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Sample records for adjuvant aromatase inhibitor

  1. Which patients benefit most from adjuvant aromatase inhibitors?

    Viale, G; Regan, M M; Dell'Orto, P;

    2011-01-01

    On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which...

  2. Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update

    Mokbel, Ramia; Karat, Isabella; Mokbel, Kefah

    2006-01-01

    There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2–3 years followed by exemestane or anastrozole for 2–3 years is a reasonable alternative...

  3. Patient adherence to aromatase inhibitor treatment in the adjuvant setting

    Verma, S.; Madarnas, Y.; Sehdev, S.; Martin, G; Bajcar, J.

    2011-01-01

    Improvements in adjuvant systemic therapy and detection of early disease have resulted in a decline of breast cancer death rates across all patient age groups in Canada. Non-adherence to adjuvant hormonal therapy in the setting of early breast cancer may significantly affect patient outcome. Factors associated with medication adherence are complex and may be patient-related, therapy-related, and health care provider–related. To date, there is a gap in the literature concerning a comprehensive...

  4. Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update.

    Mokbel, Ramia; Karat, Isabella; Mokbel, Kefah

    2006-01-01

    There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2-3 years followed by exemestane or anastrozole for 2-3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2-3 years of tamoxifen. The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures. PMID:16981992

  5. Update on Aromatase Inhibitors

    Seifert-Klauss V

    2015-01-01

    Full Text Available Aromatase inhibitors (AI block the last phase of estrogen production in many types of tissues which express the enzym aromatase, among them muscle, liver, adrenal, brain and fat. The enzyme catalyzes the last step of the biosynthesis of the estrogens, i. e. the aromatisation of testosterone to estradiol and of androstendion to estrone. Aromatase is localized in the membrane of the endoplasmatic reticulum and is also produced in the placenta and the gonads. Mutations in the gene CYP19A1, which codes for aromatase, can lead either to lack or excess of aromatase. Gene polymorphisms also influence the amount of bioavailable estrogen and bone density.br Indications: AI are approved for the treatment of postmenopausal women with hormone receptor positive breast cancer, both in the adjuvant setting as well as after recurrence and in progressive disease. In premenopausal and in perimenopausal women AI cause an increased sensitivity of the ovaries to follicle stimulating hormone (FSH and can thereby lead to a boosted estrogen answer – this effect is particularly pronounced in early perimenopausal women – so that these situations demand a combination with GnRH-analogue if AI treatment is to be initiated. Alternatively, tamoxifene may be used in premenopausal patients, with or without GnRH analogues. Treatment of premenopausal patients with hormone receptor positive breast cancer with aromatase inhibiting therapy alone constitutes an absolute contraindication. Aromatase inhibitors do not lead to estrogen receptor downregulation or block the receptor such as tamoxifene. An exceptional application is the application in reproductive medicine in women who do not have hormone receptor positive breast cancer: because of the higher sensitivity induced by AI-co-therapy, FSH-doses and -costs for assisted reproduction are reduced, and ovarian hyperstimulation syndrome (OHSS may be avoided. For premenopausal diseases which are said to be positively affected by

  6. Aromatase inhibitors and anti-synthetase syndrome.

    Mascella, Fabio; Gianni, Lorenzo; Affatato, Alessandra; Fantini, Manuela

    2016-09-01

    Adjuvant therapy in postmenopausal women with endocrine-responsive breast cancer (BC) is actually centered on the use of anti-aromatase inhibitors (AI). Several reports, however, are emerging in literature associating the use of this drugs to rheumatic disorders. This case report describes the first case of anti-synthetase syndrome diagnosis after treatment with anti-estrogen agents in a patient with pre-existing rheumatoid arthritis. PMID:27225465

  7. Molecular Docking of Aromatase Inhibitors

    Virapong Prachayasittikul

    2011-04-01

    Full Text Available Aromatase is an enzyme that plays a critical role in the development of estrogen receptor positive breast cancer. As aromatase catalyzes the aromatization of androstenedione to estrone, a naturally occurring estrogen, it is a promising drug target for therapeutic management. The undesirable effects found in aromatase inhibitors (AIs that are in clinical use necessitate the discovery of novel AIs with higher selectivity, less toxicity and improving potency. In this study, we elucidate the binding mode of all three generations of AI drugs to the crystal structure of aromatase by means of molecular docking. It was demonstrated that the docking protocol could reliably reproduce the interaction of aromatase with its substrate with an RMSD of 1.350 Å. The docking study revealed that polar (D309, T310, S478 and M374, aromatic (F134, F221 and W224 and non-polar (A306, A307, V370, L372 and L477 residues were important for interacting with the AIs. The insights gained from the study herein have great potential for the design of novel AIs.

  8. Natural Products as Aromatase Inhibitors

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

    2008-01-01

    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 purpos...

  9. Aromatase inhibitors in the treatment of endometriosis.

    Słopień, Radosław; Męczekalski, Błażej

    2016-03-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  10. Aromatase inhibitors in the treatment of endometriosis

    Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  11. QUALITY OF LIFE OF WOMEN RECIEVING ADJUVANT HORMONAL TREATMENT FOR BREAST CANCER – A RANDOMIZED TRIAL COMPARING TAMOXIFEN WITH AROMATASE INHIBITORS

    C. Volovat

    2011-05-01

    Full Text Available Purpose: The assessment and comparison of the quality of life in women with early stages breast cancer receiving Tamoxifen versus aromatase inhibitors (AINs. Methods: There were selected 223 patients treated at Center of Medical Oncology Iasi, with early stages breast cancer. The patients were divided in two groups: 115 patients receiving Tamoxifen and 107 patients receiving aromatase inhibitors. From the patients receiving AINs, 33 of patients have received Exemestane, 60 patients Letrozole and 14 patients Anastrazole. The patients have completed an EORTC C30 and EORTC BR23 questionnaire at the beginning of the treatment (after one month and after 2 years of treatment. There was calculated the difference related with global status, functional scales, emotional scales, cognitive scales and symptom scales. Results: Statistic results show a better quality of life for Anastrazole vs. Letrozole and for AINs vs. Tamoxifen group, mainly on physical scales both after 2 months and after 2 years of treatment. In the same time, the physical scales were with better results after 1 month of treatment vs. 2 years of treatment. Conclusions: Following the hormonal treatment period, there is a mild worsening of quality of life for Tamoxifen and AINs too. In the same time, the quality of life is better in the group with AINs treatment comparative with the Tamoxifen treatment.

  12. Pharmacogenomics of tamoxifen and aromatase inhibitors.

    Ingle, James N

    2008-02-01

    In selection of therapy for women with breast cancer, the focus has been almost exclusively on the characteristics of the tumor, eg, estrogen receptor (ER) and HER-2. Until recently, essentially no attention has been paid to the host and her genetic makeup as it relates to the metabolism of different drugs. The first real clinical application of pharmacogenetics in breast cancer management relates to tamoxifen's biotransformation to active anticancer metabolites. New information has arisen on the metabolism of tamoxifen to the active metabolite, 4 hydroxy-N-desmethyl-tamoxifen (endoxifen). Endoxifen is a metabolite with antitumor activity and affinity for the ER that is similar to 4-hydroxy-tamoxifen, but 1 that is normally present in substantially higher concentrations. CYP2D6 plays a central role in the metabolism to endoxifen and 1 published study shows that genotypic differences in CYP2D6 and use of CYP2D6 inhibitors has an impact on outcomes of women treated with tamoxifen. The aromatase inhibitors represent a major class of drugs in the armamentarium against breast cancer. The aromatase gene has been resequenced and functional genomics have been performed on the identified nonsynonymous coding single nucleotide polymorphisms showing significant decreases in levels of activity. These findings are consistent with a hypothesis that genetic variation in the CYP19 gene might be important in the activity of aromatase inhibitors. Currently, the emphasis is on examining multiple genes (thus pharmacogenomics) in pharmacodynamic and pharmacokinetic pathways in women receiving aromatase inhibitors for breast cancer. PMID:18072234

  13. Aromatase inhibitor strategies in metastatic breast cancer

    Heather L McArthur

    2009-07-01

    Full Text Available Heather L McArthur, Patrick G MorrisBreast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: Despite ongoing therapeutic innovations, metastatic breast cancer (MBC remains a treatable but incurable disease. In the developed world, a diagnosis of MBC without a preceding diagnosis of early stage disease is a rare event. However, approximately one-third of women with early stage breast cancer ultimately experience a distant recurrence. Because the majority of breast cancers express estrogen and/or progesterone receptors and are accordingly considered hormone-sensitive, therapeutic strategies that interfere with hormone-mediated tumorigenesis have been a cornerstone of the breast cancer management paradigm for decades. Historically, the selective estrogen receptor modulator tamoxifen has been the most extensively studied and widely used hormone maneuver in breast cancer. However, a recent therapeutic innovation, namely the successful development of third-generation aromatase inhibitors (AIs, has had a dramatic impact on the treatment paradigm for women with hormone-sensitive MBC. Because of the demonstrated efficacy in postmenopausal breast cancer patients, the generally favorable side-effect profile, and the convenience of oral administration, AIs are now in widespread clinical use. Currently, there are three clinically available third-generation AIs: two reversible, nonsteroidal AIs, letrozole and anastrozole; and one irreversible, steroidal AI, exemestane. All three agents are at least as efficacious as tamoxifen as monotherapy for postmenopausal women with hormone-sensitive MBC. Current clinical research aims to improve upon existing strategies by evaluating AIs in combination with systemic chemotherapy regimens and/or novel targeted agents. It is hoped that these therapeutic innovations will lead to ongoing improvements in quality of life parameters and ideally survival for women

  14. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study

    In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI) is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms. We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+) breast cancer. A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly. The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia. Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication

  15. Committee Opinion No. 663: Aromatase Inhibitors in Gynecologic Practice.

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214191

  16. Committee Opinion No. 663 Summary: Aromatase Inhibitors in Gynecologic Practice.

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214185

  17. Potential role of aromatase inhibitors in the treatment of endometriosis

    Abu Hashim H

    2014-07-01

    Full Text Available Hatem Abu HashimDepartment of Obstetrics and Gynecology, Faculty of Medicine, Mansoura University, Mansoura, EgyptAbstract: Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%–10% of reproductive-age women, with a prevalence of 5%–50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis

  18. Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis

    Mustata Gabriela

    2011-06-01

    Full Text Available Abstract Background The present study compares antiepileptic drugs and aromatase (CYP19 inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs are needed, especially since every individual responds differently to given treatment options. Methods Through a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits. Results The pharmacophore model returned 73% (19 out of 26 of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62 of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses. Conclusions This study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity

  19. Aromatase inhibitors in stimulated IVF cycles

    Tournaye Herman

    2011-06-01

    Full Text Available Abstract 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

  20. Long-term safety of aromatase inhibitors in the treatment of breast cancer

    Jean-Marc A Nabholtz

    2008-03-01

    Full Text Available Jean-Marc A NabholtzBreast Cancer Research Institute La Prandie, Valojoulx, FranceAbstract: Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI, anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.Keywords: breast cancer, aromatase inhibitors, adjuvant, safety profile

  1. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormone-sensitive early breast cancer: a case study

    Bryce J

    2012-03-01

    Full Text Available Jane Bryce1, Martina Bauer2, Peyman Hadji21National Cancer Institute, Naples, Italy; 2Philipps University of Marburg, Marburg, GermanyBackground: In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms.Purpose: We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+ breast cancer.Methods and sample: A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly.Results: The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia.Conclusions: Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication.Keywords: adherence, anastrozole, aromatase inhibitor, arthralgia, breast cancer, letrozole

  2. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C.

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that wer

  3. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line tr...

  4. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation

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

    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 arom...

  5. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer

    Stefano Gonnelli

    2008-11-01

    Full Text Available Stefano Gonnelli1, Roberto Petrioli21Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy (Dir. R. Nuti.; 2Department of Human Pathology and Oncology, Medical Oncology Section, University of Siena, Italy (Dir. G. FranciniAbstract: The third-generation aromatase inhibitors (AIs, letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD and lipid profile could be recommended for post-menopausal women candidate to AIs.Keywords: breast cancer, aromatase inhibitors, bone loss, lipids, cardiovascular risk

  6. Aromatase inhibitors in the treatment of deep endometriosis

    Simone Ferrero

    2009-09-01

    Full Text Available Recent case reports and pilot studies suggested that aromatase inhibitors might be effective in treating pain symptoms related to the presence of endometriosis. We present the case of a 32-year-old woman who suffered dysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia caused by rectovaginal endometriosis. Pain symptoms recurred after treatment with the oral contraceptive pill; the patient refused surgery. Therefore a double-drug regimen including letrozole (2.5 mg/day and norethisterone acetate (2.5 mg/day was offered to the patient. The scheduled length of treatment was six months. This double-drug regimen determined a quick and significant improvement in all pain symptoms. During treatment, the patient complained mild arthralgia. After the interruption of treatment, pain symptoms quickly recurred and at 6-month follow-up their intensity was similar to baseline values. Operative laparoscopy was performed, the presence of rectovaginal endometriosis was confirmed and all visible endometriotic lesions were excised. Aromatase inhibitors might be offered when pain symptoms caused by endometriosis persist during the administration of other hormonal therapies and the patient refuses surgery. However, women must be informed that these drugs determine only a temporary relief of pain symptoms and might cause adverse effects (such as arthralgia.

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

    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

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

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

    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 th...

  9. A feasibility study of a Nordic walking intervention for women experiencing aromatase inhibitor associated arthralgia

    Fields, Jo

    2015-01-01

    Background: Women taking AIs (Aromatase Inhibitors) as treatment for breast cancer commonly experience joint pain and stiffness (aromatase inhibitor associated arthralgia; AIAA) which can lead to early discontinuation of treatment. Exercise is often recommended and there is preliminary evidence it might prove helpful. Nordic Walking is a popular form of exercise in women with breast cancer, and based on a biopsychosocial model, could provide additional benefits over normal walking alone. Ther...

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

    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 aromata...

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

    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. PMID:22361454

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

    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. PMID:26232614

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

    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. |

  14. 3H- and 14C-labelling of the aromatase inhibitor ZK 138723

    It has been known for several years that the growth of certain neoplastic disorders - especially breast cancer in women -depends on the serum level of estrogen. One strategy of lowering the estrogen formation is to inhibit the action of the enzyme aromatase, which catalyzes the final step in estrogen biosynthesis in humans. For this purpose nonsteroidal compounds seem to offer advantages as compared to the classical steroid derivatives regarding intensity and duration of effect as well as selectivity to other cytochrome P450 enzymes. The competitive aromatase inhibitor ZK138723 is such a nonsteroidal compound. It was labelled with 3H and 14C to be used for further pharmacological investigations. (author)

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

    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 μM) 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 μM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 μM and 0.27 μM, 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.

  16. Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors.

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

    2016-01-14

    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

  17. Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

    Lui, Asona; New, Jacob; Ogony, Joshua; Thomas, Sufi; Lewis-Wambi, Joan

    2016-01-01

    Background mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells. Methods In this study we utilized two AI-resistant breast cancer cell lines...

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

    Introduction: Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (Ki=11.5 nM) that has Food and Drug Administration 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. Methods: Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [11C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [11C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [11C-cyano]letrozole fraction in arterial plasma were also measured. Results: [11C-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/μmol 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. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84. Conclusion: [11C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [11C]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

  19. Management of adenomyosis in infertile women: comparison between laparotomic resection and administration of aromatase inhibitor (Experience in 55 cases

    Rajuddin Rajuddin

    2006-03-01

    Full Text Available The objective of this study was to observe the results of adenomyosis mangement with resection and administration of aromatase inhibitor. Cases of ademyosis in infertile women were collected for three years (January 1999 to December 2001 and the diagnoses were confirmed using transvaginal USG. Cases were grouped into two groups, i.e. group 1 (undergoing laparotomic resection and group 2 (receiving treatment with aromatase inhibitor of anastrozole. Both groups were evaluated for changes in clinical symptoms, rate of successful pregnancy, and postoperative recurrency rate. During three years as many as 1619 infertility cases were managed, and among which 66 (4.07% cases of adenomyosis were diagnosed with transvaginal USG. As many as 55 cases were analyzed, i.e., 32 cases underwent resection and 23 cases received aromatase inhibitor. Of 32 cases of surgical resection, the histopathological results showed 30 (93.75% cases of adenomyosis and 2 (6.25% cases of uterus myoma. In the group undergoing resection three cases (9.4% were successfully pregnant, i.e., two cases had live birth, one case ended up with 6-week abortion. Moreover, 25 (78.1% cases were not pregnant and 4 (12.5% cases had recurrency, while 24 (75.35% cases experienced disappearance of symptoms yet not pregnant. On the other hand, of 23 cases in the group receiving aromatase inhibitor 2 (8.6% cases were able to be pregnant, one case had live birth and another case ended up with abortion, while 14 (59.1% cases had disappearance of symptoms yet not pregnant. During three months of treatment with aromatase inhibitor, a reduction in the lesion size between 7.31 mm3 and 25.90 mm3 were observed with CI 95% (p < 0.001. In conclusion, treatment with aromatase inihibitor did not heal lesions, but only reduced the size of adenomyosis lesions. On the other hand, resection could heal lesions, yet recurrency of disease may occur (12.5% after one postoperative year. (Med J Indones 2006; 15

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

    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.

  1. Aromatase inhibitors - a viable option for recurrent granulosa cell tumour of ovary: overview and case report

    Granulosa cell tumour of the ovary in adults is a rare tumour of low malignant potential affecting middle aged peri or post menopausal patients. These tumours are often diagnosed at an early stage, due to their hormonally active nature. They, however, have unique distinguishing histologic features and behaviour of frequent and late local or systemic relapses. The diagnosis can be challenging with unusual presentations. There is high association of endometrial carcinoma. Surgery is the mainstay of management in early low risk disease, while radiotherapy and systemic platinum based chemotherapy are employed in higher stage with poor prognostic indices. Survival is good in early stage disease. Recurrent, progressive, and treatment refractory disease is not infrequent and poses management challenge. Endocrine manipulation and hormone treatment are employed in few cases with equivocal results, as reported in literature. We present a case of recurrent and treatment refractory GCT in a postmenopausal patient, managed by aromatase inhibitor Anastrozole with reasonable efficacy. (author)

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

    Zhao XH

    2015-09-01

    Full Text Available Xihe Zhao,1 Lei Liu,2 Kai Li,1 Wusheng Li,1 Li Zhao,1 Huawei Zou1 1Department of Oncology, 2Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: 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. Keywords: CV risk, breast cancer, AI, network meta-analysis

  3. Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.

