine; Mathiesen, Randi Margit Ruud; Yri, Olav Erich; Ødegård, Hilde Presterud; Geisler, Jürgen

    2017-01-01

    Aromatase inhibition is one of the cornerstones of modern endocrine therapy of oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). The nonsteroidal aromatase inhibitors anastrozole and letrozole, as well as the steroidal aromatase inactivator exemestane, are the preferred drugs and established worldwide in all clinical phases of the disease. However, although many patients suffering from MBC experience an initial stabilisation of their metastatic burden, drug resistance and disease progression occur frequently, following in general only a few months on treatment. Extensive translational research during the past two decades has elucidated the major pathways contributing to endocrine resistance and paved the way for clinical studies investigating the efficacy of novel drug combinations involving aromatase inhibitors and emerging drugable targets like mTOR, PI3K and CDK4/6. The present review summarises the basic research that provided the rationale for new drug combinations involving aromatase inhibitors and the main findings of pivotal clinical trials that have already started to change our way to treat hormone-sensitive MBC. The challenging situation of oestrogen receptor-positive and human epidermal growth factor receptor 2-positive (HER2+) MBC is also shortly reviewed to underline the complexity of the clinical scenario in the heterogeneous subgroups of hormone receptor-positive breast cancer patients and the increasing need for personalised medicine. Finally, we summarise some of the promising findings made with the combination of aromatase inhibitors with other potent endocrine treatment options like fulvestrant, a selective oestrogen receptor downregulator. PMID:27923036

  13. Genetics Home Reference: aromatase deficiency

    MedlinePlus

    ... development, aromatase converts androgens to estrogens in the placenta, which is the link between the mother's blood supply and the fetus. This conversion in the placenta prevents androgens from directing sexual development in female ...

  14. Competitive product inhibition of aromatase by natural estrogens.

    PubMed

    Shimizu, Y; Yarborough, C; Osawa, Y

    1993-03-01

    In order to better understand the function of aromatase, we carried out kinetic analyses to assess the ability of natural estrogens, estrone (E1), estradiol (E2), 16 alpha-OHE1, and estriol (E3), to inhibit aromatization. Human placental microsomes (50 micrograms protein) were incubated for 5 min at 37 degrees C with [1 beta-3H]testosterone (1.24 x 10(3) dpm 3H/ng, 35-150 nM) or [1 beta-3H,4-14C]androstenedione (3.05 x 10(3) dpm 3H/ng, 3H/14C = 19.3, 7-65 nM) as substrate in the presence of NADPH, with and without natural estrogens as putative inhibitors. Aromatase activity was assessed by tritium released to water from the 1 beta-position of the substrates. Natural estrogens showed competitive product inhibition against androgen aromatization. The Ki of E1, E2, 16 alpha-OHE1, and E3 for testosterone aromatization was 1.5, 2.2, 95, and 162 microM, respectively, where the Km of aromatase was 61.8 +/- 2.0 nM (n = 5) for testosterone. The Ki of E1, E2, 16 alpha-OHE1, and E3 for androstenedione aromatization was 10.6, 5.5, 252, and 1182 microM, respectively, where the Km of aromatase was 35.4 +/- 4.1 nM (n = 4) for androstenedione. These results show that estrogen inhibit the process of androgen aromatization and indicate that natural estrogens regulate their own synthesis by the product inhibition mechanism in vivo. Since natural estrogen binds to the active site of human placental aromatase P-450 complex as competitive inhibitors, natural estrogens might be further metabolized by aromatase. This suggests that human placental estrogen 2-hydroxylase activity is catalyzed by the active site of aromatase cytochrome P-450 and also agrees with the fact that the level of catecholestrogens in maternal plasma increases during pregnancy. The relative affinities and concentration of androgens and estrogens would control estrogen and catecholestrogen biosynthesis by aromatase.

  15. BENZO(A)PYRENE DECREASES BRAIN AND OVARIAN AROMATASE mRNA EXPRESSION IN FUNDULUS HETEROCLITUS

    PubMed Central

    Dong, Wu; Wang, Lu; Thornton, Cammi; Scheffler, Brian E.; Willett, Kristine L.

    2008-01-01

    The higher molecular weight polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) are typically associated with genotoxicity, however, newer evidence suggests that these compounds may also act as endocrine system disruptors. We hypothesized that altered expression of the P450 enzyme aromatase genes could be a target for reproductive or developmental dysfunction caused by BaP exposure. Aromatase is at least partially responsible for estrogen homeostasis by converting androgens into estrogens. In fish, there are two isoforms of aromatase, a predominantly ovarian form, CYP19A1, and a brain form, CYP19A2. CYP19 mRNA expression was measured following BaP exposure (0, 10, 100 µg/L waterborne for 10 or 15 days) in Fundulus adults, juveniles and embryos by in situ hybridization. The CYP19A1 expression was significantly decreased after BaP exposure in the 3 month old Fundulus immature oocytes, but BaP did not affect CYP19A1 expression at any stage in adult oocytes. In embryo brains, BaP significantly decreased CYP19A2 compared to controls by 3.6-fold at 14 days post-fertilization. In adults, CYP19A2 expression was decreased significantly in the pituitary and hypothalamus (81% and 85% of controls, respectively). Promoter regions of Fundulus CYP19s were cloned, and putative response elements in the CYP19A1 and CYP19A2 promoters such as CRE, AhR and ERE may be involved in BaP-mediated changes in CYP19 expression. In order to compare the mechanism of BaP-mediated inhibition with that of a known aromatase inhibitor, fish were also exposed to fadrozole (20 and 100 µg/L). Fadrozole did not significantly decrease the mRNA expression in embryos or adult Fundulus. However, aromatase enzyme activity was significantly decreased in adult ovary and brain tissues. These studies provide a greater molecular understanding of the mechanisms of action of BaP and its potential to impact reproduction or development. PMID:18571745

  16. HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat.

    PubMed

    Fun, Axel; van Maarseveen, Noortje M; Pokorná, Jana; Maas, Renée Em; Schipper, Pauline J; Konvalinka, Jan; Nijhuis, Monique