    Ghosh, Debashis; Lo, Jessica; Egbuta, Chinaza

    2016-06-01

    Human aromatase catalyzes the synthesis of estrogen from androgen with high substrate specificity. For the past 40 years, aromatase has been a target of intense inhibitor discovery research for the prevention and treatment of estrogen-dependent breast cancer. The so-called third generation aromatase inhibitors (AIs) letrozole, anastrozole, and the steroidal exemestane were approved in the U.S. in the late 1990s for estrogen-dependent postmenopausal breast cancer. Efforts to develop better AIs with higher selectivity and lower side effects were handicapped by the lack of an experimental structure of this unique P450. The year 2009 marked the publication of the crystal structure of aromatase purified from human placenta, revealing an androgen-specific active site. The structure has reinvigorated research activities on this fascinating enzyme and served as the catalyst for next generation AI discovery research. Here, we present an account of recent developments in the AI field from the perspective of the enzyme's structure-function relationships. PMID:26689671

  4. Molecular characterization of aromatase

    Hong, Yanyan; Li, Hongzhi; Yuan, Yate-Ching; Chen, Shiuan

    2009-01-01

    Aromatase is an estrogen synthetase. Estrogens are female sex hormones involved in the development and growth of breast tumors. It has been of significant interest to elucidate the structure-function relationship of aromatase since its inhibitors have shown great promise in fighting breast cancer. Aromatase belongs to the cytochrome P450 family, and forms an electron-transfer complex with its partner, NADPH-cytochrome P450 reductase. Because of the membrane-bound character and heme-binding in...

  5. New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

    Roleira Fernanda MF

    2008-07-01

    Full Text Available Abstract Background Aromatase, the cytochrome P-450 enzyme (CYP19 responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI, which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells. Results The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death. Conclusion Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

  6. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    Schiff, Rachel; Chamness, Gary C.; Brown, Powel H.

    2003-01-01

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new s...

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

    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...

  8. Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review

    Venturini Pier L

    2011-06-01

    Full Text Available Abstract This systematic review aims to assess the efficacy of aromatase inhibitors (AIs in treating pain symptoms caused by endometriosis. A comprehensive literature search was conducted to identify all the published studies evaluating the efficacy of type II nonsteroidal aromatase inhibitors (anastrozole and letrozole in treating endometriosis-related pain symptoms. The MEDLINE, EMBASE, PubMed, and SCOPUS databases and the Cochrane System Reviews were searched up to October 2010. This review comprises of the results of 10 publications fitting the inclusion criteria; these studies included a total of 251 women. Five studies were prospective non-comparative, four were randomized controlled trials (RCTs and one was a prospective patient preference trial. Seven studies examined the efficacy of AIs in improving endometriosis-related pain symptoms, whilst three RCTs investigated the use of AIs as post-operative therapy in preventing the recurrence of pain symptoms after surgery for endometriosis. All the observational studies demonstrated that AIs combined with either progestogens or oral contraceptive pill reduce the severity of pain symptoms and improve quality of life. One patient preference study demonstrated that letrozole combined with norethisterone acetate is more effective in reducing pain and deep dyspareunia than norethisterone acetate alone. However, letrozole causes a higher incidence of adverse effects and does not improve patients' satisfaction or influence recurrence of symptoms after discontinuation of treatment. A RCT showed that combining letrozole with norethisterone acetate causes a lower incidence of adverse effects and lower discontinuation rate than combining letrozole with triptorelin. Two RCTs demonstrated that, after surgical treatment of endometriosis, the administration of AIs combined with gonadotropin releasing hormone analogue for 6 months reduces the risk of endometriosis recurrence when compared with gonadotropin

  9. Metastatic progression with resistance to aromatase inhibitors is driven by the steroid receptor coactivator SRC-1.

    McBryan, Jean; Theissen, Sarah M; Byrne, Christopher; Hughes, Eamon; Cocchiglia, Sinead; Sande, Stephen; O'Hara, Jane; Tibbitts, Paul; Hill, Arnold D K; Young, Leonie S

    2012-01-15

    Aromatase inhibitors (AI) are a standard-of-care treatment for postmenopausal, estrogen receptor-positive breast cancers. Although tumor recurrence on AI therapy occurs, the mechanisms underlying acquired resistance to AIs remain unknown. In this study, we examined a cohort of endocrine-treated breast cancer patients and used a cell line model of resistance to the AI letrozole. In patients treated with a first-line AI, hormone receptor switching between primary and resistant tumors was a common feature of disease recurrence. Resistant cells exhibited a switch from steroid-responsive growth to growth factor-responsive and endocrine-independent growth, which was accompanied by the development of a more migratory and disorganized phenotype. Both the resistant cells and tumors from AI-resistant patients showed high expression of the steroid receptor coactivator SRC-1. Direct interactions between SRC-1 and the transcription factor Ets2 regulated Myc and MMP9. SRC-1 was required for the aggressive and motile phenotype of AI-resistant cells. Interestingly, SRC-1 expression in primary and/or recurrent tumors was associated with a reduction in disease-free survival in treated patients. Moreover, there was a significant association between SRC-1 and Ets2 in the recurrent tissue compared with the matched primary tumor. Together, our findings elucidate a mechanism of AI-specific metastatic progression in which interactions between SRC-1 and Ets2 promote dedifferentiation and migration in hormone-dependent breast cancer. PMID:22108824

  10. Postmenopausal Breast Cancer, Aromatase Inhibitors, and Bone Health: What the Surgeon Should Know.

    Baatjes, K J; Apffelstaedt, J P; Kotze, M J; Conradie, M

    2016-09-01

    Breast cancer, as the most common malignancy in women, remains a major public health issue despite countless advances across decades. Endocrine therapy is the cornerstone of treatment of the hormone-sensitive subtype of breast cancer. The use of aromatase inhibitors (AIs) in the postmenopausal women has extended the survival beyond that of Tamoxifen, but harbors a subset of side effects, most notably accelerated bone loss. This, however, does not occur in all women undergoing treatment. It is vital to identify susceptible patients early, to limit such events, employ early treatment thereof, or alter drug therapy. International trials on AIs, predominantly performed in North American and European females, provide little information on what to expect in women in developing countries. Here, surgeons often prescribe and manage endocrine therapy. The prescribing surgeon should be aware of the adverse effect of the endocrine therapy and be able to attend to side effects. This review highlights clinical and biochemical factors associated with decrease in bone mineral density in an, as yet, unidentified subgroup of postmenopausal women. In the era of personalized medical care, appropriate management of bone health by surgeons based on these factors becomes increasingly important. PMID:27189076

  11. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

    Abhinav Iyengar

    2013-01-01

    Full Text Available A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no spontaneous erythroid colonies were demonstrated. Erythrocytosis is common reason for referral to a hematologist. The myeloproliferative disorder, polycythemia vera, and the rare congenital polycythemias represent primary erythrocytosis. Common secondary causes include smoking, obstructive sleep apnea, and other pulmonary diseases. Erythrocytosis is well described with certain classes of drugs, including androgens. We hypothesize that exemestane contributed to the development of erythrocytosis in our patient. To our knowledge, erythrocytosis has not been previously described in association with aromatase inhibitors. These drugs prevent the conversion of androstenedione and testosterone to estrogen; thus the physiologic mechanisms may be similar to those responsible for erythrocytosis seen with exogenous androgens. These mechanisms are not well understood, but may include altered iron metabolism by a reduction in hepcidin levels.

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

    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. PMID:27178335

  13. Aromatase inhibitors in breast cancer: the discovery of new computational design and biochemical evaluation

    Neves, Marco André Coelho das

    2009-01-01

    Continuous exposure to high levels of endogenous estrogens is associated with increased risks of developing breast cancer. In this sense, aromatase, the cytochrome P450 enzyme involved in the conversion of androgens, testosterone and androstenedione, into estrogens, estradiol and estrone, is an important target for the endocrine treatment of breast cancer in postmenopausal women. Aromatase inhibition is achieved either with compounds structurally related to the androstenedio...

  14. Evaluation of the quality and accuracy of information regarding aromatase inhibitors available on the internet.

    Beaton, Ceri; Codd, Rhodri J; Holland, Phillip A; Gateley, Christopher A

    2008-01-01

    The internet is commonly used by patients to access medical information, particularly where new treatments become available and are highlighted in the press. There is however, no regulation of the quality or accuracy of the information presented on web sites. The aim of this study was to evaluate the quality and accuracy of the information concerning the aromatase inhibitors (AIs). The three most popular search engines: Google, Yahoo, and MSN were utilized. The top ten "hits" for the generic and proprietary names of each AIs: anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara) were evaluated using a 12-point score by a single assessor. The accuracy of the information provided was compared with the National Institute for Health and Clinical Excellence guidelines. The mean score for the 180 web sites was only 6.13 out of 12 (0-11). If we consider a score of 9 or more out of 12 (> or =75%) for a web site to represent good quality information, then 51 (28%) of pages scored well. Google was slightly better than Yahoo and MSN; with the highest percentage of web sites scoring well. In evaluating hits according to type of web sites, 50 (28%) were charity web sites and 30 (17%) were drug company web sites and both groups scored significantly higher than the overall mean (charity p = 0.014, drug company p = 0.001). Only 2 of 180 hits gave accurate statistical evidence regarding the benefits of AIs over tamoxifen. We have found that the quality and accuracy of information concerning AIs provided on the Internet is poor and patients using it are unlikely to find accurate information. It is therefore our duty as healthcare providers to guide patients, so as to avoid them from being overwhelmed by irrelevant and conflicting information. PMID:18537915

  15. Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons.

    Robarge, Jason D; Duarte, Djane B; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A; Vasko, Michael R

    2016-07-01

    Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527

  16. Changing Adjuvant Breast-Cancer Therapy with a Signal for Prevention.

    Chlebowski, RT; Budoff, MJ

    2016-01-01

    Five randomized, full-scale studies have reported that 10 years of adjuvant endocrine therapy is beneficial for postmenopausal women with hormone-receptor-positive breast cancer. However, no prior study has involved more than 5 years of aromatase-inhibitor use or assessed a duration of adjuvant endocrine therapy of more than 10 years.(1) Goss and colleagues(2) now provide results from the MA.17R trial supporting the use of an aromatase inhibitor for 10 years and the use of adjuvant endocrine ...

  17. Uso de inibidores da aromatase no tratamento do câncer de mama e osteoporose = The use of aromatase inhibitors for breast cancer treatment and osteoporosis

    Cassol, Lina Barbosa

    2005-01-01

    Conclusão: Estratégias diagnósticas, preventivas e, eventualmente, terapêuticas de osteoporose devem ser empregadas precocemente em pacientes com câncer de mama tratadas com inibidores da aromatase

  18. Effects of the aromatase inhibitor Letrozole on serum immunoglobulin and lysozyme levels in immunized rainbow trout (Oncorhynchus mykiss Walbaum females

    Paria Akbary

    2013-12-01

    Full Text Available Letrozole is a synthetic aromatase inhibitor and interfere in the committed step in the synthesis of endogenous estrogens from androgens. Also estrogens regulate the immune system in teleost. Changes of 17- β- esrtradiol (E2, serum immunoglobulin and lysozyme levels were measured using a method based on the ability of lysozyme to lyse the bacterium Micrococcus lysodeikticus, enzyme-linked immunosorbent assay (ELISA and ELISA respectively. Twelve broodstocks were injected weekly with 2.5 mg kg-1 letrozole (an endocrine disrupter component two months before spawning season and vaccinated intraperitoneally (i.p with a bacterin (inactivated L. garviae one month before spawning. Twelve broodstocks for vaccination and twelve female rainbow trout as control group were also immiunised (i.p with the bacterin and injected (i.p with PBS, respectively. In the group received 2.5 mg AI kg-1 per week, serum E2 levels were significantly lower than that of other groups. Total immunoglobulin level and lysozyme activity were significantly higher in the parents received 2.5 mg kg-1 per week and were immunized with 10-9 cells ml-1 Lactococcus garvieae  compared to the group which immunized with L. garvieae and the control (non- immunized. The present study, suggests that aromatase inhibitors such as letrozole may be a potential tool to regulate the synthesis of E2, is involved in the hormone- immune system interaction in rainbow trout.

  19. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols

    Løssl, Kristine; Andersen, A N; Loft, A; Freiesleben, N L C; Bangsbøll, S; Andersen, C Yding

    2006-01-01

    Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically....

  20. Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial

    Lossl, K; Andersen, C Yding; Loft, A; Freiesleben, N L C; Bangsbøll, S; Andersen, A Nyboe; Løssl, Kristine

    2008-01-01

    Temporary exposure of follicles to increased levels of androgens may augment follicular responsiveness. The present study tested whether short-term androgen priming by aromatase inhibitor and human chorionic gonadotrophin (hCG) before controlled ovarian stimulation (COS) increases the number of top...

  1. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

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

    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. PMID:26489554

  3. Cutaneous adverse effects of hormonal adjuvant therapy for breast cancer: a case of localised urticarial vasculitis following anastrozole therapy and a review of the literature.

    Bock, Vanessa L; Friedlander, Michael; Waring, Dale; Kossard, Steven; Wood, Glenda K

    2014-11-01

    Hormonal therapy with either tamoxifen or aromatase inhibitors is commonly used to treat women with breast cancer in both the adjuvant and recurrent disease setting. Cutaneous adverse reactions to these drugs have been rarely reported in the literature. We report an unusual case of urticarial vasculitis following the aromatase inhibitor anastrozole that localised to the unilateral trunk and mastectomy scar, and review the literature on the cutaneous adverse effects of hormonal therapy for breast cancer. PMID:24575835

  4. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial.

    Rastelli, Antonella L; Taylor, Marie E; Gao, Feng; Armamento-Villareal, Reina; Jamalabadi-Majidi, Shohreh; Napoli, Nicola; Ellis, Matthew J

    2011-08-01

    A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20-29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10-19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain-severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated. PMID:21691817

  5. Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort

    Castel, Liana D.; Hartmann, Katherine E.; Mayer, Ingrid A.; Saville, Benjamin R.; Alvarez, JoAnn; Boomershine, Chad S.; Abramson, Vandana G.; Chakravarthy, A. Bapsi; Friedman, Debra L.; Cella, David F.

    2013-01-01

    BACKGROUND More than 80,000 postmenopausal breast cancer patients in the US each year are estimated to begin a five-year course of aromatase inhibitors (AIs) to prevent recurrence. AI-related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause. OBJECTIVES To describe one-year arthralgia trajectories and baseline covariates among AI patients and a postmenopausal comparison group. METHODS Patients initiating AIs (n=91) were surveyed at the time of AI initiation and at six repeated assessments over one year. A comparison group of postmenopausal women without breast cancer (n=177) completed concomitantly-timed surveys. Numeric rating scales (0–10) were used to measure pain in eight joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes). Poisson regression models were used to analyze arthralgia trajectories and risk factors. RESULTS By week six, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means=1.8, (95% CI 1.2–2.7, p=0.002), adjusting for baseline characteristics. Arthralgia then worsened further over a year in the AI group. Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe longitudinal arthralgia. CONCLUSIONS Patients initiating AI should be told about the timing of arthralgia over the first year of therapy, and advised that it does not appear to resolve over the course of a year. Menopausal symptoms and joint-related comorbidity at AI initiation can help identify patients at risk for developing AI-related arthralgia. PMID:23575918

  6. Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet: A Systematic Review.

    Ekpo, Ernest U; Brennan, Patrick C; Mello-Thoms, Claudia; McEntee, Mark F

    2016-06-01

    Background Lower breast density (BD) is associated with lower risk of breast cancer and may serve as a biomarker for the efficacy of chemopreventive strategies. This review explores parameters that are thought to be associated with lower BD. We conducted a systematic review of articles published to date using the PRISMA strategy. Articles that assessed change in BD with estrogen-receptor modulators (tamoxifene [TAM], raloxifene [RLX], and tibolone) and aromatase inhibitors (AIs), as well as cross-sectional and longitudinal studies (LSs) that assessed association between BD and physical activity (PA) or diet were reviewed. Results Ten studies assessed change in BD with TAM; all reported TAM-mediated BD decreases. Change in BD with RLX was assessed by 11 studies; 3 reported a reduction in BD. Effect of tibolone was assessed by 5 RCTs; only 1 reported change in BD. AI-mediated BD reduction was reported by 3 out of 10 studies. The association between PA and BD was assessed by 21 studies; 4 reported an inverse association. The relationship between diet and BD was assessed in 34 studies. All studies on calcium and vitamin D as well as vegetable intake reported an inverse association with BD in premenopausal women. Two RCTs demonstrated BD reduction with a low-fat, high-carbohydrate intervention. Conclusion TAM induces BD reduction; however, the effect of RLX, tibolone, and AIs on BD is unclear. Although data on association between diet and BD in adulthood are contradictory, intake of vegetables, vitamin D, and calcium appear to be associated with lower BD in premenopausal women. PMID:27130722

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

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

    2016-01-01

    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

  8. Paradoxal metabolic flare detected by 18F-fluorodeoxyglucose positron emission tomography in a patient with metastatic breast cancer treated with aromatase inhibitor and biphosphonate

    Patients with estrogen-receptor-positive advanced breast cancer are treated with endocrine therapy. The majority of breast cancer localizations show 18F-fluorodeoxyglucose (FDG) uptake at positron emission tomography (PET) examination. In these patients, the metabolic flare after therapy is common and was proposed as an index of therapy efficacy. Nevertheless, prolonged persistence of flare can lead to misinterpretation. We describe a case of a patient with invasive ductal breast cancer with bone metastases at bone scintigraphy and FDG PET scan and with expression of estrogen receptors. Initially, the patient underwent endocrine therapy in addition to a biphosfonate. Owing to progression observed in a bone scan, Tamoxifen was substituted with aromatase inhibitors. Successive bone scan examinations showed stabilization with a marked clinical improvement. A second FDG PET was performed 28 months after the first examination and showed a metabolic flare phenomenon with concomitant partial calcification of osteolitic lesions. This is an unusual case of prolonged metabolic flare

  9. Complementary or alternative medicine as possible determinant of decreased persistence to aromatase inhibitor therapy among older women with non-metastatic breast cancer.

    Laetitia Huiart

    Full Text Available PURPOSE: Aromatase inhibitor therapy (AI significantly improves survival in breast cancer patients. Little is known about adherence and persistence to aromatase inhibitors and about the causes of treatment discontinuation among older women. METHODS: We constituted a cohort of women over 65 receiving a first AI therapy for breast cancer between 2006 and 2008, and followed them until June 2011. Women were selected in the population-based French National Health Insurance databases, and data was collected on the basis of pharmacy refills, medical records and face-to-face interviews. Non-persistence to treatment was defined as the first treatment discontinuation lasting more than 3 consecutive months. Time to treatment discontinuation was studied using survival analysis techniques. RESULTS: Overall among the 382 selected women, non-persistence to treatment went from 8.7% (95%CI: 6.2-12.1 at 1 year, to 15.6% (95%CI: 12.2-19.8 at 2 years, 20.8% (95%CI: 16.7-25.6 at 3 years, and 24.7% (95%CI: 19.5-31.0 at 4 years. In the multivariate analysis on a sub-sample of 233 women with available data, women using complementary or alternative medicine (CAM (HR = 3.2; 95%CI: 1.5-6.9 or suffering from comorbidities (HR = 2.2; 95%CI: 1.0-4.8 were more likely to discontinue their treatment, whereas women with polypharmacy (HR = 0.4; 95%CI: 0.2-0.91 were less likely to discontinue. In addition, 13% of the women with positive hormonal receptor status did not fill any prescription for anti-hormonal therapy. CONCLUSION: AI therapy is discontinued prematurely in a substantial portion of older patients. Some patients may use CAM not as a complementary treatment, but as an alternative to conventional medicine. Improving patient-physician communication on the use of CAM may improve hormonal therapy adherence.

  10. The time since last menstrual period is important as a clinical predictor for non-steroidal aromatase inhibitor-related arthralgia

    The clinical predictors of aromatase inhibitor-related arthralgia (AIA), a drug-related adverse reaction of aromatase inhibitors (AIs), remain unclear. AIA was prospectively surveyed every 4 months in 328 postmenopausal breast cancer patients administered a non-steroidal AI (anastrozole). Various clinicopathological parameters were recorded and analyzed (chi-square test, Fisher's exact test and logistic regression analysis). The mean observation period was 39.9 months. AIA manifested in 114 patients (34.8%), with peaks of onset at 4 (33.7%) and 8 months (11.4%) after starting AI administration. Some cases manifested even after 13 months. AIA tended to occur in younger patients (incidences of 46.3%, 37.4% and 28.0% for ages of < 55, 55-65 and > 65 years, respectively (p = 0.063)) and decreased significantly with the age at menarche (53.3%, 35.3% and 15.4% for < 12, 12-15 and > 15 years, respectively (p = 0.036)). The incidences were 45.1%, 46.3 and 25.1% for the time since the last menstrual period (LMP) < 5 years, 5-10 years and > 10 years, being significantly lower at > 10 years (p < 0.001). In logistic regression analysis, the AIA incidence was significantly lower in the time since LMP > 10-year group versus the < 5-year group (odds ratio 0.44, p = 0.002), but the age at menarche showed no association. AIA manifested significantly earlier (≤ 6 months) as the time since LMP became shorter (< 5 years). AIA tends to manifest early after starting AI, but some cases show delayed onset. The incidence was significantly lower in patients with a duration of > 10 years since LMP. When the time since LMP was short, the onset of AIA was significantly earlier after starting AI administration

  11. A systematic review and methodological evaluation of published cost-effectiveness analyses of aromatase inhibitors versus tamoxifen in early stage breast cancer.

    Ava A John-Baptiste

    Full Text Available BACKGROUND: A key priority in developing policies for providing affordable cancer care is measuring the value for money of new therapies using cost-effectiveness analyses (CEAs. For CEA to be useful it should focus on relevant outcomes and include thorough investigation of uncertainty. Randomized controlled trials (RCTs of five years of aromatase inhibitors (AI versus five years of tamoxifen in the treatment of post-menopausal women with early stage breast cancer, show benefit of AI in terms of disease free survival (DFS but not overall survival (OS and indicate higher risk of fracture with AI. Policy-relevant CEA of AI versus tamoxifen should focus on OS and include analysis of uncertainty over key assumptions. METHODS: We conducted a systematic review of published CEAs comparing an AI to tamoxifen. We searched Ovid MEDLINE, EMBASE, PsychINFO, and the Cochrane Database of Systematic Reviews without language restrictions. We selected CEAs with outcomes expressed as cost per life year or cost per quality adjusted life year (QALY. We assessed quality using the Neumann checklist. Using structured forms two abstractors collected descriptive information, sources of data, baseline assumptions on effectiveness and adverse events, and recorded approaches to assessing parameter uncertainty, methodological uncertainty, and structural uncertainty. RESULTS: We identified 1,622 citations and 18 studies met inclusion criteria. All CE estimates assumed a survival benefit for aromatase inhibitors. Twelve studies performed sensitivity analysis on the risk of adverse events and 7 assumed no additional mortality risk with any adverse event. Sub-group analysis was limited; 6 studies examined older women, 2 examined women with low recurrence risk, and 1 examined women with multiple comorbidities. CONCLUSION: Published CEAs comparing AIs to tamoxifen assumed an OS benefit though none has been shown in RCTs, leading to an overestimate of the cost-effectiveness of AIs

  12. Long-term efficacy and safety of anastrozole for adjuvant treatment of early breast cancer in postmenopausal women

    Sharath Gangadhara

    2009-04-01

    Full Text Available Sharath Gangadhara, Gianfilippo BertelliSouth West Wales Cancer Institute, Singleton Hospital, Swansea, UKAbstract: For more than 20 years, tamoxifen has been the gold standard for the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. However, recent randomized trials have shown efficacy and tolerability benefits with the third-generation aromatase inhibitor anastrozole, resulting in an increased use of this agent in the adjuvant setting. Data on anastrozole’s long-term efficacy and tolerability are therefore of interest in clinical practice and will be reviewed here, especially in the light of the 100-month analysis of the ATAC (Anastrozole, Tamoxifen Alone or in Combination trial.Keywords: anastrozole, aromatase inhibitors, breast cancer, adjuvant therapy 

  13. 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

    Jacobsen, Naja Wessel; Hansen, Cecilie Hurup; Nellemann, Christine;

    2015-01-01

    shown to inhibit the aromatase enzyme in both types of aromatase assays. The IC50 values ranged from 3 to 600μM. 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 0.9μM and 3.1μ...

  14. 芳香化酶抑制剂致骨质疏松研究进展%Research of aromatase inhibitor induced osteoporosis

    马翠翠

    2008-01-01

    Breast cancer patients treated by aromatase inhibitor(AI) may cause ovarian failure, resulting in decreased hormone levels. Then bone loss increases, which may result in thinning bone and osteoporosis. In clinic, attention should be given and appropriate means must be chosen to prevent and treat this disease. Calcium + vitamin D, diphosphonate, selective estrogen receptor modulator, Chinese medicine are recommen-ded to reduce the incidence of esteoporosis.%乳腺癌患者服用芳香化酶抑制剂(AI)使得卵巢功能缺失导致体内雌激素水平下降,从而加速骨代谢发生骨质疏松.在临床中应给予重视并根据具体情况选择适当防治手段.推荐使用钙剂+维生素D、双膦酸盐、选择性雌激素受体调节剂、中药等药物治疗,减少骨质疏松的发病率.

  15. 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

    Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14α-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 IC5 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 IC5 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

  16. Evolution of Long-Term Adjuvant Anti-hormone Therapy: Consequences and Opportunities. The St. Gallen Prize Lecture

    Jordan, V. Craig; Obiorah, Ifeyinwa; Fan, Ping; Kim, Helen R.; Ariazi, Eric; Cunliffe, Heather; Brauch, Hiltrud

    2011-01-01

    The successful translation of the scientific principles of targeting the breast tumour oestrogen receptor (ER) with the nonsteroidal anti-oestrogen tamoxifen and using extended durations (at least 5-years) of adjuvant therapy, dramatically increased patient survivorship and significantly enhanced a drop in national mortality rates from breast cancer. The principles are the same for the validation of aromatase inhibitors to treat post-menopausal patients but tamoxifen remains a cheap, life-sav...

  17. Effects of 17α-Methyltestosterone and Aromatase Inhibitor Letrozole on Sex Reversal, Gonadal Structure, and Growth in Yellow Catfish Pelteobagrus fulvidraco.

    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. PMID:25920714

  18. miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors.

    Bacci, Marina; Giannoni, Elisa; Fearns, Antony; Ribas, Ricardo; Gao, Qiong; Taddei, Maria Letizia; Pintus, Gianfranco; Dowsett, Mitch; Isacke, Clare M; Martin, Lesley-Ann; Chiarugi, Paola; Morandi, Andrea

    2016-03-15

    Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER(+)) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER(+) breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy. PMID:26795347

  19. Combining Computational and Biochemical Studies for a Rationale on the Anti-Aromatase Activity of Natural Polyphenols

    Neves, Marco A. C.; Dinis, Teresa C. P.; Colombo, Giorgio; Melo, M. Luísa Sá e

    2007-01-01

    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 bas...

  20. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer

    Khan, Qamar J.; Reddy, Pavan S.; Kimler, Bruce F; Sharma, Priyanka; Baxa, Susan E.; O’Dea, Anne P.; Klemp, Jennifer R.; Fabian, Carol J.

    2009-01-01

    Vitamin D deficiency and insufficiency may contribute to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs). This study was conducted to determine the prevalence of suboptimal vitamin D levels in women initiating adjuvant letrozole for breast cancer and to determine whether supplementation with 50,000 IU of vitamin D3 weekly could reduce musculoskeletal symptoms and fatigue in women who have suboptimal vitamin D levels. Sixty women about to begin an adj...

  1. Origin of aromatase inhibitory activity via proteochemometric modeling.

    Simeon, Saw; Spjuth, Ola; Lapins, Maris; Nabu, Sunanta; Anuwongcharoen, Nuttapat; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents. PMID:27190705

  2. Potential utility of natural products as regulators of breast cancer-associated aromatase promoters

    Walker Larry A

    2011-06-01

    Full Text Available Abstract 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

  3. Glassy-state stabilization of a dominant negative inhibitor anthrax vaccine containing aluminum hydroxide and glycopyranoside lipid A adjuvants.

    Hassett, Kimberly J; Vance, David J; Jain, Nishant K; Sahni, Neha; Rabia, Lilia A; Cousins, Megan C; Joshi, Sangeeta; Volkin, David B; Middaugh, C Russell; Mantis, Nicholas J; Carpenter, John F; Randolph, Theodore W

    2015-02-01

    During transport and storage, vaccines may be exposed to temperatures outside of the range recommended for storage, potentially causing efficacy losses. To better understand and prevent such losses, dominant negative inhibitor (DNI), a recombinant protein antigen for a candidate vaccine against anthrax, was formulated as a liquid and as a glassy lyophilized powder with the adjuvants aluminum hydroxide and glycopyranoside lipid A (GLA). Freeze-thawing of the liquid vaccine caused the adjuvants to aggregate and decreased its immunogenicity in mice. Immunogenicity of liquid vaccines also decreased when stored at 40°C for 8 weeks, as measured by decreases in neutralizing antibody titers in vaccinated mice. Concomitant with efficacy losses at elevated temperatures, changes in DNI structure were detected by fluorescence spectroscopy and increased deamidation was observed by capillary isoelectric focusing (cIEF) after only 1 week of storage of the liquid formulation at 40°C. In contrast, upon lyophilization, no additional deamidation after 4 weeks at 40°C and no detectable changes in DNI structure or reduction in immunogenicity after 16 weeks at 40°C were observed. Vaccines containing aluminum hydroxide and GLA elicited higher immune responses than vaccines adjuvanted with only aluminum hydroxide, with more mice responding to a single dose. PMID:25581103

  4. Aromatase: Contributions to Physiology and Disease in Women and Men.

    Blakemore, Jennifer; Naftolin, Fredrick

    2016-07-01

    Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products. PMID:27252161

  5. Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

    Rios, Adan; Hsu, Sigmund H.; Blanco, Angel; Buryanek, Jamie; Day, Arthur L.; McGuire, Mary F.; Brown, Robert E.

    2016-01-01

    Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. Significance The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration. PMID:27489862

  6. 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

    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. 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. 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. TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function

  7. Inhibition of rainbow trout (Oncorhynchus mykiss) P450 aromatase activities in brain and ovarian microsomes by various environmental substances.

    Hinfray, Nathalie; Porcher, Jean-Marc; Brion, François

    2006-11-01

    Aromatase, a key steroidogenic enzyme that catalyses the conversion of androgens to estrogens, represent a target for endocrine disrupting chemicals. However, little is known about the effect of pollutants on aromatase enzymes in fish. In this study, we first optimized a rainbow trout (Oncorhynchus mykiss) microsomal aromatase assay to measure the effects of 43 substances belonging to diverse chemical classes (steroidal and non steroidal aromatase inhibitors, pesticides, heavy metals, organotin compounds, dioxins, polycyclic aromatic hydrocarbons) on brain and ovarian aromatase activities in vitro. Our results showed that 12 compounds were able to inhibit brain and ovarian aromatase activities in a dose-dependent manner with IC50 values ranging from the low nM to the high microM range depending on the substance: steroidal and non steroidal inhibitors of aromatase (4-hydroxyandrostenedione, androstatrienedione, aminogluthethimide), imidazole fungicides (clotrimazole, imazalil, prochloraz), triazole fungicides (difenoconazole, fenbuconazole, propiconazole, triadimenol), the pyrimidine fungicide fenarimol and methylmercury. Overall, this study demonstrates that rainbow trout brain and ovarian microsomal aromatase assay is suitable for evaluating potential aromatase inhibitors in vitro notably with respect to environmental screening. The results highlight that methylmercury and some pesticides that are currently used throughout the world, have the potential to interfere with the biosynthesis of endogenous estrogens in fish. PMID:17081805

  8. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    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 (11C)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 (11C)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.

  9. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    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.

  10. Imaging of aromatase distribution in rat and rhesus monkey brains with [11C]vorozole

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [11C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K d of [11C]vorozole binding to aromatase in MA was determined to be 0.60±0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [11C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons

  11. Imaging of aromatase distribution in rat and rhesus monkey brains with [{sup 11}C]vorozole

    Takahashi, Kayo [Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala SE-75124 (Sweden); Uppsala Imanet, Uppsala SE-75109 (Sweden)]. E-mail: kayo.takahashi@uppsala.imanet.se; Bergstroem, Mats [Uppsala Imanet, Uppsala SE-75109 (Sweden); Department of Pharmaceutical Biosciences, Uppsala University, Uppsala SE-75124 (Sweden); Fraendberg, Pernilla [Uppsala Imanet, Uppsala SE-75109 (Sweden); Vesstroem, Eva-Lotta [Uppsala Imanet, Uppsala SE-75109 (Sweden); Watanabe, Yasuyoshi [Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585 (Japan); Langstroem, Bengt [Uppsala Imanet, Uppsala SE-75109 (Sweden)

    2006-07-15

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [{sup 11}C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K {sub d} of [{sup 11}C]vorozole binding to aromatase in MA was determined to be 0.60{+-}0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [{sup 11}C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons.

  12. Adjuvant treatment of breast cancer by concomitant hormonotherapy and radiotherapy: state of the art

    Combining radiation and hormone therapy has become common clinical practice in recent years for locally advanced prostate cancer. The use of such concomitant therapy in the treatment of breast disease has been very infrequently reported in the literature, but such an application seems justified given the common hormonal dependence of breast cancer and the potential synergetic effect of these two treatment modalities. As adjuvant therapy, tamoxifen is the key drug in the hormonal treatment arsenal, providing a significant improvement in both local control and global survival rates. Aromatase inhibitors are currently being evaluated in this setting, and initial results are promising. In vitro, tamoxifen does not seem to offer a protective effect against radiation. In clinical use, the few available published studies confirm the superiority of the association of radiation with tamoxifen as opposed to radiation therapy alone in decreasing local recurrences of surgically removed breast tumors. Toxicity associated with such concomitant therapy includes mainly subcutaneous and pulmonary fibrosis. However, subcutaneous fibrosis and its cosmetic impact on the treated breast are frequently described side effects of radiation therapy, and their incidence may actually be reduced when tamoxifen is associated. The evidence is less controversial for pulmonary fibrosis, which is more common with the concomitant therapy. The association of radiation and aromatase inhibitors has as of yet rarely been reported. Letrozole (Femara) has a radiosensitizing effect on breast-cancer cell lines transfected with the aromatase gene. Clinical data assessing this effect in vivo are not available. The FEMTABIG study (letrozole vs. tamoxifen vs. sequential treatment) did not specify the sequence of radiation and hormonal therapy. The ATAC study comparing the adjuvant use of anastrozole (Arimidex )and tamoxifen does not provide any information on the number of patients receiving radiation

  13. Genetics Home Reference: aromatase excess syndrome

    ... males, the increased aromatase and subsequent conversion of androgens to estrogen are responsible for the gynecomastia and limited bone growth characteristic of aromatase excess syndrome . Increased estrogen in females can cause symptoms ...

  14. 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.

    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 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 this product as first choice in women on AI with severe dyspareunia. PMID:26223323

  15. Genetics Home Reference: aromatase deficiency

    ... regulating bone growth and blood sugar levels. During fetal development, aromatase converts androgens to estrogens in the placenta, ... link between the mother's blood supply and the fetus. This conversion in the ... sexual development in female fetuses. After birth, the conversion of ...

  16. Aromatase inhibitors in the treatment of endometriosis

    Słopień, Radosław; Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and c...

  17. Aromatase inhibitors in stimulated IVF cycles

    Papanikolaou, Evangelos G; Polyzos, Nikolaos P; Al Humaidan, Peter Samir Heskjær;

    2011-01-01

    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....... 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...

  18. Aromatase in human liver and its diseases

    Estrogens play important roles in the cell proliferation and invasion of estrogen-dependent human neoplasms. Aromatase overexpression has been also reported in hepatitis and hepatocellular carcinoma (HCC) compared with normal liver but its details in these hepatic disorders have remained unclear. Therefore, in this study, we first immunolocalized aromatase using immunohistochemistry in patients with liver cirrhosis, steatosis, hepatitis, HCC, and metastasis liver carcinoma (MLC) in order to study the detailed status of intrahepatic aromatase. Aromatase immunoreactivity was predominantly detected in nonneoplastic hepatocytes around tumor cells. We then evaluated the effects of an interaction between hepatocytes and carcinoma cells upon aromatase mRNA expression, using HepG2 as a substitute model of hepatocytes by coculture systems. Aromatase mRNA levels in HepG2 were significantly increased by coculture with all carcinoma cell lines examined. We also evaluated alternative splicing of aromatase exon 1 but the same splicing variant was used in HepG2 cells regardless of carcinoma cell lines employed in the coculture system. These findings obtained in HepG2 indicated that carcinoma cells, whether metastatic or primary, induced aromatase expression in adjacent normal hepatocytes possibly through the soluble aromatase inducible factors in human hepatic microenvironments

  19. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro

    Vinggaard, A.M.; Hnida, C.; Breinholt, V.;

    2000-01-01

    Many pesticides are able to block or activate the steroid hormone receptors and/or to affect the levels of sex hormones, thereby potentially affecting the development or expression of the male and female reproductive system or both. This emphasizes the relevance of screening pesticides for a wide...... range of hormone-mimicking effects. Twenty-two pesticides were tested for their ability to affect CYP19 aromatase activity in human placental microsomes using the classical [H-3](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon tall fungicides), and dicofol tan...... triadimenol were identified as weak aromatase inhibitors. In conclusion, seven out of 22 tested pesticides turned out to be weak to moderate aromatase inhibitors in vitro, indicating the relevance of elucidating the endocrine effects in vivo of these compounds....