    2011-08-24

    Maturation inhibitors are an experimental class of antiretrovirals that inhibit Human Immunodeficiency Virus (HIV) particle maturation, the structural rearrangement required to form infectious virus particles. This rearrangement is triggered by the ordered cleavage of the precursor Gag polyproteins into their functional counterparts by the viral enzyme protease. In contrast to protease inhibitors, maturation inhibitors impede particle maturation by targeting the substrate of protease (Gag) instead of the protease enzyme itself. Direct cross-resistance between protease and maturation inhibitors may seem unlikely, but the co-evolution of protease and its substrate, Gag, during protease inhibitor therapy, could potentially affect future maturation inhibitor therapy. Previous studies showed that there might also be an effect of protease inhibitor resistance mutations on the development of maturation inhibitor resistance, but the exact mechanism remains unclear. We used wild-type and protease inhibitor resistant viruses to determine the impact of protease inhibitor resistance mutations on the development of maturation inhibitor resistance. Our resistance selection studies demonstrated that the resistance profiles for the maturation inhibitor bevirimat are more diverse for viruses with a mutated protease compared to viruses with a wild-type protease. Viral replication did not appear to be a major factor during emergence of bevirimat resistance. In all in vitro selections, one of four mutations was selected: Gag V362I, A364V, S368N or V370A. The impact of these mutations on maturation inhibitor resistance and viral replication was analyzed in different protease backgrounds. The data suggest that the protease background affects development of HIV-1 resistance to bevirimat and the replication profiles of bevirimat-selected HIV-1. The protease-dependent bevirimat resistance and replication levels can be explained by differences in CA/p2 cleavage processing by the different

  17. Regulation of aromatase expression in breast cancer tissue.

    PubMed

    Bulun, S E; Lin, Z; Zhao, H; Lu, M; Amin, S; Reierstad, S; Chen, D

    2009-02-01

    Epithelial-stromal interactions play key roles for aromatase expression and estrogen production in breast cancer tissue. Upregulated aromatase expression in breast fibroblasts increases the tissue concentration of estradiol (E2), which then activates a large number of carcinogenic genes via estrogen receptor-alpha (ERalpha) in malignant epithelial cells. This clinically pertains, since aromatase inhibitors (AIs) are the most effective hormonal treatment of ERalpha-positive breast tumors. A single gene encodes aromatase, the key enzyme in estrogen biosynthesis, the inhibition of which by an AI effectively eliminates E2 production. Since alternative promoters regulated by distinct signaling pathways control aromatase expression, it is possible to target these pathways and inhibit estrogen production in a tissue-selective fashion. We and others previously found that the majority of estrogen production in breast cancer tissue was accounted for by the aberrant activation of the proximal promoter I.3/II region. PGE(2) that is secreted in large amounts by malignant breast epithelial cells is the most potent known natural inducer of this promoter region in breast adipose fibroblasts. Signaling effectors/transcriptional regulators that mediate PGE(2) action include the activator pathways p38/CREB-ATF and JNK/jun and the inhibitory factor BRCA1 in breast adipose fibroblasts. Selective inhibition of this promoter region may treat breast cancer while permitting aromatase expression via alternative promoters in the brain and bone and thus obviate the key side effects of the current AIs. The signaling pathways that mediate the regulation of the promoter I.3/II region in undifferentiated fibroblasts in malignant breast tumors are reviewed.

  18. Aromatase inhibition by synthetic lactones and flavonoids in human placental microsomes and breast fibroblasts - A comparative study

    SciTech Connect

    Meeuwen, J.A. van Nijmeijer, S.; Mutarapat, T.; Ruchirawat, S.; Jong, P.C. de; Piersma, A.H.; Berg, M. van den

    2008-05-01

    Interference of exogenous chemicals with the aromatase enzyme can be useful as a tool to identify chemicals that could act either chemopreventive for hormone-dependent cancer or adverse endocrine disruptive. Aromatase is the key enzyme in the biosynthesis of steroids, as it converts androgens to estrogens. Certain flavonoids, plant derived chemicals, are known catalytic aromatase inhibitors. Various systems are in use to test aromatase inhibitory properties of compounds. Commonly used are microsomes derived from ovary or placental tissue characterized by high aromatase activity. To a lesser extent whole cell systems are used and specifically cell systems that are potential target tissue in breast cancer development. In this study aromatase inhibitory properties of fadrozole, 8-prenylnaringenin and a synthetic lactone (TM-7) were determined in human placental microsomes and in human primary breast fibroblasts. In addition, apigenin, chrysin, naringenin and two synthetic lactones (TM-8 and TM-9) were tested in human microsomes only. Comparison of the aromatase inhibitory potencies of these compounds between the two test systems showed that the measurement of aromatase inhibition in human placental microsomes is a good predictor of aromatase inhibition in human breast fibroblasts.

  19. Aromatase inhibition by synthetic lactones and flavonoids in human placental microsomes and breast fibroblasts--a comparative study.

    PubMed

    van Meeuwen, J A; Nijmeijer, S; Mutarapat, T; Ruchirawat, S; de Jong, P C; Piersma, A H; van den Berg, M

    2008-05-01

    Interference of exogenous chemicals with the aromatase enzyme can be useful as a tool to identify chemicals that could act either chemopreventive for hormone-dependent cancer or adverse endocrine disruptive. Aromatase is the key enzyme in the biosynthesis of steroids, as it converts androgens to estrogens. Certain flavonoids, plant derived chemicals, are known catalytic aromatase inhibitors. Various systems are in use to test aromatase inhibitory properties of compounds. Commonly used are microsomes derived from ovary or placental tissue characterized by high aromatase activity. To a lesser extent whole cell systems are used and specifically cell systems that are potential target tissue in breast cancer development. In this study aromatase inhibitory properties of fadrozole, 8-prenylnaringenin and a synthetic lactone (TM-7) were determined in human placental microsomes and in human primary breast fibroblasts. In addition, apigenin, chrysin, naringenin and two synthetic lactones (TM-8 and TM-9) were tested in human microsomes only. Comparison of the aromatase inhibitory potencies of these compounds between the two test systems showed that the measurement of aromatase inhibition in human placental microsomes is a good predictor of aromatase inhibition in human breast fibroblasts.

  20. Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells.

    PubMed

    Kim, Hyung Gyun; Jin, Sun Woo; Kim, Yong An; Khanal, Tilak; Lee, Gi Ho; Kim, Se Jong; Rhee, Sang Dal; Chung, Young Chul; Hwang, Young Jung; Jeong, Tae Cheon; Jeong, Hye Gwang

    2017-08-01

    Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E2. Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Role of P-450 aromatase in sex determination of the diamondback terrapin, Malaclemys terrapin.

    PubMed

    Jeyasuria, P; Roosenburg, W M; Place, A R

    1994-09-15

    Sex determination in the diamondback terrapin, Malaclemys terrapin, is temperature-dependent. Eggs incubated at 31 degrees C, and above, hatch in approximately 45 days as females. Eggs incubated below 27 degrees C hatch in about 60 days as males. Sex is not reversible after hatching. Nest temperatures in the wild can be as low as 20 degrees C and as high as 37 degrees C with as much as a 10 degrees C diel cycle. The shortest incubation time measured in nature was 56 days and the longest approaching 120 days. Nests in our study site produced predominantly (> 95%) male hatchlings. Treatment of developing embryos with estrogen produces females at male producing temperatures while treatment with fadrozole (a nonsteroidal aromatase inhibitor) induces partial male-like gonads. Treatment with a steroidal aromatase inhibitor (4-hydroxyandrostenedione, 4-OHA) had no effect on sex determination. Both fadrozole and 4-OHA are potent competitive inhibitors (Ki approximately 40-50 nM) for terrapin in vitro aromatase activity. These findings are consistent with aromatase expression being a key step in sex determination of terrapins. We have cloned a partial single copy P-450 aromatase from the terrapin using a cDNA library constructed from ovarian mRNA. This partial clone is highly homologous to other vertebrate aromatases.

  2. Genetics Home Reference: aromatase excess syndrome

    MedlinePlus

    ... Sources for This Page Fukami M, Shozu M, Ogata T. Molecular bases and phenotypic determinants of aromatase ... T, Nishigaki T, Yokoya S, Binder G, Horikawa R, Ogata T. Aromatase excess syndrome: identification of cryptic duplications ...

  3. Aromatase Expression in the Hippocampus of AD Patients and 5xFAD Mice

    PubMed Central

    Prange-Kiel, Janine; Dudzinski, Danuta A.; Pröls, Felicitas; Glatzel, Markus; Matschke, Jakob; Rune, Gabriele M.

    2016-01-01

    Numerous studies show that 17β-estradiol (E2) protects against Alzheimer's disease (AD) induced neurodegeneration. The E2-synthesizing enzyme aromatase is expressed in healthy hippocampi, but although the hippocampus is severely affected in AD, little is known about the expression of hippocampal aromatase in AD. To better understand the role of hippocampal aromatase in AD, we studied its expression in postmortem material from patients with AD and in a mouse model for AD (5xFAD mice). In human hippocampi, aromatase-immunoreactivity was observed in the vast majority of principal neurons and signal quantification revealed higher expression of aromatase protein in AD patients compared to age- and sex-matched controls. The tissue-specific first exons of aromatase I.f, PII, I.3, and I.6 were detected in hippocampi of controls and AD patients by RT-PCR. In contrast, 3-month-old, female 5xFAD mice showed lower expression of aromatase mRNA and protein (measured by qRT-PCR and semiquantitative immunohistochemistry) than WT controls; no such differences were observed in male mice. Our findings stress the importance of hippocampal aromatase expression in neurodegenerative diseases. PMID:27298742

  4. Computational Modeling of Hypothalamic-Pituitary-Gonadal Axis to Predict Adaptive Responses in Female Fathead Minnows Exposed to an Aromatase Inhibitor

    EPA Science Inventory

    Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose response and time-course...

  5. Computational Modeling of Hypothalamic-Pituitary-Gonadal Axis to Predict Adaptive Responses in Female Fathead Minnows Exposed to an Aromatase Inhibitor

    EPA Science Inventory

    Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose response and time-course...

  6. Cholinesterase inhibitors affect brain potentials in amnestic mild cognitive impairment

    PubMed Central

    Irimajiri, Rie; Michalewski, Henry J; Golob, Edward J; Starr, Arnold

    2007-01-01

    Amnestic mild cognitive impairment (MCI) is an isolated episodic memory disorder that has a high likelihood of progressing to Alzheimer’s disease. Auditory sensory cortical responses (P50, N100) have been shown to be increased in amplitude in MCI compared to older controls. We tested whether (1) cortical potentials to other sensory modalities (somatosensory and visual) were also affected in MCI and (2) cholinesterase inhibitors (ChEIs), one of the therapies used in this disorder, modulated sensory cortical potentials in MCI. Somatosensory cortical potentials to median nerve stimulation and visual cortical potentials to reversing checkerboard stimulation were recorded from 15 older controls and 15 amnestic MCI subjects (single domain). Results were analyzed as a function of diagnosis (Control, MCI) and ChEIs treatment (Treated MCI, Untreated MCI). Somatosensory and visual potentials did not differ significantly in amplitude in MCI subjects compared to controls. When ChEIs use was considered, somatosensory potentials (N20, P50) but not visual potentials (N70, P100, N150) were of larger amplitude in untreated MCI subjects compared to treated MCI subjects. Three individual MCI subjects showed increased N20 amplitude while off ChEIs compared to while on ChEIs. An enhancement of N20 somatosensory cortical activity occurs in amnestic single domain MCI and is sensitive to modulation by ChEIs. PMID:17320833

  7. PAAn-1b and PAAn-E: two phosphorothioate antisense oligodeoxynucleotides inhibit human aromatase gene expression.

    PubMed

    Auvray, P; Sourdaine, P; Séralini, G E

    1998-12-09

    Estrogen-dependent diseases, especially breast cancers, are frequently treated with aromatase inhibitors. Another more recent strategy is the antisense technology. In this study, after predicting aromatase mRNA secondary structure, we describe the design, the efficiency, and the toxicity of two antisense phosphorothioate oligodeoxynucleotides (PAAn-1b and PAAn-E) directed toward aromatase mRNA. Indeed, 2 microM PAAn-1b and PAAn-E encapsulated with 54 microM polyethylenimine inhibit aromatase activity by 71 and 79%, respectively, in transfected 293 cells, with IC50 values of 0.2 and 0.6 microM. The mechanism of inhibition appears to be specific after using sense and scramble oligodeoxynucleotides as controls and largely decreases aromatase mRNA and protein amounts. Moreover, PAAn-1b and PAAn-E are not cytotoxic for 293 cells. This study finally provides a new strategy for aromatase inhibition. It offers new tools for studying aromatase gene expression and its role in cancer for instance, and this could be of help for the therapy of estrogen-dependent diseases.