  20. Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia.

    Bajpai, Anurag; Simm, Peter J; McPherson, Stephen J; Russo, Vincenzo C; Azar, Walid J; Wark, John D; Risbridger, Gail P; Werther, George A

    2010-10-01

    Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved. PMID:20675302

  1. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice

    Wong, Tsz Yan; Li, Fengjuan; Lin, Shu-mei; Franky L Chan; Chen, Shiuan; Leung, Lai K.

    2014-01-01

    Background Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk. Methods In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-express...

  2. Ginkgo biloba extract EGb 761-mediated inhibition of aromatase for the treatment of hormone-dependent breast cancer.

    Park, Yong Joo; Ahn, Hui Yeon; Kim, Ha Ryong; Chung, Kyu Hyuck; Oh, Seung Min

    2016-01-01

    Ginkgo biloba has been used in herbal medicines for thousands of years. Although a standard G. biloba extract, EGb 761 has been used to improve cognition in breast cancer patients, its effects on breast cancer are unknown. Therefore, we investigated the antitumorigenic effects of EGb 761 using an in vitro cell model and an in vivo xenograft model. EGb 761 significantly inhibited aromatase activity in aromatase over-expressing MCF-7 cells (MCF-7 AROM). In addition, EGb 761 exposure reduced cytochrome p450 aromatase (CYP19) mRNA and protein expression; CYP19 promoter I.3 and PII expression particularly decreased. These inhibitory effects on aromatase were accompanied by reduced 17β-estradiol levels in MCF-7 AROM cells. For elucidating antitumorigenic effects, MCF-7 AROM cells were implanted in BALB/c nude mice prior to oral EGb 761 treatment for 3 weeks. EGb 761 reduced the tumor size and significantly reduced tumor CYP19 mRNA expression. Taken together, our results indicated that EGb 761 inhibited aromatase and exerted antitumor effects on breast cancer cells both in vitro and in vivo. These findings suggest that EGb761 may be a useful aromatase inhibitor for the treatment for estrogen-sensitive breast cancer. PMID:26706698

  3. Effects of transferrin on aromatase activity in porcine granulosa cells in vitro.

    Małgorzata Duda

    2009-01-01

    Full Text Available Proliferating cells have an absolute requirement for iron, which is delivered by transferrin with subsequent intracellular transport via the transferrin receptor. Recent studies have reported that transferrin plays a crucial role in the local regulation of ovarian function, apart from its iron-binding characteristic. Therefore, the present study was undertaken to explore the possible role of transferrin in porcine granulosa cells function by examining its influence on aromatase activity, the most important indicator of follicular cell differentiation. In the first series of studies, pig granulosa cells isolated from small, immature follicles were cultured in the presence of transferrin alone (10 microg/ml or 100 microg/ml or with the addition of FSH (100ng/ml. The second series of studies was undertaken to determine transferrin-stimulated granulosa cells ability to aromatize exogenous testosterone (1x10(-7M. One hour after the establishment of cultures an aromatase inhibitor CGS16949A was added to test its influence on estradiol production. After 48 hours, cultures were terminated and cells were processed for immunocytochemical staining of aromatase. Media were frozen for further estradiol level analysis. Positive immunostaining for aromatase was found in all granulosa cell cultures. The intensity of immunostaining was always stronger in cultures supplemented with FSH whereas the addition of transferrin had no effect. Granulosa cells in vitro synthesized the highest amount of estradiol after the addition of FSH and exogenous testosterone as measured radioimmunologically. Concomitant treatment with FSH and transferrin caused an inhibition of FSH-stimulated aromatase activity. The production of estradiol also declined in the presence of FSH, testosterone and transferrin. This study demonstrates that transferrin had a dose-dependent inhibitory effect on FSH-stimulated aromatase activity, which was confirmed by radioimmunoassay. Our results indicate

  4. Potential usefulness of glycolytic inhibitors as adjuvants in temozolomide-radiation therapy of malignant gliomas: in vitro studies

    Malignant gliomas remain virtually incurable, in spite of increase in median survival with Temozolomide (TMZ)-Radiation therapy after surgical resection. Following a span of initial remission-depending on the degree of malignancy-there is tumour recurrence and impairment of vital body functions, leading ultimately to death. Therefore, it is important to carry out further preclinical studies to improve treatment of these tumours. Inhibitors of glycolytic energy metabolism, such as 2-deoxy-D-glucose (2-DG) and Lonidamine (LND) have been shown earlier to differentially inhibit growth and survival of tumour cells invitro. They also increase tumour regression and animal survival in preclinical studies; and have been used as radio/chemosensitizers in a several clinical trials. In our present studies, TMZ ± LND or 2-DG were added to exponentially growing cultures. The drugs were continuously present for 2-6 days in the initial experiments. Subsequently, cells were exposed to 60Co-Gamma-rays (1-2 Gy) and drugs were removed 4 hours later. Effects on proliferation response, viability and cell death were studied after post-treatment growth. Ultra-structural damage was studied immediately after cytotoxic treatments

  5. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis

    Meyer Debra M

    2010-08-01

    Full Text Available Abstract Background The Janus kinase (JAK family of tyrosine kinases includes JAK1, JAK2, JAK3 and TYK2, and is required for signaling through Type I and Type II cytokine receptors. CP-690,550 is a potent and selective JAK inhibitor currently in clinical trials for rheumatoid arthritis (RA and other autoimmune disease indications. In RA trials, dose-dependent decreases in neutrophil counts (PBNC were observed with CP-690,550 treatment. These studies were undertaken to better understand the relationship between JAK selectivity and PBNC decreases observed with CP-690,550 treatment. Methods Potency and selectivity of CP-690,550 for mouse, rat and human JAKs was evaluated in a panel of in vitro assays. The effect of CP-690,550 on granulopoiesis from progenitor cells was also assessed in vitro using colony forming assays. In vivo the potency of orally administered CP-690,550 on arthritis (paw edema, plasma cytokines, PBNC and bone marrow differentials were evaluated in the rat adjuvant-induced arthritis (AIA model. Results CP-690,550 potently inhibited signaling through JAK1 and JAK3 with 5-100 fold selectivity over JAK2 in cellular assays, despite inhibiting all four JAK isoforms with nM potency in in vitro enzyme assays. Dose-dependent inhibition of paw edema was observed in vivo with CP-690,550 treatment. Plasma cytokines (IL-6 and IL-17, PBNC, and bone marrow myeloid progenitor cells were elevated in the context of AIA disease. At efficacious exposures, CP-690,550 returned all of these parameters to pre-disease levels. The plasma concentration of CP-690,550 at efficacious doses was above the in vitro whole blood IC50 of JAK1 and JAK3 inhibition, but not that of JAK2. Conclusion Results from this investigation suggest that CP-690,550 is a potent inhibitor of JAK1 and JAK3 with potentially reduced cellular potency for JAK2. In rat AIA, as in the case of human RA, PBNC were decreased at efficacious exposures of CP-690,550. Inflammatory end points

  6. Molecular simulations of aromatase reveal new insights into the mechanism of ligand binding.

    Park, Jiho; Czapla, Luke; Amaro, Rommie E

    2013-08-26

    CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model of the lipid bilayer and the transmembrane helix are performed. The dynamics of aromatase and the role of titration of an important amino acid residue involved in aromatization of androgens are investigated via two 250-ns long simulations. One simulation treats the protonated form of the catalytic aspartate 309, which appears more consistent with crystallographic data for the active site, while the simulation of the deprotonated form shows some notable conformational shifts. Ensemble-based computational solvent mapping experiments indicate possible novel druggable binding sites that could be utilized by next-generation inhibitors. In addition, the effects of protonation on the ligand positioning and channel dynamics are investigated using geometrical models that estimate the opening width of critical channels. Significant differences in channel dynamics between the protonated and deprotonated trajectories are exhibited, suggesting that the mechanism for substrate and product entry and the aromatization process may be coupled to a "locking" mechanism and channel opening. Our results may be particularly relevant in the design of novel drugs, which may be useful therapeutic treatments of cancers such as those of the breast and prostate. PMID:23927370

  7. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-11C]Vorozole

    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.

  8. Aromatase imaging with [N-methyl-C-11]vorozole PET in healthy men and women

    Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aims to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathological situations can be studied. Methods: (11)C-vorozole (111-296 MBq/subject) was injected I.V in 13 men and 20 women (age range 23 to 67). PET data were acquired over a 90 minute period. Each subject had 4 scans, 2/day separated by 2-6 weeks, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned following pretreatment with a clinical dose of the aromatase inhibitor letrozole.Time activity curves were obtained and standard uptake values (SUV) calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole body radiation exposures were calculated using Olinda software. Results: Liver uptake was higher than all other organs, but was not blocked by pretreatment with letrozole. Mean SUVs in men were higher than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than all other organs (ranging from 0.48±0.05 in lungs to 1.5±0.13 in kidneys). Mean ovarian SUVs (3.08±0.7) were comparable to brain levels and higher than all other organs. Furthermore, ovarian SUVs In young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, while aging and cigarette smoking reduced (11)C-vorozole uptake. Conclusions: PET with (11)C-vorozole is useful for assessing physiological changes in estrogen synthesis capacity in the human body. Baseline levels in

  9. Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

    Prachayasittikul V

    2014-08-01

    Full Text Available Veda Prachayasittikul,1 Ratchanok Pingaew,2 Chanin Nantasenamat,3 Supaluk Prachayasittikul,3 Somsak Ruchirawat,4,5 Virapong Prachayasittikul1 1Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 2Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand; 3Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 4Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 5Chulabhorn Graduate Institute, Bangkok, Thailand Purpose: Estrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni complexes of 8-hydroxyquinoline (8HQ and uracil derivatives (4–9 were investigated for their aromatase inhibitory and cytotoxic activities. Methods: The aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5 using 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Results: Only Cu complexes (6 and 9 exhibited aromatase inhibitory effect with IC50 0.30 and 1.7 µM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6, as well as free ligand 8HQ, exhibited activity with IC50 range 0.74–6.27 µM. Conclusion: Cu complexes (6 and 9 were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer

  10. Tumor tissue levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and outcome following adjuvant chemotherapy in premenopausal lymph node-positive breast cancer patients: A retrospective study

    We have previously demonstrated that high tumor tissue levels of TIMP-1 are associated with no or limited clinical benefit from chemotherapy with CMF and anthracyclines in metastatic breast cancer patients. Here, we extend our investigations to the adjuvant setting studying outcome after adjuvant chemotherapy in premenopausal lymph node-positive patients. We hypothesize that TIMP-1 high tumors are less sensitive to chemotherapy and accordingly that high tumor tissue levels are associated with shorter survival. From our original retrospectively collected tumor samples we selected a group of 525 pre-menopausal lymph node-positive patients (adjuvant treatment: CMF, 324 patients; anthracycline-based, 99 patients; no adjuvant chemotherapy, 102 patients). TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. TIMP-1 was analyzed as a continuous variable and as a dichotomized one using the median TIMP-1 concentration as a cut point between high and low TIMP-1 groups. We analyzed the benefit of adjuvant CMF and anthracyclines in univariate and multivariable survival models; endpoints were disease-free (DFS) and overall survival (OS). In this selected cohort of high-risk patients, and in the subgroup of patients receiving no adjuvant therapy, TIMP-1 was not associated with prognosis. In the subgroup of patients treated with anthracyclines, when analyzed as a continuous variable we observed a tendency for increasing TIMP-1 levels to be associated with shorter DFS (multivariable analysis, HR 1.75, 95% CI 1.00-3.07, P = 0.05) and a significant association between increasing TIMP-1 and shorter OS in both univariate (HR 3.52, 95% CI 1.54-8.06, P = 0.003) and multivariable analyses (HR 4.19, 95% CI 1.67-10.51, P = 0.002). No statistically significant association between TIMP-1 and DFS was observed in the CMF-treated patients although high TIMP-1 was associated with shorter OS when analyzed as a dichotomized variable (HR 1.64, 95% CI 1.02-2.65, P

  11. Developmental regulation of aromatase activity in the rat hypothalamus

    The brain of all mammalian species studied thus far contain an enzymatic activity (aromatase) that catalyzes the conversion of androgens to estrogens. The activity is highest during prenatal development and contributes to the establishment of sex differences which determine adult gonadotropin secretion patterns and reproductive behavior. The studies presented in this dissertation represent a systematic effort to elucidate the mechanism(s) that control the initiation of and contribute to maintaining rat hypothalamic aromatase activity during pre- and postnatal development. Aromatase enzyme activity was measured by the 3H2O release assay or by traditional estrogen product isolation. Brain aromatase mRNA was detected by hybridization to a cDNA encoding rat aromatase cytochrome P-450. In both males and females the time of puberty was associated with a decline in hypothalamic aromatase activity. This decline may represent a factor underlying the peri-pubertal decrease in the sensitivity to gonadal steroid feedback that accompanies completion of puberty. The results also indicate that androgens regulate brain aromatase levels during both the prepubertal and peri-pubertal stages of sexual development and that this regulation is transiently lost in young adults. Utilizing a hypothalamic organotypic culture system, aromatase activity in vitro was maintained for as long as two days. The results of studies of a variety of hormonal and metabolic regulators suggest that prenatal aromatase activity is regulated by factor(s) that function independently from the classical cyclic AMP and protein kinase C trans-membrane signaling pathways

  12. 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)

    Guo, Jiajia [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Yuan, Yun [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Lu, Danfeng; Du, Baowen [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Xiong, Liang; Shi, Jiangong [State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Yang, Lijuan [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Liu, Wanli [MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Yuan, Xiaohong [School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Zhang, Guolin, E-mail: zhanggl@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China); Wang, Fei, E-mail: wangfei@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China)

    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

  13. 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)

    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: 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 inhibited

  14. Modulation of Δ9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase

    Δ9-Tetrahydrocannabinol (Δ9-THC), a major constituent of marijuana, has been shown to stimulate the growth of MCF-7 breast cancer cells through cannabinoid receptor-independent signaling [Takeda, S., Yamaori, S., Motoya, E., Matsunaga, T., Kimura, T., Yamamoto, I., Watanabe, K., 2008. Δ9-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology 245, 141-146]. Although the growth of MCF-7 cells is known to be stimulated by 17β-estradiol (E2), the interaction of Δ9-THC and E2 in MCF-7 cell growth is not fully clarified so far. In the present study, by using E2-sensitive MCF-7 cells that have expressed cyclooxygenase-2 (COX-2) and cytochrome P450 19 (aromatase), we studied whether or not COX-2 and aromatase are involved in Δ9-THC-mediated MCF-7 cell proliferation. It was shown that Δ9-THC-induced MCF-7 cell growth was inhibited by COX-2 inhibitors and was stimulated by arachidonic acid (a COX substrate). However, the growth of MCF-7 cells induced by Δ9-THC was not stimulated by PGE2, and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE2, suggesting that there is a disconnection between COX-2 (PGE2) and aromatase in Δ9-THC-mediated MCF-7 cell proliferation. On the other hand, Δ9-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ9-THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E2, it is suggested that (1) the growth stimulatory effects of Δ9-THC are mediated by the product(s) of COX-2 except for PGE2, (2) the action of Δ9-THC is modulated by E2, and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ9-THC.

  15. Inhibitors

    ... wrong place in the body. Immune Tolerance Induction (ITI) Therapy: The goal of ITI therapy is to stop the inhibitor reaction from ... body to accept clotting factor concentrate treatments. With ITI therapy, people receive large amounts of clotting factor ...

  16. Assessment of psychosocial factors and distress in women having adjuvant endocrine therapy for breast cancer: the relationship among emotional distress and patient and treatment-related factors

    Ates, Ozturk; Soylu, Cem; Babacan, Taner; Sarici, Furkan; Kertmen, Neyran; Allen, Deborah; Sever, Ali Riza; Altundag, Kadri

    2016-01-01

    Purpose The aims of this study were to comprehensively describe the psychosocial and medical characteristics of women who initiated tamoxifen or aromatase inhibitors for breast cancer and to compare levels of emotional distress according to their medical (tumor demographics, treatment type, treatment duration) and psychosocial (self-esteem, perceived social support, sociodemographic) characteristics. Methods A total of 104 women currently receiving tamoxifen or aromatase inhibitors was recrui...

  17. Tumor tissue levels of tissue inhibitor of metalloproteinases-I (TIMP-I) and outcome following adjuvant chemotherapy in premenopausal lymph node-positive breast cancer patients

    Schrohl, Anne-Sofie; Look, Maxime P.; Gelder, Marion E. Meijer-van;

    2009-01-01

    variable and as a dichotomized one using the median TIMP-1 concentration as a cut point between high and low TIMP-1 groups. We analyzed the benefit of adjuvant CMF and anthracyclines in univariate and multivariable survival models; endpoints were disease-free (DFS) and overall survival (OS). RESULTS: In...... this selected cohort of high-risk patients, and in the subgroup of patients receiving no adjuvant therapy, TIMP-1 was not associated with prognosis. In the subgroup of patients treated with anthracyclines, when analyzed as a continuous variable we observed a tendency for increasing TIMP-1 levels to be...... associated with shorter DFS (multivariable analysis, HR 1.75, 95% CI 1.00-3.07, P = 0.05) and a significant association between increasing TIMP-1 and shorter OS in both univariate (HR 3.52, 95% CI 1.54-8.06, P = 0.003) and multivariable analyses (HR 4.19, 95% CI 1.67-10.51, P = 0.002). No statistically...