  8. Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors.

    PubMed

    Donders, G; Bellen, G; Neven, P; Grob, P; Prasauskas, V; Buchholz, S; Ortmann, O

    2015-10-01

    This study was a detailed microscopic analysis of the changes of vaginal microflora characteristics after application of 0.03 mg estriol-lactobacilli combination on the vaginal ecosystem in postmenopausal breast cancer (BC) survivors on aromatase inhibitors (AI) with severe atrophic vaginitis. A total of 16 BC women on AI applied daily one vaginal tablet of Gynoflor® for 28 days followed by a maintenance therapy of three tablets weekly for 8 weeks. During four follow up visits a smear from the upper lateral vaginal wall was analysed by phase contrast microscopy at 400 times magnification in order to classify the lactobacillary grades(LBG), bacterial vaginosis (BV), aerobic vaginitis (AV), vulvovaginal candidosis (VVC), proportional number of leukocytes and evidence of parabasal cells and epitheliolysis. LBG improved from 81% LBG-III at entry to 88% LBG-I&IIa after 2 weeks of initial therapy, which further improved upon follow up (p < 0.001). Whereas BV was a rare event, AV was frequent and substantially improved during treatment (p < 0.01). While at entry most patients had moderate or severe AV, after maintenance therapy no patient except one had AV. The number of leukocytes dropped dramatically from a score of 1.78 ± 0.70 to 1.06 ± 0.25 which was consistent till the end of the study (p < 0.01). Parabasal cells dropped from a score of 3.4 ± 0.64 at entry to 1.3 ± 0.60 at the final visit (p trend < 0.01). Starting from a low rate of Candida colonisation of 2/14 (14%), a sudden rise to 7/16 (44%) occurred after 2 weeks, to return back to base levels at subsequent visits. The vaginal use of ultra-low dose estriol and lactobacilli results in rapid and enduring improvement of all markers of the vaginal microflora and epithelial vaginal cell quality in women with breast cancer on AI with dyspareunia. Candida may develop soon after its use, but rapidly disappears again upon their prolonged use. Due to its excellent safety profiles and clinical efficacy we recommend

  9. Digital image analysis of breast epithelial cells collected by random periareolar fine-needle aspirates (RPFNA) from women at high risk for breast cancer taking hormone replacement and the aromatase inhibitor, letrozole, for six months.

    PubMed

    Frank, Denise H; Kimler, Bruce F; Fabian, Carol J; Ranger-Moore, James; Yozwiak, Michael; Bartels, Hubert G; Alberts, David S; Bartels, Peter H

    2009-06-01

    Aromatase inhibitors are currently being evaluated as preventive agents in post-menopausal women at high risk for breast cancer. A phase II trial of 42 women on hormone replacement therapy (HRT) treated with letrozole for 6 months showed Ki-67 was reduced by 66% but showed no change in cytomorphology or Masood score. Subsequent image analytical procedures (karyometry) conducted on a subset of the samples captured subvisual information that showed reduced cellular abnormality after 6 months of letrozole. In the present study we expanded on the preliminary karyometry study to determine if the change in karyometric measurements corresponded to changes in risk biomarkers quantified in the Phase II trial; and secondly, whether these biomarkers might be used together to serve as markers of response in individual cases. Pap stained slides from the Phase II trial were used. Epithelial cell images were digitized on a CCD video-microphotometer and the nuclei were segmented from the field using a semiautomatic algorithm. Nine out of 37 cases analyzed showed a numerical decrease in all three markers, although only three of these exhibited changes substantial enough to be considered as an improvement. However, 12 cases showed improvement by cytology (a decrease in Masood score of at least 2), an additional 13 cases demonstrated a reduction in Ki-67 expression by 50% of the median baseline value, and an additional five cases exhibited a decrease of at least 10% in abnormal cells by nuclear morphometry. Thus, a total of 30 of 37 cases (81%) showed improvement in at least one marker. There was no correlation between changes in Ki-67%, karyometric abnormality, and Masood score change other than specimens that exhibited an improvement in cytology also displayed greater decreases in nuclear morphometry abnormalities. Given the heterogeneity of mechanisms leading to malignancy, the quantitative analysis of nuclear chromatin patterns may be valuable as a global, or integrating

  10. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance).

    PubMed

    Ellis, Matthew J; Suman, Vera J; Hoog, Jeremy; Goncalves, Rodrigo; Sanati, Souzan; Creighton, Chad J; DeSchryver, Katherine; Crouch, Erika; Brink, Amy; Watson, Mark; Luo, Jingqin; Tao, Yu; Barnes, Michael; Dowsett, Mitchell; Budd, G Thomas; Winer, Eric; Silverman, Paula; Esserman, Laura; Carey, Lisa; Ma, Cynthia X; Unzeitig, Gary; Pluard, Timothy; Whitworth, Pat; Babiera, Gildy; Guenther, J Michael; Dayao, Zoneddy; Ota, David; Leitch, Marilyn; Olson, John A; Allred, D Craig; Hunt, Kelly