  18. Neuroinflammation induces glial aromatase expression in the uninjured songbird brain

    Saldanha Colin J

    2011-07-01

    Full Text Available Abstract Background Estrogens from peripheral sources as well as central aromatization are neuroprotective in the vertebrate brain. Under normal conditions, aromatase is only expressed in neurons, however following anoxic/ischemic or mechanical brain injury; aromatase is also found in astroglia. This increased glial aromatization and the consequent estrogen synthesis is neuroprotective and may promote neuronal survival and repair. While the effects of estradiol on neuroprotection are well studied, what induces glial aromatase expression remains unknown. Methods Adult male zebra finches (Taeniopygia guttata were given a penetrating injury to the entopallium. At several timepoints later, expression of aromatase, IL-1β-like, and IL-6-like were examined using immunohisotchemistry. A second set of zebra birds were exposed to phytohemagglutinin (PHA, an inflammatory agent, directly on the dorsal surface of the telencephalon without creating a penetrating injury. Expression of aromatase, IL-1β-like, and IL-6-like were examined using both quantitative real-time polymerase chain reaction to examine mRNA expression and immunohistochemistry to determine cellular expression. Statistical significance was determined using t-test or one-way analysis of variance followed by the Tukey Kramers post hoc test. Results Following injury in the zebra finch brain, cytokine expression occurs prior to aromatase expression. This temporal pattern suggests that cytokines may induce aromatase expression in the damaged zebra finch brain. Furthermore, evoking a neuroinflammatory response characterized by an increase in cytokine expression in the uninjured brain is sufficient to induce glial aromatase expression. Conclusions These studies are among the first to examine a neuroinflammatory response in the songbird brain following mechanical brain injury and to describe a novel neuroimmune signal to initiate aromatase expression in glia.

  19. Paternal Retrieval Behavior Regulated by Brain Estrogen Synthetase (Aromatase) in Mouse Sires that Engage in Communicative Interactions with Pairmates

    Akther, Shirin; Huang, Zhiqi; Liang, Mingkun; Zhong, Jing; Fakhrul, Azam A. K. M.; Yuhi, Teruko; Lopatina, Olga; Salmina, Alla B.; Yokoyama, Shigeru; Higashida, Chiharu; Tsuji, Takahiro; Matsuo, Mie; Higashida, Haruhiro

    2015-01-01

    Parental behaviors involve complex social recognition and memory processes and interactive behavior with children that can greatly facilitate healthy human family life. Fathers play a substantial role in child care in a small but significant number of mammals, including humans. However, the brain mechanism that controls male parental behavior is much less understood than that controlling female parental behavior. Fathers of non-monogamous laboratory ICR mice are an interesting model for examining the factors that influence paternal responsiveness because sires can exhibit maternal-like parental care (retrieval of pups) when separated from their pups along with their pairmates because of olfactory and auditory signals from the dams. Here we tested whether paternal behavior is related to femininity by the aromatization of testosterone. For this purpose, we measured the immunoreactivity of aromatase [cytochrome P450 family 19 (CYP19)], which synthesizes estrogen from androgen, in nine brain regions of the sire. We observed higher levels of aromatase expression in these areas of the sire brain when they engaged in communicative interactions with dams in separate cages. Interestingly, the number of nuclei with aromatase immunoreactivity in sires left together with maternal mates in the home cage after pup-removing was significantly larger than that in sires housed with a whole family. The capacity of sires to retrieve pups was increased following a period of 5 days spent with the pups as a whole family after parturition, whereas the acquisition of this ability was suppressed in sires treated daily with an aromatase inhibitor. The results demonstrate that the dam significantly stimulates aromatase in the male brain and that the presence of the pups has an inhibitory effect on this increase. These results also suggest that brain aromatization regulates the initiation, development, and maintenance of paternal behavior in the ICR male mice. PMID:26696812

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

    ... Cancer? Breast Cancer Colon/Rectum Cancer Lung Cancer Prostate Cancer Skin Cancer Show All Cancer Types News and Features Cancer Glossary ACS Bookstore Cancer Information Cancer Basics Cancer Prevention & Detection Signs & Symptoms of Cancer Treatments & Side Effects ...

  1. Evolution of Long-Term Adjuvant Anti-hormone Therapy: Consequences and Opportunities. The St. Gallen Prize Lecture

    Jordan, V. Craig; Obiorah, Ifeyinwa; Fan, Ping; Kim, Helen R.; Ariazi, Eric; Cunliffe, Heather; Brauch, Hiltrud

    2012-01-01

    The successful translation of the scientific principles of targeting the breast tumour oestrogen receptor (ER) with the nonsteroidal anti-oestrogen tamoxifen and using extended durations (at least 5-years) of adjuvant therapy, dramatically increased patient survivorship and significantly enhanced a drop in national mortality rates from breast cancer. The principles are the same for the validation of aromatase inhibitors to treat post-menopausal patients but tamoxifen remains a cheap, life-saving medicine for the pre-menopausal patient. Results from the Oxford Overview Analysis illustrate the scientific principle of “longer is better” for adjuvant therapy in pre-menopausal patients. One-year of adjuvant therapy is ineffective at preventing disease recurrence or reducing mortality, whereas five-years of adjuvant tamoxifen reduces recurrence by 50% which is maintained for a further ten-years after treatment stops. Mortality is reduced but the magnitude continues to increase to 30% over a 15-year period. With this clinical database, it is now possible to implement simple solutions to enhance survivorship. Compliance with long-term anti-hormone adjuvant therapy is critical. In this regard, the use of selective serotonin reuptake inhibitors (SSRIs) to reduce severe menopausal side effects may be inappropriate. It is known that SSRIs block the CYP2D6 enzyme that metabolically activates tamoxifen to its potent anti-oestrogenic metabolite, endoxifen. The selective nor-epinephrine reuptake inhibitor, venlafaxine, does not block CYP2D6, and may be a better choice. Nevertheless, even with perfect compliance, the relentless drive of the breast cancer cell to acquire resistance to therapy persists. The clinical application of long-term anti-hormonal therapy for the early treatment and prevention of breast cancer, focused laboratory research on the discovery of mechanisms involved in acquired anti-hormone resistance. Decades of laboratory study to reproduce clinical

  2. The St. Gallen Prize Lecture 2011: evolution of long-term adjuvant anti-hormone therapy: consequences and opportunities.

    Jordan, V Craig; Obiorah, Ifeyinwa; Fan, Ping; Kim, Helen R; Ariazi, Eric; Cunliffe, Heather; Brauch, Hiltrud

    2011-10-01

    The successful translation of the scientific principles of targeting the breast tumour oestrogen receptor (ER) with the nonsteroidal anti-oestrogen tamoxifen and using extended durations (at least 5 years) of adjuvant therapy, dramatically increased patient survivorship and significantly enhanced a drop in national mortality rates from breast cancer. The principles are the same for the validation of aromatase inhibitors to treat post-menopausal patients but tamoxifen remains a cheap, life-saving medicine for the pre-menopausal patient. Results from the Oxford Overview Analysis illustrate the scientific principle of "longer is better" for adjuvant therapy in pre-menopausal patients. One year of adjuvant therapy is ineffective at preventing disease recurrence or reducing mortality, whereas five years of adjuvant tamoxifen reduces recurrence by 50% which is maintained for a further ten years after treatment stops. Mortality is reduced but the magnitude continues to increase to 30% over a 15-year period. With this clinical database, it is now possible to implement simple solutions to enhance survivorship. Compliance with long-term anti-hormone adjuvant therapy is critical. In this regard, the use of selective serotonin reuptake inhibitors (SSRIs) to reduce severe menopausal side effects may be inappropriate. It is known that SSRIs block the CYP2D6 enzyme that metabolically activates tamoxifen to its potent anti-oestrogenic metabolite, endoxifen. The selective norepinephrine reuptake inhibitor, venlafaxine, does not block CYP2D6, and may be a better choice. Nevertheless, even with perfect compliance, the relentless drive of the breast cancer cell to acquire resistance to therapy persists. The clinical application of long-term anti-hormonal therapy for the early treatment and prevention of breast cancer, focused laboratory research on the discovery of mechanisms involved in acquired anti-hormone resistance. Decades of laboratory study to reproduce clinical experience

  3. Cytochrome P450 aromatase expression in human seminoma

    Montanaro Daniela; Aquila Saveria; Romeo Francesco; Rago Vittoria; Andò Sebastiano; Carpino Amalia

    2005-01-01

    Abstract Background The enzyme cytochrome P450 aromatase, catalysing the conversion of androgens into estrogens, has been detected in normal human testicular cells suggesting a physiological role of local estrogen biosynthesis on spermatogenesis control. Estrogens, regulating cell growth and apoptosis, can also be involved in tumorigenesis process, but the possible link between estrogens and testicular neoplastic process is, up to now, scarcely known. This study examined aromatase expression ...

  4. Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition.

    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. PMID:27296990

  5. Aromatase expression is increased in BRCA1 mutation carriers

    Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls. We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women. We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts. Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers

  6. The relationship of bone-tumor-induced spinal cord astrocyte activation and aromatase expression to mechanical hyperalgesia and cold hypersensitivity in intact female and ovariectomized mice.

    Smeester, B A; O'Brien, E E; Michlitsch, K S; Lee, J-H; Beitz, A J

    2016-06-01

    Recently, our group established a relationship between tumor-induced spinal cord astrocyte activation and aromatase expression and the development of bone tumor nociception in male mice. As an extension of this work, we now report on the association of tumor-induced mechanical hyperalgesia and cold hypersensitivity to changes in spinal cord dorsal horn GFAP and aromatase expression in intact (INT) female mice and the effect of ovariectomy on these parameters. Implantation of fibrosarcoma cells produced robust mechanical hyperalgesia in INT animals, while ovariectomized (OVX) females had significantly less mechanical hyperalgesia. Cold hypersensitivity was apparent by post-implantation day 7 in INT and OVX females compared to their saline-injected controls and increased throughout the experiment. The decrease in mechanical hyperalgesia in OVX females was mirrored by significant decreases in spinal astrocyte activity in laminae I-II, III-IV, V-VI and X and aromatase expression in laminae V-VI and X in the dorsal horn of tumor-bearing animals. Administration of the aromatase inhibitor letrozole reduced tumor-induced hyperalgesia in INT females only suggesting that the tumor-induced increase in aromatase expression and its associated increase in spinal estrogen play a role in the development of bone tumor-induced hyperalgesia. Finally, intrathecal (i.t.) administration of 17β-estradiol caused a significant increase in tumor-induced hyperalgesia in INT tumor-bearing females. Since i.t. 17β-estradiol increases tumor pain and ovariectomy significantly decreases tumor pain, as well as spinal aromatase, estrogen may play a critical role in the spinal cord response to the changing tumor environment and the development of tumor-induced nociception. PMID:26995084

  7. Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes

    Jerusalem G

    2014-04-01

    Full Text Available Guy Jerusalem, Andree Rorive, Joelle Collignon Medical Oncology, CHU Sart Tilman Liege, Domaine Universitaire du Sart Tilman, Liege, Belgium Abstract: Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2 therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus. This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease. Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is

  8. Organizing effects of sex steroids on brain aromatase activity in quail.

    Charlotte A Cornil

    Full Text Available Preoptic/hypothalamic aromatase activity (AA is sexually differentiated in birds and mammals but the mechanisms controlling this sex difference remain unclear. We determined here (1 brain sites where AA is sexually differentiated and (2 whether this sex difference results from organizing effects of estrogens during ontogeny or activating effects of testosterone in adulthood. In the first experiment we measured AA in brain regions micropunched in adult male and female Japanese quail utilizing the novel strategy of basing the microdissections on the distribution of aromatase-immunoreactive cells. The largest sex difference was found in the medial bed nucleus of the stria terminalis (mBST followed by the medial preoptic nucleus (POM and the tuberal hypothalamic region. A second experiment tested the effect of embryonic treatments known to sex-reverse male copulatory behavior (i.e., estradiol benzoate [EB] or the aromatase inhibitor, Vorozole on brain AA in gonadectomized adult males and females chronically treated as adults with testosterone. Embryonic EB demasculinized male copulatory behavior, while vorozole blocked demasculinization of behavior in females as previously demonstrated in birds. Interestingly, these treatments did not affect a measure of appetitive sexual behavior. In parallel, embryonic vorozole increased, while EB decreased AA in pooled POM and mBST, but the same effect was observed in both sexes. Together, these data indicate that the early action of estrogens demasculinizes AA. However, this organizational action of estrogens on AA does not explain the behavioral sex difference in copulatory behavior since AA is similar in testosterone-treated males and females that were or were not exposed to embryonic treatments with estrogens.

  9. Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

    Meijer Danielle

    2011-07-01

    Full Text Available Abstract Background Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Estrogen signaling is known to play an important role in proliferation and differentiation of chondrocytes and in growth plate regulation at puberty. Our experiments focus on unraveling the role of estrogen signaling in the regulation of neoplastic cartilage growth and on interference with estrogen signaling in chondrosarcomas in vitro and in vivo. Methods We investigated the protein expression of estrogen receptor alpha (ESR1, androgen receptor (AR, and aromatase in tumor specimens of various chondrosarcoma subtypes, and (primary chondrosarcoma cultures. Dose-response curves were generated of conventional central chondrosarcoma cell lines cultured in the presence of 17β-estradiol, dihydrotestosterone, 4-androstene-3,17 dione, 4-hydroxytamoxifen, fulvestrant and aromatase inhibitors. In a pilot series, the effect of anastrozole (n = 4 or exemestane (n = 2 treatment in 6 chondrosarcoma patients with progressive disease was explored. Results We showed protein expression of ESR1 and aromatase in a large majority of all subtypes. Only a minority of the tumors showed few AR positive cells. The dose-response assays showed no effect of any of the compounds on proliferation of conventional chondrosarcoma in vitro. The median progression-free survival of the patients treated with aromatase inhibitors did not significantly deviate from untreated patients. Conclusions The presence of ESR1 and aromatase in chondrosarcoma tumors and primary cultures supports a possible role of estrogen signaling in chondrosarcoma proliferation. However, our in vitro and pilot in vivo studies have shown no effect of estrogen-signaling inhibition on tumor growth.

  10. Aromatase immunolocalization in human ductuli efferentes and proximal ductus epididymis.

    Carpino, A; Romeo, F; Rago, V

    2004-03-01

    Abstract Cytochrome P450 aromatase is a terminal enzyme that catalyses the conversion of androgens into oestrogens. This study investigated the immunohistochemical localization of aromatase in human efferent ductules and proximal ductus epididymis using a mouse anti-human monoclonal P450arom IgG as primary antibody and a goat anti-mouse biotinylated IgG as secondary antibody. A strong immunoreaction was observed in the epithelial cell cytoplasm of both ductuli efferentes and proximal ductus epididymis, whereas the smooth muscle cells were immunonegative in the two regions. The results show, for the first time in humans, that epithelial cells of ductuli efferentes and proximal caput epididymis express aromatase, suggesting that locally produced oestrogens may have a role in epididymal function. PMID:15032911

  11. The effects of diabetes on placental aromatase activity.

    McRobie, D J; Korzekwa, K R; Glover, D D; Tracy, T S

    1997-01-01

    Diabetes complicates 2-3% of all pregnancies and is associated with an increase in both perinatal morbidity and mortality, though reasons for these adverse outcomes are unknown. Estrogen biosynthesis is a critical factor during pregnancy and is carried out in the placenta via aromatase (cytochrome P450 19A1), which catalyzes the conversion of C-19 androgens to C-18 estrogens. Previous studies have shown that hormones such as insulin-like growth factors and insulin regulate aromatase activity when studied in vitro. Interestingly, levels of these hormones are altered in patients with diabetes. Thus, we hypothesized that the presence of maternal diabetes may alter placental aromatase activity and thus estrogen biosynthesis, possibly serving as one factor in the adverse outcomes of babies born to mothers with diabetes. To this end, we measured the production of 19-hydroxyandrostenedione, 19-oxoadrostenedione and estrone in 30 placental tissues from diabetic patients, using [7-3H]androst-4-ene-3,17-dione as a model substrate for aromatase (P450 19A1). A statistical difference was detected in the percentage of 19-oxoandrostenedione formed between the overt and control groups (P < 0.05). Additionally, NADPH P450-reductase levels were measured in these same tissues to determine whether alterations in this enzyme necessary for aromatase activity could be affected by diabetes. No differences in reductase levels were detected among the patient groups. However, a statistical correlation was found between NADPH P450-reductase activity and the formation velocities of all three estrogen products (P < 0.05). Thus, it appears that the presence of diabetes does not affect placental aromatase activity. PMID:9449216

  12. Effect of a randomized controlled exercise trial on bone outcomes: influence of adjuvant endocrine therapy.

    Knobf, M Tish; Jeon, Sangchoon; Smith, Barbara; Harris, Lyndsay; Kerstetter, Jane; Thompson, A Siobhan; Insogna, Karl

    2016-02-01

    Bone loss is a significant clinical problem for female cancer survivors (FCS) and increases fracture risk. The aim of the Yale Fitness Intervention Trial (Yale FIT) was to determine the effects of a 12-month aerobic-resistance exercise intervention compared to a home-based physical activity group on bone outcomes [bone mineral density (BMD)] and biomarkers bone turnover). Early postmenopausal FCS (N = 154) were randomized to the exercise intervention (3 times/week) or to a home-based physical activity group. Calcium (1200 mg) and Vitamin D (400 IU) supplements were provided to both groups. BMD was measured at baseline and 12 months. No significant difference in BMD was observed for the exercise vs home-based group. However, subjects on Tamoxifen or no endocrine therapy did not significantly lose BMD, with the exception of the femoral neck (FN). In contrast subjects on aromatase inhibitors (AIs) had significant BMD loss at all sites. The majority of subjects had sufficient serum levels of Vitamin D (>20 ng/mL) but there was significantly less bone loss in subjects in the 20-29 ng/mL range at the LS (p = 0.01), hip (p = 0.03), and GT (p = 0.008) compared to lower or higher levels. Exercise stimulates bone remodeling but the intervention was not superior for BMD outcomes at one year. The dose of the osteogenic stimulus in the intervention has been effective in preserving BMD in healthy postmenopausal women but it may be inadequate for survivors with chemotherapy-induced menopause and for those on adjuvant AI therapy. PMID:26850265

  13. [Influenza vaccine and adjuvant].