    2017-04-01

    Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate

  11. Quantitative AOP-based predictions for two aromatase ...

    EPA Pesticide Factsheets

    The adverse outcome pathway (AOP) framework can be used to support the use of mechanistic toxicology data as a basis for risk assessment. For certain risk contexts this includes defining, quantitative linkages between the molecular initiating event (MIE) and subsequent key events (KEs) within an AOP. One AOP for which strong, quantitative linkages have been established is aromatase inhibition leading to reproductive dysfunction in fish. A series of computational models have been linked to develop a quantitative AOP (Q-AOP). A measure of aromatase inhibition is used as the model input to estimate circulating plasma estradiol (E2) concentration and resultant circulating plasma vitellogenin (VTG) concentration. To evaluate model predictions, two aromatase inhibitors, letrozole and epoxiconazole, were selected based upon their relative aromatase inhibition potency in US EPA ToxCast assays. Reproductively mature female fathead minnows (Pimephales promelas) were exposed to varying concentrations of either letrozole (0.5, 7.5, 25, 75, 250 µg/L) or epoxiconazole (8, 25, 80, 250, 800 µg/L) in 24h flow through exposures. One additional consideration for model predictions was bioaccumulation of exposure chemicals and resultant circulating plasma concentration. To identify this, plasma from exposed minnows was extracted by supported liquid extraction (SLE) and concentrations of letrozole or epoxiconazole determined by LC-MS/MS. Plasma bioaccumulation factors (BAFplasma)

  12. The integrin inhibitor cilengitide affects meningioma cell motility and invasion.

    PubMed

    Wilisch-Neumann, Annette; Kliese, Nadine; Pachow, Doreen; Schneider, Thomas; Warnke, Jan-Peter; Braunsdorf, Werner Ek; Böhmer, Frank-Dietmar; Hass, Peter; Pasemann, Diana; Helbing, Cornelia; Kirches, Elmar; Mawrin, Christian

    2013-10-01

    Meningiomas are frequent intracranial or spinal neoplasms, which recur frequently and can show aggressive clinical behaviour. We elucidated the impact of the integrin inhibitor cilengitide on migration, proliferation, and radiosensitization of meningioma cells. We analyzed integrin expression in tissue microarrays of human meningiomas and the antimeningioma properties of cilengitide in cell cultures, subcutaneous and intracranial nude mouse models by measuring tumor volumes and survival times. αvβ5 was the predominantly expressed integrin heterodimer in meningiomas, whereas αvβ3 was mainly detected in tumor blood vessels. Application of up to 100 μg/mL cilengitide resulted in only mildly reduced proliferation/survival of meningioma cell lines. Effects on cell survival could be enhanced by irradiation. One μg/mL cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. A daily dosage of 75 mg/kg did neither affect tumor volumes nor overall survival (P = 0.813, log-rank test), but suppressed brain invasion in a significant fraction of treated animals. A combination of 75 mg/kg cilengitide daily and irradiation (2 × 5 Gy) led to a 67% reduction of MRI-estimated tumor volumes in the intracranial model (P < 0.01), whereas the corresponding reduction reached by irradiation alone was only 55% (P < 0.05). These data show that a monotherapy with cilengitide is not likely to achieve major responses in rapidly growing malignant meningiomas, although brain invasion may be reduced because of the strong antimigratory properties of the drug. The combination with radiotherapy warrants further attention. ©2013 AACR.

  13. A three-dimensional model of CYP19 aromatase for structure-based drug design.

    PubMed

    Karkola, Sampo; Höltje, Hans-Dieter; Wähälä, Kristiina

    2007-01-01

    Aromatase (CYP450(arom), CYP19) is an enzyme responsible for converting the aliphatic androgens androstenedione and testosterone to the aromatic estrogens estrone and estradiol, respectively. These endogenous hormones are a key factor in cancer tumor formation and proliferation through a cascade starting from estrogen binding to estrogen receptor. To interfere with the overproduction of estrogens especially in tumor tissue, it is possible to inhibit aromatase activity. This can be achieved using aromatase inhibitors. In order to design novel aromatase inhibitors, it is necessary to have an understanding of the active site of aromatase. As no crystal structure of the enzyme has yet been published, we built a homology model of aromatase using the first crystallized mammalian cytochrome enzyme, rabbit 21-progesterone hydroxylase 2C5, as a template structure. The initial model was validated with exhaustive molecular dynamics simulation with and without the natural substrate androstenedione. The resulting enzyme-substrate complex shows very good stability and only two of the residues are in disallowed regions in a Ramachandran plot.

  14. The binding of lignans, flavonoids and coumestrol to CYP450 aromatase: a molecular modelling study.

    PubMed

    Karkola, Sampo; Wähälä, Kristiina

    2009-03-25

    Androgens are transformed into aromatic estrogens by CYP450 aromatase in a three-step reaction consuming three equivalents of oxygen and three equivalents of NADPH. Estrogens are substrates for nuclear estrogen receptors (ERs) and play a key role in estrogen-dependent tumour cell formation and proliferation. Natural phytoestrogens are proved to be competitive inhibitors of aromatase enzyme at IC(50) values in micromolar levels. In order to understand the mechanisms involved in the binding of various phytoestrogens, we used our model of CYP450 aromatase to study the binding of phytoestrogens using molecular dynamics simulations with a bound phytoestrogen. The simulation trajectory was analysed to find the essential interactions which take place upon binding and a representative structure of the trajectory was minimized for docking studies. Sets of phytoestrogens, such as lignans, flavonoids/isoflavonoids and coumestrol, were docked into the aromatase active site and the binding modes were studied.

  15. Characterization of aromatase binding agents from the dichloromethane extract of Corydalis yanhusuo using ultrafiltration and liquid chromatography tandem mass spectrometry.

    PubMed

    Shi, Jing; Zhang, Xiaoyu; Ma, Zhongjun; Zhang, Min; Sun, Fang

    2010-05-14

    Aromatase represents an important target for the treatment of hormone-dependent breast cancer. In the present study, nine alkaloids from the dichloromethane extract of Corydalis yanhusuo were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) and tested for their aromatase binding activities using an ultrafiltration LC-MS method by investigating the differences of peak areas of compounds before and after incubations with aromatase. It was demonstrated that the quaternary protoberberine alkaloids and the tertiary protoberberine alkaloids exhibited potent aromatase binding activities. The quaternary ammonium group and the methyl group at C-13 position of tertiary protoberberine alkaloids might be necessary for the activity. The findings should provide guidance for the discovery of potential aromatase inhibitors from natural products.