    Nakayama, Tetsuo

    2011-01-01

    Adjuvant is originated from the Latin word "adjuvare" which means "help" in English to enhance the immunological responses when given together with antigens. The beginning of adjuvant was mineral oil which enhanced the immune response when it was given with inactivated Salmonella typhimurium. Aluminium salt was used to precipitate diphtheria toxoid and increased level of antibody response was demonstrated when administered with alum-precipitated antigens. Since 1930, aluminium salt has been used as DTaP (diphtheria-tetanus-acellular pertussis vaccine) adjuvant. Many candidates were tested for adjuvant activity but only aluminum salt is allowed to use for human vaccines. New adjuvant MF59, oil-in-water emulsion type, was developed for influenza vaccine for elderly (Fluad) and series of AS adjuvant are used for hepatitis B, pandemic flue, and human papiloma virus vaccines. Oil-adjuvanted influenza pandemic vaccines induced higher antibody response than alum-adjuvanted vaccine with higher incidence of adverse events, especially for local reactions. Alum-adjuvanted whole virion inactivated H5N1 vaccine was developed in Japan, and it induced relatively well immune responses in adults. When it applied for children, febrile reaction was noted in approximately 60% of the subjects, with higher antibodies. Recent investigation on innate immunity demonstrates that adjuvant activity is initiated from the stimulation on innate immunity and/or inflammasome, resulting in cytokine induction and antigen uptake by monocytes and macrophages. The probable reason for high incidence of febrile reaction should be investigated to develop a safe and effective influenza vaccine. PMID:22129866

  14. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex is...

  15. ADJUVANTS IN MODERN VACCINOLOGY

    Belozersky V. I.

    2013-12-01

    Full Text Available A concept of adjuvants and their story of creation ischaracterized in the article. They’re presented thevarious types of non-specific stimulators of immunesysteme, thier excipients and classification. They’redescribed basic properties of adjuvant systems, their significant advantages and disadvantages. Particular attention is paid to the numerous antigen delivery systems, including alive vectors, nanoparticles, bacterial toxins, etc. They’re considered non-specific stimulators mechanisms of action on immune system and theirinteraction with antigens. They’re given examples of different adjuvants in licensed vaccines use.

  16. Second malignancies after breast cancer: The impact of adjuvant therapy

    Dong, Chunhui; Chen, Ling

    2014-01-01

    Second malignant neoplasms (SMNs) are potentially life-threatening late sequelae of the adjuvant therapy for breast cancer (BC). The increased risk of SMNs is associated with adjuvant chemotherapy (development of secondary acute myeloid leukemia and myelodysplastic syndrome) and hormonal therapy (risk of uterine cancer secondary to tamoxifen treatment). Previous studies have demonstrated an increased risk of SMNs associated with alkylating agents, topoisomerase-II inhibitors, granulocyte-stim...

  17. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice

    Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk. In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. The animals were given celecoxib at 1500 ppm or aspirin at 200 ppm by oral administration with androstenedione injection. Our results showed that both COX inhibitors could suppress the cancer xenograft growth without changing the plasma estrogen level. Protein expression of ERα, COX-2, Cyclin A, and Bcl-xL were reduced in celecoxib-treated tumor samples, whereas only Bcl-xL expression was suppressed in those treated with aspirin. Among the breast cancer-related miRNAs, miR-222 expression was elevated in samples treated with celecoxib. Further studies in culture cells verified that the increase in miR-222 expression might contribute to ERα downregulation but not the growth deterrence of cells. Overall, this study suggested that both celecoxib and aspirin could prevent breast cancer growth by regulating proteins in the cell cycle and apoptosis without blocking estrogen synthesis. Besides, celecoxib might affect miR expression in an undesirable fashion

  18. ADJUVANTS IN MODERN VACCINOLOGY

    Belozersky V. I; Zhdamarova L.A.; Yelyseyeva I. V; Babych Ye. M.; Isaenko Ye. Yu.; Kolpak S. A

    2013-01-01

    A concept of adjuvants and their story of creation ischaracterized in the article. They’re presented thevarious types of non-specific stimulators of immunesysteme, thier excipients and classification. They’redescribed basic properties of adjuvant systems, their significant advantages and disadvantages. Particular attention is paid to the numerous antigen delivery systems, including alive vectors, nanoparticles, bacterial toxins, etc. They’re considered non-specific stimulators mechanisms of a...

  19. Differential expression of genes for aromatase and estrogen receptor during the gonadal development in chicken embryos.

    Nakabayashi, O; Kikuchi, H; Kikuchi, T; Mizuno, S

    1998-04-01

    In birds, differentiation of embryonic gonads is not as strictly determined by the genetic sex as it is in mammals, and can be influenced by early manipulation with a sex steroid hormone. Thus administration of an aromatase inhibitor induces testis development in the genetic female, and administration of estrogen induces a left ovotestis in the genetic male embryo. Another feature of avian gonadogenesis is that only the left ovary develops in most species. Molecular mechanisms underlying these features at the level of gene expression have not been elucidated. In this paper, we present evidence that a gene for aromatase cytochrome P-450, an enzyme required for the last step in the synthesis of estradiol-17beta, is expressed in medullae of the left and right gonads of a female chicken embryo, but not in those of a male chicken embryo, and that an estrogen receptor gene is expressed only in epithelium (and cortex later, in the female) of the left, not the right, gonad of both sexes, but the expression in the male left gonad is temporary and restricted to an early stage of development. Differential expression of these two genes serves well to explain the above features of gonadal development in birds. Furthermore, in ovo administration of estradiol-17beta from the 5th to the 14th day of incubation does not cause expression of the estrogen receptor gene in the right gonad of chicken embryos of either sex, suggesting that the absence of expression of the estrogen receptor gene in the right gonad is not the result of down-regulation, but may be regarded as an important cause of the unilateral ovarian development. PMID:9584834

  20. The ferrous-oxy complex of human aromatase

    In this communication, we document the self-assembly of heterologously expressed truncated human aromatase (CYP19) into nanometer scale phospholipids bilayers (Nanodiscs). The resulting P450 CYP19 preparation is stable and can tightly associate with the substrate androstenedione to form a nearly complete high-spin ferric protein. Ferrous CYP19 in Nanodiscs was mixed anaerobically in a rapid-scan stopped-flow with atmospheric dioxygen and the formation of the ferrous-oxy complex observed. First order decay of the oxy-complex to release superoxide and regenerate the ferric enzyme was monitored kinetically. Surprisingly, the ferrous-oxy complex of aromatase is more stable than that of hepatic CYP3A4, opening the path to precisely determine the biochemical and biophysical properties of the reaction cycle intermediates in this important human drug target

  1.   Tumor tissue levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and survival following adjuvant chemotherapy in pre-menopausal lymph node-positive breast cancer patients (N=525)

    Rasmussen, Anne-Sofie Schrohl; Look, Maxime P.; Meijer-van Gelder, Marion E.;

    ) suggesting that TIMP-1 may be a predictive marker in breast cancer patients. Purpose: This study investigates the association of tumor tissue TIMP-1 levels with response to adjuvant chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil) or an anthracycline-containing regimen. Patients and...... Predictive markers are needed to guide planning of adjuvant therapy for patients with breast cancer. We have recently shown that high tumor tissue levels of TIMP-1 are associated with decreased response to chemotherapy in metastatic breast cancer patients (Schrohl et al, Clin Cancer Res, 2006...

  2. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    Gorrochategui, Eva; Pérez-Albaladejo, Elisabet [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Casas, Josefina [Department of Biomedicinal Chemistry, IQAC–CSIC, 08034 Barcelona, Catalonia (Spain); Lacorte, Sílvia, E-mail: slbqam@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Porte, Cinta, E-mail: cinta.porte@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain)

    2014-06-01

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  3. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  4. Cytochrome P450 aromatase expression in human seminoma

    Montanaro Daniela

    2005-12-01

    Full Text Available Abstract Background The enzyme cytochrome P450 aromatase, catalysing the conversion of androgens into estrogens, has been detected in normal human testicular cells suggesting a physiological role of local estrogen biosynthesis on spermatogenesis control. Estrogens, regulating cell growth and apoptosis, can also be involved in tumorigenesis process, but the possible link between estrogens and testicular neoplastic process is, up to now, scarcely known. This study examined aromatase expression in human seminoma, which is the most common germ cell tumour of the testis. Methods The tumour-bearing testes were obtained from 20 patients with classic seminoma undergoing to therapeutic orchidectomy. Paraffin embedded tissues were processed for immunohistochemistry using a mouse monoclonal antibody generated against human placental cytochrome P450 arom, as primary antibody, and a biotinylated goat-anti-mouse IgG, as secondary antibody. Furthermore, Western blot analysis of seminoma extracts was carried out. Results Intense P450 arom immunoreactivity was observed in the seminoma cells and Western blot analysis confirmed the immunodetection. A strong immunostaining was also detected in cells of intratubular germ cell neoplasia (IGCN, adjacent to seminoma. Conclusion The present study demonstrated, for the first time in human, aromatase expression in neoplastic cells of seminoma suggesting a relation between local estrogen biosynthesis and germ cell tumorigenesis. The P450 arom immunolocalization in the cells of IGCN, representing the common precursor of most germ cell tumors, seems to support these findings.

  5. Synthesis of highly-labeled with tritium steroid hormones and their use for estimation of aromatase activity

    Highly-labeled steroids - progesterone, estradiol, and androsterone are synthesized. They are used for determination of aromatase activity in different pathologies. It is shown that high activity of aromatase in endometrium in patients with endometrium neoplasms without myome deteriorates disease prognosis. At the same time high aromatase activity in endometrium in patients with endometrium neoplasms with myome has frequently opportune result

  6. ERM immersion vaccination and adjuvants

    Skov, J.; Chettri, J. K.; Jaafar, R. M.;

    2015-01-01

    Two candidate adjuvants were tested with a commercial ERM dip vaccine (AquaVac™ Relera, MSD Animal Health) for rainbow trout in an experimental design compatible with common vaccination practices at farm level, i.e. immersion of fish in vaccine (±adjuvant) for 30 s. The adjuvants were the...

  7. Aromatase Expression in the Hippocampus of AD Patients and 5xFAD Mice

    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

  8. Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study

    Colleoni, Marco; Giobbie-Hurder, Anita; Regan, Meredith M;

    2011-01-01

    Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged...... overall survival (OS) compared with tamoxifen monotherapy....

  9. Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test.

    Muth-Köhne, Elke; Westphal-Settele, Kathi; Brückner, Jasmin; Konradi, Sabine; Schiller, Viktoria; Schäfers, Christoph; Teigeler, Matthias; Fenske, Martina

    2016-07-01

    The Fish Sexual Development Test (FSDT) is a non-reproductive test to assess adverse effects of endocrine disrupting chemicals. With the present study it was intended to evaluate whether gene expression endpoints would serve as predictive markers of endocrine disruption in a FSDT. For proof-of-concept, a FSDT according to the OECD TG 234 was conducted with the non-steroidal aromatase inhibitor fadrozole (test concentrations: 10μg/L, 32μg/L, 100μg/L) using zebrafish (Danio rerio). Gene expression analyses using quantitative RT-PCR were included at 48h, 96h, 28days and 63days post fertilization (hpf, dpf). The selection of genes aimed at finding molecular endpoints which could be directly linked to the adverse apical effects of aromatase inhibition. The most prominent effects of fadrozole exposure on the sexual development of zebrafish were a complete sex ratio shift towards males and an acceleration of gonad maturation already at low fadrozole concentrations (10μg/L). Due to the specific inhibition of the aromatase enzyme (Cyp19) by fadrozole and thus, the conversion of C19-androgens to C18-estrogens, the steroid hormone balance controlling the sex ratio of zebrafish was altered. The resulting key event is the regulation of directly estrogen-responsive genes. Subsequently, gene expression of vitellogenin 1 (vtg1) and of the aromatase cyp19a1b isoform (cyp19a1b), were down-regulated upon fadrozole treatment compared to controls. For example, mRNA levels of vtg1 were down-regulated compared to the controls as early as 48 hpf and 96 hpf. Further regulated genes cumulated in pathways suggested to be controlled by endocrine mechanisms, like the steroid and terpenoid synthesis pathway (e.g. mevalonate (diphospho) decarboxylase (mvd), lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase; lss), methylsterol monooxygenase 1 (sc4mol)) and in lipid transport/metabolic processes (steroidogenic acute regulatory protein (star), apolipoprotein Eb (apoEb)). Taken together

  10. Adjuvant Treatment for Ampullary Cancer

    Richard Kim; John Chabot; Muhammad Wasif Saif

    2011-01-01

    Ampullary cancer is an uncommon tumor and tends to have a better prognosis than pancreatic cancer. However, one half of patients will die from recurrent disease suggesting the need for effective adjuvant therapy. Currently, there is lack of randomized trials to guide the use of adjuvant therapy in ampullary cancer. At the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, the largest trial (Abstract #4006) evaluating adjuvant treatment of ampullary cancer was presented.

  11. Adjuvant Treatment for Ampullary Cancer

    Richard Kim

    2011-07-01

    Full Text Available Ampullary cancer is an uncommon tumor and tends to have a better prognosis than pancreatic cancer. However, one half of patients will die from recurrent disease suggesting the need for effective adjuvant therapy. Currently, there is lack of randomized trials to guide the use of adjuvant therapy in ampullary cancer. At the 2011 American Society of Clinical Oncology (ASCO Annual Meeting, the largest trial (Abstract #4006 evaluating adjuvant treatment of ampullary cancer was presented.

  12. Adjuvant Therapy Trials.

    Ursem, Carling; Van Loon, Katherine; Venook, Alan

    2016-01-01

    In 2015, ramucirumab and TAS-102 became the 10th and 11th drugs approved by the Food and Drug administration for the treatment of patients with colorectal cancer, not counting leucovorin, and yet only 3 agents, 5-fluorouracil, capecitabine, and oxaliplatin, have proven benefit in adjuvant treatment. In fact, there have been no additions (and 1 subtraction levamisole) to our arsenal of therapies for patients with stages II and III colon cancer for more than a decade. How did we get here? Are we stuck? And how do we move forward? PMID:27341598

  13. Psychosocial factors related to non-persistence with adjuvant endocrine therapy among women with breast cancer: the Breast Cancer Quality of Care Study (BQUAL).

    Hershman, Dawn L; Kushi, Lawrence H; Hillyer, Grace Clarke; Coromilas, Ellie; Buono, Donna; Lamerato, Lois; Bovbjerg, Dana H; Mandelblatt, Jeanne S; Tsai, Wei-Yann; Zhong, Xiaobo; Jacobson, Judith S; Wright, Jason D; Neugut, Alfred I

    2016-05-01

    Non-adherence to adjuvant endocrine therapy (ET) for breast cancer (BC) is common. Our goal was to determine the associations between psychosocial factors and ET non-persistence. We recruited women with BC receiving care in an integrated healthcare system between 2006 and 2010. Using a subset of patients treated with ET, we investigated factors related to ET non-persistence (discontinuation) based on pharmacy records (≥90 days gap). Serial interviews were conducted at baseline and every 6 months. The Functional Assessment of Cancer Therapy (FACT), Medical Outcomes Survey, Treatment Satisfaction Questionnaire (TSQM), Impact of Events Scale (IES), Interpersonal Processes of Care measure, and Decision-making beliefs and concerns were measured. Multivariate models assessed factors associated with non-persistence. Of the 523 women in our final cohort who initiated ET and had a subsequent evaluation, 94 (18 %) were non-persistent over a 2-year follow-up. The cohort was primarily white (74.4 %), stage 1 (60.6 %), and on an aromatase inhibitor (68.1 %). Women in the highest income category had a lower odds of being non-persistent (OR 0.43, 95 % CI 0.23-0.81). Quality of life and attitudes toward ET at baseline were associated with non-persistence. At follow-up, the FACT, TSQM, and IES were associated with non-persistence (p intrusive/avoidant thoughts were more likely to be non-persistent. Interventions to enhance the psychosocial well-being of patients should be evaluated to increase adherence. PMID:27086286

  14. Correlation between aromatase expression in the eutopic endometrium of symptomatic patients and the presence of endometriosis

    Maia Jr H

    2012-02-01

    Full Text Available Hugo Maia Jr1,2, Clarice Haddad1,2, Julio Casoy11CEPARH, 2Itaigara Memorial Day Hospital, Salvador, Bahia, BrazilObjective: To investigate whether aromatase expression in the eutopic endometrium correlates with the presence and severity of endometriosis in patients with infertility and/or dysmenorrhea undergoing laparoscopy and hysteroscopy.Patients: The study involved 106 patients of reproductive age with symptoms of dysmenorrhea and infertility. Sixteen endometriosis-free asymptomatic patients were used as a control group.Methods: Concomitant laparoscopy and hysteroscopy was carried out in all cases. An endometrial biopsy was taken to determine aromatase p450 expression by immunohistochemistry. Endometriosis was staged according to the American Society of Reproductive Medicine classification.Results: Endometriosis was diagnosed by laparoscopy in 92/106 symptomatic patients. In this group, aromatase expression was detected in the eutopic endometrium of 66/92 patients with endometriosis (72% and in 13/14 (95% patients in the symptomatic, endometriosis-free group (P = 0.09. Aromatase expression was not detected in any patients from the control group. In the endometriosis group, aromatase expression was detected in the eutopic endometrium of 28/45 patients (62% with American Society of Reproductive Medicine classification stage 1 of the disease, in 11/14 patients (78% with stage II, 14/20 patients (70% with stage III, and in 12/13 patients (92% with stage IV; however, the difference was only statistically significant between stages I and IV (P = 0.04.Conclusion: Aromatase expression in the endometrium was associated with the presence of dysmenorrhea and infertility irrespective of the presence of endometriosis. When endometriosis was present, however, there was a tendency for aromatase expression to be positively correlated with dysmenorrhea severity.Keywords: aromatase, endometrium, endometriosis, Cox-2, dysmenorrhea

  15. Sex Differences in Brain Aromatase Activity: Genomic and Non-Genomic Controls

    JacquesBalthazart; NobuhiroHarada; AnneT.M.Konkle; CornelliaVoigt; GregoryFBall

    2011-01-01

    Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months), brain aromatase activity and transcription are markedly (4-6 fold) increased by genomic actions of se...

  16. Effects of aromatase inhibition on spatial working memory and hippocampal astrocyte numbers

    José I. Arias; Héctor González-Pardo; Nélida M. Conejo; Jorge L. Arias

    2012-01-01

    Sex hormones are known to induce the sexual differentiation of the brain during early development in mammals. Testosterone secreted by males already during gestation is classically believed to contribute to brain and behavioural sexual differentiation thanks to its conversion to estradiol by the enzyme aromatase. However, there is evidence suggesting that aromatase inhibition may also impair cognitive functions in women receiving hormonal treatment for breast cancer. In order to evaluate the ...

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

    Dickens, Molly J; Cornil, Charlotte; 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, s...

  18. Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk

    Siegelmann-Danieli, N; Buetow, K H

    1999-01-01

    The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat...