  16. Structural basis for androgen specificity and oestrogen synthesis in human aromatase

    SciTech Connect

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter

    2009-03-06

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O{sub 2}, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16{alpha}-hydroxytestosterone to oestrone, 17{beta}-oestradiol and 17{beta},16{alpha}-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

  17. Structural basis for androgen specificity and oestrogen synthesis in human aromatase.

    PubMed

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter

    2009-01-08

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O(2), 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16alpha-hydroxytestosterone to oestrone, 17beta-oestradiol and 17beta,16alpha-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

  18. Structural basis for androgen specificity and oestrogen synthesis in human aromatase

    PubMed Central

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter

    2009-01-01

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens1–3. Aromatase inhibitors therefore constitute a front-line therapy for oestrogen-dependent breast cancer3,4. In a three-step process, each step requiring 1 mol of O2, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to oestrone, 17β-oestradiol and 17β,16α-oestriol, respectively1–3. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme’s androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors. PMID:19129847

  19. Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: II. Computational modeling.

    PubMed

    Breen, Miyuki; Villeneuve, Daniel L; Ankley, Gerald T; Bencic, David C; Breen, Michael S; Watanabe, Karen H; Lloyd, Alun L; Conolly, Rory B

    2013-06-01

    Endocrine-disrupting chemicals can affect reproduction and development in humans and wildlife. We developed a computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC) behaviors for endocrine effects of the aromatase inhibitor, fadrozole (FAD). The model describes adaptive responses to endocrine stress involving regulated secretion of a generic gonadotropin (LH/FSH) from the hypothalamic-pituitary complex. For model development, we used plasma 17β-estradiol (E2) concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two time-course experiments, each of which included both an exposure and a depuration phase, and plasma E2 data from a third 4-day study. Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 µg/l FAD exposure concentrations, and good fits to these data were obtained. The model accurately predicted CYP19A mRNA fold changes for controls and three FAD doses (0, 0.5, and 3 µg/l) and plasma E2 dose response from the 4-day study. Comparing the model-predicted DRTC with experimental data provided insight into how the feedback control mechanisms in the HPG axis mediate these changes: specifically, adaptive changes in plasma E2 levels occurring during exposure and "overshoot" occurring postexposure. This study demonstrates the value of mechanistic modeling to examine and predict dynamic behaviors in perturbed systems. As this work progresses, we will obtain a refined understanding of how adaptive responses within the vertebrate HPG axis affect DRTC behaviors for aromatase inhibitors and other types of endocrine-active chemicals and apply that knowledge in support of risk assessments.

  20. Higher order organization of human placental aromatase.

    PubMed

    Ghosh, Debashis; Jiang, Wenhua; Lo, Jessica; Egbuta, Chinaza

    2011-07-01

    Aromatase (CYP19A1) is an integral membrane enzyme that catalyzes the removal of the 19-methyl group and aromatization of the A-ring of androgens. All human estrogens are synthesized from their androgenic precursors by this unique cytochrome P450. The crystal structure of active aromatase purified from human placenta has recently been determined in complex with its natural substrate androstenedione in the high-spin ferric state of heme. Hydrogen bond forming interactions and tight packing hydrophobic side chains closely complement puckering of the steroid backbone, thereby providing the molecular basis for the androgenic specificity of aromatase. In the crystal, aromatase molecules are linked by a head-to-tail intermolecular interaction via a surface loop between helix D and helix E of one aromatase molecule that penetrates the heme-proximal cavity of the neighboring, crystallographically related molecule, thus forming in tandem a polymeric aromatase chain. This intermolecular interaction is similar to the aromatase-cytochrome P450 reductase coupling and is driven by electrostatics between the negative potential surface of the D-E loop region and the positively charged heme-proximal cavity. This loop-to-proximal site link in aromatase is rather unique--there are only a few of examples of somewhat similar intermolecular interactions in the entire P450 structure database. Furthermore, the amino acids involved in the intermolecular contact appear to be specific for aromatase. Higher order organization of aromatase monomers may have implications in lipid integration and catalysis.

  1. Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme.

    PubMed

    Viciano, Ignacio; Martí, Sergio

    2016-04-07

    Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three-step oxidative process. The estrogens are necessary in humans, mainly in women, because of the role they play in sexual and reproductive development. However, these also are involved in the development and growth of hormone-dependent breast cancer. Therefore, inhibition of the enzyme aromatase, by means of drugs known as aromatase inhibitors, is the frontline therapy for these types of cancers. Exemestane is a suicidal third-generation inhibitor of aromatase, currently used in breast cancer treatment. In this study, the hydroxylation of exemestane catalyzed by aromatase has been studied by means of hybrid QM/MM methods. The Free Energy Perturbation calculations provided a free energy of activation for the hydrogen abstraction step (rate-limiting step) of 17 kcal/mol. The results reveal that the hydroxylation of exemestane is not the inhibition stage, suggesting a possible competitive mechanism between the inhibitor and the natural substrate androstenedione in the first catalytic subcycle of the enzyme. Furthermore, the analysis of the interaction energy for the substrate and the cofactor in the active site shows that the role of the enzymatic environment during this reaction consists of a transition state stabilization by means of electrostatic effects.

  2. Treatment with Ruta graveolens 5CH and Rhus toxicodendron 9CH may reduce joint pain and stiffness linked to aromatase inhibitors in women with early breast cancer: results of a pilot observational study.

    PubMed

    Karp, Jean-Claude; Sanchez, Carole; Guilbert, Philippe; Mina, William; Demonceaux, Antoine; Curé, Hervé

    2016-11-01

    To determine the possible effect of two homeopathic medicines, Ruta graveolens 5CH and Rhus toxicodendron 9CH, in the prevention of aromatase inhibitor (AI) associated joint pain and/or stiffness in women with early, hormone-receptor positive, breast cancer. This prospective, unrandomized observational study was carried out between April and October 2014. Women were recruited in two groups, according to which of the two study centres they attended: one receiving homeopathy in addition to standard treatment (group H) and a control group, receiving standard treatment (group C). All women were treated with an AI. In addition, women in group H also took Ruta graveolens 5CH and Rhus toxicodendron 9CH (5 granules, twice a day) up to 7 days before starting AI treatment. The homeopathic medicines were continued for 3 months. Demographic and clinical data were recorded using a self-assessment questionnaire at inclusion (T0) and 3 months (T3). Primary evaluation criteria were the evolution of scores for joint pain and stiffness, the impact of pain on sleep and analgesic consumption in the two groups after 3 months of treatment. Forty patients (mean age 64.9±8.1 years) were recruited, 20 in each group. Two-thirds of the patients had joint pain before starting AI treatment. There was a significant difference in the evolution of mean composite pain score between T0 and T3 in the two groups (-1.3 in group H vs. +3.4 in group C; p=0.0001). The individual components of the pain score (frequency, intensity and number of sites of pain) also decreased significantly in group H. Nine patients in group C (45%) vs. 1 (5%) in group H increased their analgesic consumption between T0 and T3 (p=0.0076). After 3 months of treatment, joint pain had a worse impact on sleep in patients in group C (35% vs. 0% of patients; p=0.0083). The differences observed in the evolution of morning and daytime stiffness between the two groups were smaller (p=0.053 and p=0.33, respectively), with the exception

  3. Pharmacophore mapping of flavone derivatives for aromatase inhibition.

    PubMed

    Nagar, Shuchi; Islam, Md Ataul; Das, Suvadra; Mukherjee, Arup; Saha, Achintya

    2008-02-01

    Aromatase, which catalyses the final step in the steroidogenesis pathway of estrogen, has been target for the design of inhibitor in the treatment of hormone dependent breast cancer for postmenopausal women. The extensive SAR studies performed in the last 30 years to search for potent, selective and less toxic compounds, have led to the development of second and third generation of non-steroidal aromatase inhibitors (AI). Besides the development of synthetic compounds, several naturally occurring and synthetic flavonoids, which are ubiquitous natural phenolic compounds and mediate the host of biological activities, are found to demonstrate inhibitory effects on aromatase. The present study explores the pharmacophores, i.e., the structural requirements of flavones (Fig. 1) for inhibition of aromatase activity, using quantitative structure activity relationship (QSAR) and space modeling approaches. The classical QSAR studies generate the model (R (2) = 0.924, Q (2) = 0.895, s = 0.233) that shows the importance of aromatic rings A and C, along with substitutional requirements in meta and para positions of ring C for the activity. 3D QSAR of Comparative Molecular Field Analysis (CoMFA, R (2) = 0.996, R(2)(cv) = 0.791) and Comparative Molecular Similarity Analysis (CoMSIA, R (2) = 0.992, R(2)(cv) = 0.806) studies show contour maps of steric and hydrophobic properties and contribution of acceptor and donor of the molecule, suggesting the presence of steric hindrance due to ring C and R''-substituent, bulky hydrophobic substitution in ring A, along with acceptors at positions 11, and alpha and gamma of imidazole ring, and donor in ring C favor the inhibitory activity. Further space modeling (CATALYST) study (R = 0.941, Delta( cost ) = 96.96, rmsd = 0.876) adjudge the presence of hydrogen bond acceptor (keto functional group), hydrophobic (ring A) and aromatic rings (steric hindrance) along with critical distance among features are important for the inhibitory activity.

  4. A novel method for measuring aromatase activity in tissue samples by determining estradiol concentrations.

    PubMed

    Tinwell, H; Rascle, J B; Colombel, S; Al Khansa, I; Freyberger, A; Bars, R

    2011-07-01

    Increasing scrutiny of endocrine disrupters has led to changes to European pesticide and biocide legislation and to the introduction of the Endocrine Disrupter Screening Program by the US EPA. One element of endocrine disrupter identification is to determine its effects on aromatase, but most available assays are limited as they depend on tritiated water production to indicate enzyme activity. Whilst acceptable for determining aromatase effects using a cell-free approach, this method is unreliable for cell or tissue-based investigations as other cytochrome P-450 isoenzyme activities can similarly produce tritiated water and consequently confound interpretation of the aromatase data. To address this lack of specificity an assay directly measuring the final estrogen product by incubating rat tissue protein with testosterone and measuring the resultant estradiol concentration was developed. Using this approach we demonstrated marked increases in enzyme activity in pregnant rat ovary samples and dose-related inhibitions when incubating non-pregnant rat ovary samples with known aromatase inhibitors. Hepatic aromatase activity was investigated using our method and by tritiated water production with microsomes from rats dosed with the antiandrogen 1,1-dichloro-2,2-bis(4 chlorophenyl)ethane. Additional cytochrome P-450s were also measured. Treatment-related increased tritiated water production and general hepatic enzyme activity were recorded but estradiol was not increased, indicating that the increased tritiated water was due to general enzyme activity and not aromatase activity. A simple and specific method has been developed that can detect aromatase inhibition and induction, which when applied to tissue samples, provides a means of generating relevant animal data concerning chemical effects on the aromatase enzyme.

  5. SIRT1 positively regulates breast cancer associated human aromatase (CYP19A1) expression.

    PubMed

    Holloway, Kimberly R; Barbieri, Andreia; Malyarchuk, Svitlana; Saxena, Madhurima; Nedeljkovic-Kurepa, Ana; Cameron Mehl, Mathieu; Wang, Allison; Gu, Xin; Pruitt, Kevin