  19. Adjuvant therapies for colorectal cancer

    2007-01-01

    The management of colon and rectal cancer has changed dramatically over the last 25 years. The use of adjuvant therapies has become standard practice in locally advanced (stage Ⅲ and selected stage Ⅱ) colorectal cancer. Improved surgical techniques, chemotherapeutics and radiotherapy are resulting in higher cure rates and the development of agents targeting proliferative and angiogenic pathways offer further promise. Here we explore risk factors for local and distant recurrence after resection of colon and rectal cancer, and the role of adjuvant treatments. Discussion will focus on the evidence base for adjuvant therapies utilised in colorectal cancer, and the treatment of sub-groups such as the elderly and stage Ⅱ disease. The role of adjuvant radiotherapy in rectal cancer in reduction of recurrence will be explored and the role and optimal methods for surveillance post-curative resection with or without adjuvant therapy will also be addressed.

  20. Overexpression of aromatase alone is sufficient for ovarian development in genetically male chicken embryos.

    Luke S Lambeth

    Full Text Available Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterised steroidogenic pathway, which is a multi-step process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1 is expressed female-specifically from the time of gonadal sex differentiation. To further explore the role of aromatase in sex determination, we ectopically delivered this enzyme using the retroviral vector RCASBP in ovo. Aromatase overexpression in male chicken embryos induced gonadal sex-reversal characterised by an enlargement of the left gonad and development of ovarian structures such as a thickened outer cortex and medulla with lacunae. In addition, the expression of key male gonad developmental genes (DMRT1, SOX9 and Anti-Müllerian hormone (AMH was suppressed, and the distribution of germ cells in sex-reversed males followed the female pattern. The detection of SCP3 protein in late stage sex-reversed male embryonic gonads indicated that these genetically male germ cells had entered meiosis, a process that normally only occurs in female embryonic germ cells. This work shows for the first time that the addition of aromatase into a developing male embryo is sufficient to direct ovarian development, suggesting that male gonads have the complete capacity to develop as ovaries if provided with aromatase.

  1. Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer

    Erber, Ramona; Gluz, Oleg; Brünner, Nils;

    2015-01-01

    this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which......Taxane-anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In...... status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38-0.986), age <50 years old (HR = 1.682; 95 %CI 1.025-2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809-11.989), and high Ki...

  2. Innate immunity and adjuvants.

    Akira, Shizuo

    2011-10-12

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  3. Purification of human placental aromatase cytochrome P-450 with monoclonal antibody and its characterization

    A simple and efficient method is described for the purification of microsomal aromatase cytochrome P-450 from human placenta. The enzyme was solubilized with Emulgen 913 and sodium cholate and subjected to chromatography on a column of Sepharose 4B couples with a specific monoclonal antibody, followed by hydroxyapatite column chromatography. The specific cytochrome P-450 content of purified aromatase was 13.1 (12-14.8) nmol/mg of protein. Aromatase assays were carried out with reconstituted systems of bovine liver P-450 reductase and dilauroyl-L-α-phosphatidylcholine with [1β-3H,4-14C]androstenedione as substrate. The total recovery of purified aromatase activity was 32.2%, and P-450 recovery was 17.6%. The very high Km value for 16α-hydroxytestosterone aromatization gives a reasonable indication that estriol is not the directly aromatized product in the fetoplacental unit of human pregnancy. The aromatase P-450 was subjected to SDS-polyacrylamide gel electrophoresis in increasing quantities. Silver stain detection techniques indicated a single band having a molecular mass of 55 kDa with greater than 97% purity. The stability analysis showed a half-life of over 4 years on storage at -80C

  4. Are separable aromatase systems involved in hormonal regulation of the male brain

    Hutchison, J.B.; Schumacher, M.; Steimer, T.; Gahr, M. (Institute of Animal Physiology, Babraham, Cambridge (England))

    1990-07-01

    In vitro study of testosterone (T) metabolism shows that formation of estradiol-17 beta (E2) is regionally specific within the preoptic area (POA) of the male ring dove. The POA is known to be involved in the formation of E2 required for specific components of male sexual behavior. Two sub-areas of high aromatase activity, anterior (aPOA) and posterior preoptic (pPOA) areas, have been identified. Aromatase activity is higher in aPOA than in pPOA. The aromatase activity within the aPOA is also more sensitive to the inductive effects of low circulating T, derived from subcutaneous silastic implants, than the enzyme activity in pPOA. Kinetic analysis of preoptic fractions indicates that a similar high-affinity enzyme occurs in both areas (apparent Km less than 14 nM), but the Vmax of aPOA enzyme activity is higher than pPOA. Cells containing estrogen receptors (ER) are localized in areas of high aromatase activity. There is overlap between immunostained cells in the aPOA and in samples containing inducible aromatase activity measured in vitro. Within the aPOA there is a higher density of ER cells in the nucleus preopticus medialis. The pPOA area also contains ER, notably in the nucleus interstitialis, but at a lower density. We conclude that the hormonal regulation of the male preoptic-anterior hypothalamic region, which is a target for the behavioral action of T, involves at least two inducible aromatase systems with associated estrogen receptor cells.

  5. Sex differences in brain aromatase activity: genomic and non-genomic controls

    Jacques eBalthazart

    2011-09-01

    Full Text Available Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months, brain aromatase activity and transcription are markedly (4-6 fold increased by genomic actions of sex steroids. Initial work indicated that the preoptic aromatase activity is higher in males than in females and it was hypothesized that this differential production of estrogen could be a critical factor responsible for the lack of behavioral activation in females. Subsequent studies revealed, however, that this enzymatic sex difference might contribute but is not sufficient to explain the sex difference in behavior. Studies of aromatase activity, immunoreactivity and mRNA concentrations revealed that sex differences observed when measuring enzymatic activity are not necessarily observed when one measures mRNA concentrations. Discrepancies potentially reflect post-translational controls of the enzymatic activity. Aromatase activity in quail brain homogenates is rapidly inhibited by phosphorylation processes. Similar rapid inhibitions occur in hypothalamic explants maintained in vitro and exposed to agents affecting intracellular calcium concentrations or to glutamate agonists. Rapid changes in aromatase activity have also been observed in vivo following sexual interactions or exposure to short-term restraint stress and these rapid changes in estrogen production modulate expression of male sexual behaviors. These data suggest that brain estrogens display most if not all characteristics of neuromodulators if not neurotransmitters. Many questions remain however concerning the mechanisms controlling these rapid changes in estrogen production and their behavioral

  6. Are separable aromatase systems involved in hormonal regulation of the male brain

    In vitro study of testosterone (T) metabolism shows that formation of estradiol-17 beta (E2) is regionally specific within the preoptic area (POA) of the male ring dove. The POA is known to be involved in the formation of E2 required for specific components of male sexual behavior. Two sub-areas of high aromatase activity, anterior (aPOA) and posterior preoptic (pPOA) areas, have been identified. Aromatase activity is higher in aPOA than in pPOA. The aromatase activity within the aPOA is also more sensitive to the inductive effects of low circulating T, derived from subcutaneous silastic implants, than the enzyme activity in pPOA. Kinetic analysis of preoptic fractions indicates that a similar high-affinity enzyme occurs in both areas (apparent Km less than 14 nM), but the Vmax of aPOA enzyme activity is higher than pPOA. Cells containing estrogen receptors (ER) are localized in areas of high aromatase activity. There is overlap between immunostained cells in the aPOA and in samples containing inducible aromatase activity measured in vitro. Within the aPOA there is a higher density of ER cells in the nucleus preopticus medialis. The pPOA area also contains ER, notably in the nucleus interstitialis, but at a lower density. We conclude that the hormonal regulation of the male preoptic-anterior hypothalamic region, which is a target for the behavioral action of T, involves at least two inducible aromatase systems with associated estrogen receptor cells

  7. Xanthones from the Botanical Dietary Supplement Mangosteen (Garcinia mangostana) with Aromatase Inhibitory Activity

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

    2008-01-01

    Twelve xanthone constituents of the botanical dietary supplement, mangosteen (the pericarp of Garcinia mangostina) were screened using a non-cellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5)α-mangostin (8), and γ-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was γ-mangosti...

  8. Adjuvant chemotherapy and cancer cure

    The use of chemotherapy as an adjuvant to surgery and/or radiotherapy is well founded in experimental tumor systems and appears to be effective in patients in some circumstances. It is clear from both clinical and experimental studies that (1) the dose is important, (2) the earlier chemotherapy is started after primary therapy the better, and (3) combination chemotherapy may be more effective than single-agent treatment. The better the estimation of risk of recurrence, the better the assessment of the risk-benefit ratio with adjuvant therapy. Salvage therapy as well as relative risk of recurrence are considerations in the choice of patients to be treated. Finally, some evidence is presented to indicate that alkylating agents may not be necessary in combination regimens for adjuvant therapy if effective antimetabolite combinations are available

  9. Adjuvant Therapy of Pancreatic Cancer

    Chakra P Chaulagain

    2011-07-01

    Full Text Available There is no clear consensus on what type of adjuvant therapy should be used for patients with pancreatic cancer. Chemoradiation is the favored treatment modality by many in the United States while gemcitabine based chemotherapy is favored in Europe. Both of these approaches have been shown by large prospective, randomized trials to improve disease free intervals and in some studies overall survival. This year at the American Society of Clinical Oncology (ASCO Gastrointestinal Cancer Symposium, the randomized phase III study presented by Uesaka et al. from Japan (Abstract #145 represents a newer paradigm of oral adjuvant S-1 chemotherapy in place of the traditional standard of care intravenous gemcitabine in terms of prolonging patients’ survival. Another study by Fan et al. (Abstract #269 examined the value of targeted therapy using erlotinib with adjuvant chemoradiation and chemotherapy. We present the summary of these two studies and discuss the potential impact on our clinical practice on this highly lethal cancer.

  10. Muramyl dipeptide-induced adjuvant arthritis.

    Nagao, S.; Tanaka, A.

    1980-01-01

    Muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine, induced adjuvant arthritis in WKA rats when injected in a water-in-oil emulsion prepared with Freund incomplete adjuvant (Difco), but not when emulsified with Drackeol and Arlacel A.

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

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

    2010-01-01

    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 bi...

  12. Aromatase inhibitor-associated bone loss and its management with bisphosphonates in patients with breast cancer

    Bauer M; Bryce J; Hadji P

    2012-01-01

    M Bauer,1 J Bryce,2 P Hadji11University of Marburg, Marburg, Germany; 2National Cancer Institute, Naples, ItalyAbstract: Postmenopausal women have an increased risk of osteopenia and osteoporosis due to loss of the bone-protective effects of estrogen. Disease-related processes may also contribute to the risk of bone loss in postmenopausal women with breast cancer. One of the most common and severe safety issues associated with cancer therapy for patients with breast cancer is bone loss and th...

  13. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

    Abhinav Iyengar; Dawn Sheppard

    2013-01-01

    A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO) level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no...

  14. A Review and Prospect on Herbicide Adjuvants

    2005-01-01

    The history, present status and future prospects of adjuvants application in herbicides were briefly reviewed. Adjuvants can be separated into two groups, activator adjuvants and utility adjuvants. The former directly enhances the efficacy of a herbicide through increasement of herbicide absorption, spreading, cuticular penetration, rainfastness and retention enhancement, and photodegradation of the herbicide can also be decreased. And the latter is utilized for improving application characteristics, behaviors and physical properties of herbicides and reducing or minimizing unwanted side effects on application.

  15. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors. PMID:26899138

  16. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain

    Anat Biegon

    2012-11-01

    Full Text Available Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking are sexually dimorphic. Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product. Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction.

  17. Adjuvant therapy in pancreatic cancer

    Paula Ghaneh; John Slavin; Robert Sutton; Mark Hartley; John P Neoptolemos

    2001-01-01

    The outlook for patients with pancreatic cancer has been grim. There have been major advances in the surgical treatment of pancreatic csncer, leading to a drsmatic reduction in post-operative mortality from the development of high volume specialized centres. This stimulated the study of adjuvant and neoadjuvant treatments in pancreatic cancer including chemoradiotherapy and chemotherapy. Initial protocols have been based on the original but rather small GITSG study first reported in 1985. There have been two large European trials totalling over 600 patients (EORTC and ESPAC-1) that do not support the use of chemoradiation as adjuvant therapy. A second major finding from the ESPAC-1 trial (541 patients randomized) was some but not conclusive evidence for a survival benefit associated with chemotherapy. A third major finding from the ESPAC-1 trial was that the quality of life was not affected by the use of adjuvant treatments compared to surgery alone.The ESPAC-3 trial aims to assess the definitive use of adjuvant chemotherapy in a randomized controlled trial of 990 patients.

  18. Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

    Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 μM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment

  19. Improving vaccine delivery using novel adjuvant systems.

    Pichichero, Michael E

    2008-01-01

    Adjuvants have been common additions to vaccines to help facilitate vaccine delivery. With advancements in vaccine technology, several adjuvants which activate immune specific responses have emerged. Available data show these adjuvants elicit important immune responses in both healthy and immunocompromised populations, as well as the elderly. Guidelines for the use and licensure of vaccine adjuvants remain under discussion. However, there is a greater understanding of the innate and adaptive immune response, and the realization of the need for immune specific adjuvants appears to be growing. This is a focused review of four adjuvants currently in clinical trial development: ASO4, ASO2A, CPG 7907, and GM-CSF. The vaccines including these adjuvants are highly relevant today, and are expected to reduce the disease burden of cervical cancer, hepatitis B and malaria. PMID:18398303

  20. Effects of Pharmaceuticals Used for Breast Cancer Treatment on Reproduction and Aromatase Activity in a Marine Fish

    Laboratory experiments were conducted with the marine fish cunner (Tautogolabrus adspersus) to evaluate whether four pharmaceuticals used in breast cancer treatment have an impact on reproduction or aromatase activity. Tamoxifen binds to estrogen receptors, while anastrozole, let...

  1. EFFECTS OF INCUBATION TEMPERATURE AND ESTROGEN EXPOSURE ON AROMATASE ACTIVITY IN THE BRAIN AND GONADS OF EMBRYONIC ALLIGATORS

    During embryogenesis, incubation temperature and the hormonal environment influence gonadal differentiation of some reptiles, including all crocodilians. Current evidence suggests that aromatase, the enzyme that converts androgens to estrogens, has a role in sexual differentiatio...

  2. Post-proliferative immature radial glial cells female-specifically express aromatase in the medaka optic tectum.

    Akio Takeuchi

    Full Text Available Aromatase, the key enzyme responsible for estrogen biosynthesis, is present in the brain of all vertebrates. Much evidence has accumulated that aromatase is highly and exclusively expressed in proliferating mature radial glial cells in the brain of teleost fish even in adulthood, unlike in other vertebrates. However, the physiological significance of this expression remains unknown. We recently found that aromatase is female-specifically expressed in the optic tectum of adult medaka fish. In the present study, we demonstrated that, contrary to the accepted view of the teleost brain, female-specific aromatase-expressing cells in the medaka optic tectum represent a transient subset of post-proliferative immature radial glial cells in the neural stem cell lineage. This finding led us to hypothesize that female-specific aromatase expression and consequent estrogen production causes some sex difference in the life cycle of tectal cells. As expected, the female tectum exhibited higher expression of genes indicative of cell proliferation and radial glial maturation and lower expression of an anti-apoptotic gene than did the male tectum, suggesting a female-biased acceleration of the cell life cycle. Complicating the interpretation of this result, however, is the additional observation that estrogen administration masculinized the expression of these genes in the optic tectum, while simultaneously stimulating aromatase expression. Taken together, these results provide evidence that a unique subpopulation of neural stem cells female-specifically express aromatase in the optic tectum and suggest that this aromatase expression and resultant estrogen synthesis have an impact on the life cycle of tectal cells, whether stimulatory or inhibitory.

  3. Adjuvant Therapy of Pancreatic Cancer

    Chakra P Chaulagain; Muhammad Wasif Saif; Goodman, Martin D.; John Ng

    2011-01-01

    There is no clear consensus on what type of adjuvant therapy should be used for patients with pancreatic cancer. Chemoradiation is the favored treatment modality by many in the United States while gemcitabine based chemotherapy is favored in Europe. Both of these approaches have been shown by large prospective, randomized trials to improve disease free intervals and in some studies overall survival. This year at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposiu...

  4. Immunocytochemical and biochemical evidence for aromatase in neurons of the retina, optic tectum and retinotectal pathways in goldfish.

    Gelinas, D; Callard, G V

    1993-12-01

    Using an animal model in which neural aromatase is apparently overexpressed (the goldfish, Carassius auratus) and an anti-human placental antibody which specifically crossreacts with goldfish brain aromatase, aromatase-immunoreactive neuronal cell bodies and fibers have been localized within the retina. These include a subset of horizontal cells, bipolar cells, and amacrine cells of the inner nuclear layer, some fibers of the outer and inner synaptic layers and certain cells of the ganglion cell layer; photoreceptors were never labeled. Some ganglion cell projections to the brain via the optic nerve and optic tract were aromatase-positive, as were small neurons of the stratum periventriculare (SPV) and fibers of two other strata of the optic tectum. Aromatase activity, as measured by [3H]androgen by tissue homogenates and cell cultures, confirmed the presence of aromatase in retina and in brain regions containing the optic tectum. This localization of the rate-limiting enzyme in estrogen biosynthesis suggests that neuroestrogen derived from circulating androgen m ay modulate transmission and integration of visual information important for reproduction in this species. PMID:8680435

  5. In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

    Lykkesfeldt, Anne E; Henriksen, Katrine L; Rasmussen, Birgitte B;

    2009-01-01

    Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. RESULTS: Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from...... TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. CONCLUSION: TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2...... estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. TRIAL REGISTRATION: Sub-study of trial P025 for advanced breast cancer....

  6. Toxicological Risks of Agrochemical Spray Adjuvants: Organosilicone Surfactants May Not Be Safe

    Mullin, Christopher A.; Fine, Julia D.; Reynolds, Ryan D.; Frazier, Maryann T.