    2013-03-01

    Breast cancer remains one of the leading causes of death in women diagnosed with cancer. In breast cancer, aberrant expression of the CYP19A1 gene, which encodes the aromatase enzyme, contributes to increased intratumoral levels of estradiol. Regardless of whether this estrogen is produced by peripheral tissues or within specific subpopulations of cells within the breast tumor, it is clear that the aromatase enzymatic activity is critical for the growth of estrogen-dependent tumors. Currently, aromatase inhibitors have proven to be highly effective in blocking the growth of estrogen-dependent forms of breast cancer. CYP19A1 transcription is tightly controlled by 10 tissue-specific promoters. In breast cancer, however, aromatase transcription is driven by multiple promoters that somehow override the tissue-specific regulation of normal tissue. Here, we explore the role that the deacetylase, sirtuin-1 (SIRT1), plays in positively regulating aromatase in breast cancer. We demonstrate that the use of cambinol and the SIRT1/2 inhibitor VII, 2 small molecule inhibitors of SIRT1 and SIRT2, as well as small molecule inhibitors and small interfering RNA specific to SIRT1, all reduce the levels of aromatase mRNA. We further demonstrate that pharmacologic inhibition causes a marked reduction in aromatase protein levels. Additionally, by chromatin immunoprecipitation, we demonstrate that SIRT1 occupies the promoter regions PI.3/PII and PI.4, and its inhibition leads to increased acetylation of estrogen-related receptorα, a transcription factor that positively regulates CYP19A1 transcription in epithelial cells. Finally, we demonstrate by immunohistochemistry that SIRT1 is significantly up-regulated in invasive ductal carcinoma relative to normal tissue adjacent to tumor, further suggesting a role of SIRT1 in breast cancer. This work uncovers a new mechanism for the regulation of aromatase and provides rationale for further investigation of how the inhibition of specific

  6. Aromatase, estrogen receptors and brain development in fish and amphibians.

    PubMed

    Coumailleau, Pascal; Pellegrini, Elisabeth; Adrio, Fátima; Diotel, Nicolas; Cano-Nicolau, Joel; Nasri, Ahmed; Vaillant, Colette; Kah, Olivier

    2015-02-01

    Estrogens affect brain development of vertebrates, not only by impacting activity and morphology of existing circuits, but also by modulating embryonic and adult neurogenesis. The issue is complex as estrogens can not only originate from peripheral tissues, but also be locally produced within the brain itself due to local aromatization of androgens. In this respect, teleost fishes are quite unique because aromatase is expressed exclusively in radial glial cells, which represent pluripotent cells in the brain of all vertebrates. Expression of aromatase in the brain of fish is also strongly stimulated by estrogens and some androgens. This creates a very intriguing positive auto-regulatory loop leading to dramatic aromatase expression in sexually mature fish with elevated levels of circulating steroids. Looking at the effects of estrogens or anti-estrogens in the brain of adult zebrafish showed that estrogens inhibit rather than stimulate cell proliferation and newborn cell migration. The functional meaning of these observations is still unclear, but these data suggest that the brain of fish is experiencing constant remodeling under the influence of circulating steroids and brain-derived neurosteroids, possibly permitting a diversification of sexual strategies, notably hermaphroditism. Recent data in frogs indicate that aromatase expression is limited to neurons and do not concern radial glial cells. Thus, until now, there is no other example of vertebrates in which radial progenitors express aromatase. This raises the question of when and why these new features were gained and what are their adaptive benefits. This article is part of a Special Issue entitled: Nuclear receptors in animal development.

  7. Effects of Aromatase Inhibition and Androgen Activity on Serotonin and Behavior in Male Macaques

    PubMed Central

    Bethea, Cynthia L.; Reddy, Arubala P.; Robertson, Nicola; Colemen, Kristine

    2014-01-01

    Aggression in humans and animals has been linked to androgens and serotonin function. To further our understanding of the effect of androgens on serotonin and aggression in male macaques, we sought to manipulate circulating androgens and the activity of aromatase; and to then determine behavior and the endogenous availability of serotonin. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with [1] placebo, [2] testosterone (T), [3] T+Dutasteride (5a reductase inhibitor; AvodartTM), [4] T+Letrozole (non-steroidal aromatase inhibitor; FemeraTM), [5] Flutamide+ATD (androgen antagonist plus steroidal aromatase inhibitor) or [6] dihydrotestosterone (DHT)+ATD (n=5/group). Behavioral observations were made during treatments. At the end of the treatment period, each animal was sedated with propofol and administered a bolus of fenfluramine (5 mg/kg). Fenfluramine causes the release of serotonin proportional to endogenous availability and in turn, serotonin stimulates the secretion of prolactin. Therefore, serum prolactin concentrations reflect endogenous serotonin. Fenfluramine significantly increased serotonin/prolactin in all groups (p <0.0001). Fenfluramine-induced serotonin/prolactin in the T-treated group was significantly higher than the other groups (p<0.0001). Castration partially reduced the serotonin/prolactin response; and Letrozole partially blocked the effect of T. Complete inhibition of aromatase with ATD, a non-competitve inhibitor, significantly and similarly reduced the fenfluramine-induced serotonin/prolactin response in the presence or absence of DHT. Neither aggressive behavior nor yawning (indicators of androgen activity) correlated with serotonin/prolactin, but posited aromatase activity correlated significantly with prolactin (p<0.0008; r2 =0.95). In summary, androgens induced aggressive behavior but they did not regulate serotonin. Altogether, the data suggest that aromatase activity supports

  8. Novel glycosaminoglycan biosynthetic inhibitors affect tumor-associated angiogenesis

    PubMed Central

    Raman, Karthik; Ninomiya, Masayuki; Nguyen, Thao Kim Nu; Tsuzuki, Yasuhiro; Koketsu, Mamoru; Kuberan, Balagurunathan

    2011-01-01

    Heparan sulfate proteoglycans (HSPGs) are essential players in several steps of tumor-associated angiogenesis. As co-receptors for several pro-angiogenic factors such as VEGF and FGF, HSPGs regulate receptor-ligand interactions and play a vital role in signal transduction. Previously, we have employed an enzymatic strategy to show the importance of cell surface HSPGs in endothelial tube formation in vitro. We have recently found several fluoro-xylosides that can selectively inhibit proteoglycan synthesis in endothelial cells. The current study demonstrates that these fluoro-xylosides are effective inhibitors of endothelial tube formation in vitro using a matrigel based assay to simulate tumor-associated angiogenesis. These first generation scaffolds offer a promising stepping-stone to the discovery of more potent fluoro-xylosides that can effectively neutralize tumor growth. PMID:21094131