    2016-01-01

    Agrochemical risk assessment that takes into account only pesticide active ingredients without the spray adjuvants commonly used in their application will miss important toxicity outcomes detrimental to non-target species, including humans. Lack of disclosure of adjuvant and formulation ingredients coupled with a lack of adequate analytical methods constrains the assessment of total chemical load on beneficial organisms and the environment. Adjuvants generally enhance the pesticidal efficacy and inadvertently the non-target effects of the active ingredient. Spray adjuvants are largely assumed to be biologically inert and are not registered by the USA EPA, leaving their regulation and monitoring to individual states. Organosilicone surfactants are the most potent adjuvants and super-penetrants available to growers. Based on the data for agrochemical applications to almonds from California Department of Pesticide Regulation, there has been increasing use of adjuvants, particularly organosilicone surfactants, during bloom when two-thirds of USA honey bee colonies are present. Increased tank mixing of these with ergosterol biosynthesis inhibitors and other fungicides and with insect growth regulator insecticides may be associated with recent USA honey bee declines. This database archives every application of a spray tank adjuvant with detail that is unprecedented globally. Organosilicone surfactants are good stand alone pesticides, toxic to bees, and are also present in drug and personal care products, particularly shampoos, and thus represent an important component of the chemical landscape to which pollinators and humans are exposed. This mini review is the first to possibly link spray adjuvant use with declining health of honey bee populations. PMID:27242985

  7. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro

    Andersen, Helle Raun; Vinggaard, Anne; Rasmussen, Thomas Høj;

    2002-01-01

    Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides ...... to the natural ligands, the integrated response in the organism might be amplified by the ability of the pesticides to act via several mechanism and the frequent simultaneous exposure to several pesticides.......Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides...... to their frequent use in Danish greenhouses. In addition, the metabolite mercaptodimethur sulfoxide, the herbicide tribenuron-methyl, and the organochlorine dieldrin, were included. Several of the pesticides, dieldrin, endosulfan, methiocarb, and fenarimol, acted both as estrogen agonists and...

  8. Systemic adjuvant therapies in renal cell carcinoma

    Sebastiano Buti; Melissa Bersanelli; Maddalena Donini; Andrea Ardizzoni

    2012-01-01

    Renal cell carcinoma (RCC) is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to d...

  9. Boar seminal immunosuppressor inhibitors development of adjuvant arthritis in rats

    Veselský, Leopold; Železná, Blanka; Stančíková, M.; Svik, K.; Rokyta, R.; Dostál, Jaromír; Jurčovičová, J.

    Zdár nad Sázavou, 2000. s. -. [Symposium českých reprodukčních imunologů s mezinárodní účastí /6./. 26.05.2000-28.05.2000, Zdár nad Sázavou] Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  10. Ligula intestinalis infection is associated with alterations of both brain and gonad aromatase expression in roach (Rutilus rutilus).

    Boulange-Lecomte, C; Geraudie, P; Forget-Leray, J; Gerbron, M; Minier, C

    2011-09-01

    The tapeworm Ligula intestinalis commonly infests roach (Rutilus rutilus) and is responsible for the inhibition of gonad development. In order to better understand the effect of the plerocercoid on fish physiology, and to discriminate parasitization effects from those of endocrine-disrupting compounds (EDC), Cyp19b and Cyp19a aromatase expression was investigated by real-time quantitative polymerase chain reaction (PCR) in brain and gonads of ligulosed roach, caught from a reference site. Data were compared to reproductive and endocrine endpoints previously reported in a larger cohort study (including the sampled population of the present one), such as gonadosomatic index, Fulton index, gonadal histology, plasma sex steroid levels and brain aromatase activity. A decrease in Cyp19b expression in the brain of infected fish was demonstrated, in agreement with the reduction of aromatase activity previously described. In contrast, Cyp19a expression in the gonads appeared to be enhanced in ligulosed fish, in accordance with the presence of immature but differentiated sexual tissues. Together these results show that: (1) L. intestinalis infestation results in an alteration of aromatase expression which, in particular, may have profound effects on the fish brain; and (2) L. intestinalis infection must be considered as a major confounding factor in ecotoxicological studies using aromatase expression as an EDC biomarker. Moreover, the concordance between activity and expression--investigated for the first time in the same population--gives a functional relevance to the transcript aromatase dosage in the brain. Finally, quantitative PCR was confirmed as a sensitive approach, enabling aromatase status to be defined in the poorly developed gonads of ligulosed individuals. PMID:21062527

  11. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs)

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in many different polymers, resins and substrates. Due to their widespread production and use, their high binding affinity to particles, and their lipophilic properties, several PBDE congeners can bioaccumulate in the environment. As a result, PBDEs and their hydroxylated metabolites (OH-PBDEs) have been detected in humans and various wildlife samples, such as birds, seals, and whales. Furthermore, certain OH-PBDEs and their methoxylated derivatives (MeO-PBDEs) are natural products in the marine environment. Recently, our laboratory focused on the possible effects on steroidogenesis of PBDEs and OH-PBDEs, e.g. in the human adrenocortical carcinoma (H295R) cell line indicating that some OH-PBDEs can significantly influence steroidogenic enzymes like CYP19 (aromatase) and CYP17. In the present study, human placental microsomes have been used to study the possible interaction of twenty two OH-PBDEs and MeO-PBDEs with aromatase, the enzyme that mediates the conversion of androgens into estrogens. All OH-PBDE derivates showed significant inhibition of placental aromatase activity with IC50 values in the low micromolar range, while the MeO-PBDEs did not have any effect on this enzyme activity. Enzyme kinetics studies indicated that two OH-PBDEs, 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE47) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47), had a mixed-type inhibition of aromatase activity with apparent Ki/Ki' of 7.68/0,02 μM and 5.01/0.04 μM respectively. For comparison, some structurally related compounds, a dihydroxylated polybrominated biphenyl, which is a natural product (2,2'-dihyroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80)) and its non-bromo derivative were also included in the study. Again inhibition of aromatase activity could be measured, but their potency was significantly less than those observed for the OH-PBDEs. These results show that a wide range of

  12. Neural stem cell sex dimorphism in aromatase (CYP19 expression: a basis for differential neural fate

    Jay Waldron

    2010-11-01

    Full Text Available Jay Waldron1, Althea McCourty1, Laurent Lecanu1,21The Research Institute of the McGill University Health Centre, Montreal, Canada; 2Department of Medicine, McGill University, Quebec, CanadaPurpose: Neural stem cell (NSC transplantation and pharmacologic activation of endogenous neurogenesis are two approaches that trigger a great deal of interest as brain repair strategies. However, the success rate of clinical attempts using stem cells to restore neurologic functions altered either after traumatic brain injury or as a consequence of neurodegenerative disease remains rather disappointing. This suggests that factors affecting the fate of grafted NSCs are largely understudied and remain to be characterized. We recently reported that aging differentially affects the neurogenic properties of male and female NSCs. Although the sex steroids androgens and estrogens participate in the regulation of neurogenesis, to our knowledge, research on how gender-based differences affect the capacity of NSCs to differentiate and condition their neural fate is lacking. In the present study, we explored further the role of cell sex as a determining factor of the neural fate followed by differentiating NSCs and its relationship with a potential differential expression of aromatase (CYP19, the testosterone-metabolizing enzyme.Results: Using NSCs isolated from the subventricular zone of three-month-old male and female Long-Evans rats and maintained as neurospheres, we showed that differentiation triggered by retinoic acid resulted in a neural phenotype that depends on cell sex. Differentiated male NSCs mainly expressed markers of neuronal fate, including ßIII-tubulin, microtubule associated protein 2, growth-associated protein 43, and doublecortin. In contrast, female NSCs essentially expressed the astrocyte marker glial fibrillary acidic protein. Quantification of the expression of aromatase showed a very low level of expression in undifferentiated female NSCs

  13. Novel Adjuvants and Immunomodulators for Veterinary Vaccines

    Heegaard, Peter M. H.; Fang, Yongxiang; Jungersen, Gregers

    2016-01-01

    Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the va...

  14. 21 CFR 178.3300 - Corrosion inhibitors used for steel or tinplate.

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Corrosion inhibitors used for steel or tinplate... AIDS, AND SANITIZERS Certain Adjuvants and Production Aids § 178.3300 Corrosion inhibitors used for steel or tinplate. Corrosion inhibitors may be safely used for steel or tinplate intended for use in,...

  15. Adjuvants: Classification, Modus Operandi, and Licensing

    Apostólico, Juliana de Souza

    2016-01-01

    Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations.

  16. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  17. Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain.

    Cisternas, Carla D; Tome, Karina; Caeiro, Ximena E; Dadam, Florencia M; Garcia-Segura, Luis M; Cambiasso, María J

    2015-10-15

    Aromatase, which converts testosterone in estradiol, is involved in the generation of brain sex dimorphisms. Here we used the "four core genotypes" mouse model, in which the effect of gonadal sex and sex chromosome complement is dissociated, to determine if sex chromosomes influence the expression of brain aromatase. The brain of 16 days old XY mouse embryos showed higher aromatase expression in the stria terminalis and the anterior amygdaloid area than the brain of XX embryos, independent of gonadal sex. Furthermore, estradiol or dihydrotestosterone increased aromatase expression in cultures of anterior amygdala neurons derived from XX embryos, but not in those derived from XY embryos. This effect was also independent of gonadal sex. The expression of other steroidogenic molecules, estrogen receptor-α and androgen receptor was not influenced by sex chromosomes. In conclusion, sex chromosomes determine sex dimorphisms in aromatase expression and regulation in the developing mouse brain. PMID:26231585

  18. Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast

    Estrogen is a mitogenic factor that is implicated in the genesis and progression of breast cancer via its binding to estrogen receptor (ER)-α. Synthesis of estrogen in situ is believed to be catalyzed mainly by aromatase. Previous studies comparing the relative contributions from tumor cells and stromal cells to local estrogen synthesis, as assessed by immunohistochemical analysis, were quite controversial and no consistent relationship was found between the presence of aromatase and any clinicopathologic factor. In addition, previous studies into aromatase gene expression and clinicopathologic factors are limited. We assessed the level of expression of aromatase mRNA, using quantitative real-time RT-PCR, in 162 cases of invasive ductal carcinoma of the breast. Associations between aromatase expression and different clinicopathologic factors were sought. It was found that aromatase mRNA was expressed at significantly higher levels in patients older than 50 years, in those without axillary lymph node involvement, in those with tumor size less than 2 cm, and in ER-α positive tumors. However, no relationship was found between aromatase mRNA expression and any other clinicopathologic factor, including histologic grade and progesterone receptor status. Patients with high levels of expression of aromatase mRNA tended to have a better prognosis than did those patients with low expression. These findings imply that ER-α and aromatase may be coexpressed in endocrine responsive patients. They may also indicate that aromatase expression could be a marker of endocrine responsiveness, and it may have prognostic implications for breast cancer progression

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

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie, E-mail: ebj@mil.au.dk

    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

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

    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 [3H]2O 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. - Highlights:

  1. Glucocorticosteroids: as Adjuvant Therapy for Bacterial Infections

    WONDIM MELKAM

    2015-01-01

    Full Text Available Glucocorticoids (GCs, synthetic analogues of the natural steroid hormones, are well known for their antiinflammatory and immunosuppressive properties in the periphery. They are widely and successfully used in the treatment of autoimmune diseases, chronic inflammation, and transplant rejection. Nowadays, GCs are claimed to have a beneficial role being as adjunct therapy in various infections. Different studies have been conducted to investigate their use as adjuvant therapy for different bacterial infection. This review, therefore, summarizes various bacterial infections for which glucocorticoids are reported to be used as adjuvant therapy, strategies for administration of glucocorticoids, and challenges of using glucocorticoids as adjuvant therapy.

  2. Effects of Nutrition Relevant Mixtures of Phytoestrogens on Steroidogenesis, Aromatase, Estrogen, and Androgen Activity

    Taxvig, Camilla; Engell-Kofoed, Anders Elleby; Sonne-Hansen, Katrine;

    2010-01-01

    Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects on...... steroid hormone production, aromatase activity, estrogenic activity, and for interaction with the androgen receptor. The results show that a mixture of all tested PEs increased estradiol production and decreased testosterone production in H295R human adrenal corticocarcinoma cells, indicating an induced...

  3. Plant Sterols as Dietary Adjuvants in the Reduction of Cardiovascular Risk: Theory and Evidence

    Patch, Craig S; Tapsell, Linda C; Williams, Peter G.; Gordon, Michelle

    2006-01-01

    Plant sterol-enriched foods are an effective dietary adjuvant in reducing cardiovascular risk by lowering total cholesterol and low density lipoprotein-cholesterol (LDL-C) in serum by up to ∼15%. The mechanism of action of plant sterols is different from those of 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) and thus their effect is additive. Combining plant sterols with other dietary components known to reduce cholesterol in a portfolio approach has proven to be most effective f...

  4. Cancer therapy disparity: unequal access to breast cancer therapeutics and drug funding in Canada

    Verma, S.; Sehdev, S.; Joy, A.A.

    2007-01-01

    Adjuvant therapy has made a significant contribution in reducing breast cancer–specific mortality. Standard chemotherapeutics and tamoxifen have been the mainstay treatment for years, but recent clinical evidence supports the use of novel small-molecule therapy and aromatase inhibitor therapy in selected settings, challenging not only the traditional paradigm of breast cancer treatment, but also provincial funding of oncologic care across Canada. The disparity in access to aromatase inhibitor...

  5. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.

  6. Adjuvant interferon treatment for melanoma.

    Agarwala, S S; Kirkwood, J M

    1998-08-01

    After decades of research, the adjuvant therapy of patients with melanoma has recently shown significant survival and relapse-free interval benefit for the intravenous and subcutaneous administration of maximally tolerable dosages of recombinant IFN alpha 2b in a trial conducted by the ECOG (E1684). Despite the toxicity of this therapy, retrospective analyses of its impact upon quality-of-life using Q-TWiST methods and cost-efficacy analyses all argue for the benefit and utility of this intervention, especially for node-positive patients with resectable melanoma at highest risk of relapse. A confirmatory trial has been completed and will mature in the spring of 1998. The impact of lower dosages of IFN, apparent transiently during and for a period of time following treatment has not been sustained with longer follow-up in a number of trials. Current approaches in Europe and North America focus upon refinement of dose and duration of treatment with IFN and their potential interactions with, and comparison with, active specific immunotherapy with vaccines. A recently emerging area of research is the patient with stage IIA melanoma and the potential role of an abbreviated high-dose regimen of IFN alpha in this patient subset. PMID:9759581

  7. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics

    There is concern widely on the increase in human exposure to exogenous (anti)estrogenic compounds. Typical are certain ingredients in cosmetic consumer products such as musks, phthalates and parabens. Monitoring a variety of human samples revealed that these ingredients, including the ones that generally are considered to undergo rapid metabolism, are present at low levels. In this in vitro research individual compounds and combinations of parabens and endogenous estradiol (E2) were investigated in the MCF-7 cell proliferation assay. The experimental design applied a concentration addition model (CA). Data were analyzed with the estrogen equivalency (EEQ) and method of isoboles approach. In addition, the catalytic inhibitory properties of parabens on an enzyme involved in a rate limiting step in steroid genesis (aromatase) were studied in human placental microsomes. Our results point to an additive estrogenic effect in a CA model for parabens. In addition, it was found that parabens inhibit aromatase. Noticeably, the effective levels in both our in vitro systems were far higher than the levels detected in human samples. However, estrogenic compounds may contribute in a cumulative way to the circulating estrogen burden. Our calculation for the extra estrogen burden due to exposure to parabens, phthalates and polycyclic musks indicates an insignificant estrogenic load relative to the endogenous or therapeutic estrogen burden

  8. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection.

    Cohen, P G

    2001-06-01

    In males, aging, health and disease are processes that occur over physiologic time and involve a cascade of hormonal, biochemical and physiological changes that accompany the down-regulation of the hypothalamic-anterior pituitary-testicular axis. As aging progresses there are relative increases of body fat and decreases in muscle mass. The increased adipose tissue mass is associated with the production of a number of newly generated factors. These include aromatase, leptin, PAI-1, insulin resistance, and the dyslipidemias, all of which can lead to tissue damage. Fatty tissue becomes the focal point for study as it represents the intersection between energy storage and mobilization. The increase in adipose tissue is associated with an increase in the enzyme aromatase that converts testosterone to estradiol and leads to diminished testosterone levels that favor the preferential deposition of visceral fat. As the total body fat mass increases, hormone resistance develops for leptin and insulin. Increasing leptin fails to prevent weight gain and the hypogonadal-obesity cycle ensues causing further visceral obesity and insulin resistance. The progressive insulin resistance leads to a high triglyceride-low HDL pattern of dyslipidemia and increased cardiovascular risk. All of these factors eventually contribute to the CHAOS Complex: coronary disease, hypertension, adult-onset diabetes mellitus, obesity and/or stroke as permanent changes unfold. Other consequences of the chronic hypogonadal state include osteopenia, extreme fatigue, depression, insomnia, loss of aggressiveness and erectile dysfunction all of which develop over variable periods of time. PMID:11399122

  9. EGFR-TKIs in adjuvant treatment of lung cancer: to give or not to give?

    Milovancev, Aleksandar; Stojsic, Vladimir; Zaric, Bojan; Kovacevic, Tomi; Sarcev, Tatjana; Perin, Branislav; Zarogoulidis, Konstantinos; Tsirgogianni, Katerina; Freitag, Lutz; Darwiche, Kaid; Tsavlis, Drosos; Zissimopoulos, Athanasios; Stratakos, Grigoris; Zarogoulidis, Paul

    2015-01-01

    Epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs) brought a significant revolution in the treatment of non-small-cell lung cancer (NSCLC). In a short period of time, EGFR-TKIs became the standard of treatment for mutation-positive, advanced stage non-squamous NSCLC. In recent years, second- and third-generation EGFR-TKIs are emerging, further widening the clinical use. However, the question of EGFR-TKIs efficiency in the treatment of early stage NSCLC still remains open. Early clinical trials failed to approve the use of EGFR-TKIs in adjuvant setting. The majority of these early trials were performed in unselected NSCLC populations and without standardized biomarker identification. One should certainly not rely solely on these results and dismiss the use of EGFR-TKIs as adjuvant therapy. Many important questions are still unanswered. Most important issues such as stage heterogeneity (IA–IIIA), timing (after or concomitantly with chemotherapy), and type of administration (monotherapy or combination) need to be answered in near future. Adjuvant TKIs in the treatment of lung cancer might offer significant number of advancements. Having in mind the significant duration of response observed in advance disease setting, there could be place for prolongation of response in adjuvant setting potentially, leading to improvement in survival. TKIs could offer less-toxic adjuvant treatment with better efficiency than chemotherapy. However, there is a chronic lack of randomized controlled trials in this field, leading to inability to draw any scientifically sound conclusion with regard to the adjuvant treatment. For now, the use of EGFR-TKIs outside clinical trial setting is not recommended. The purpose of this review is to evaluate current and available data. PMID:26508876

  10. Review: Adjuvant effects of saponins on animal immune responses

    RAJPUT Zahid Iqbal; HU Song-hua; XIAO Chen-wen; ARIJO Abdullah G.

    2007-01-01

    Vaccines require optimal adjuvants including immunopotentiator and delivery systems to offer long term protection from infectious diseases in animals and man. Initially it was believed that adjuvants are responsible for promoting strong and sustainable antibody responses. Now it has been shown that adjuvants influence the isotype and avidity of antibody and also affect the properties of cell-mediated immunity. Mostly oil emulsions, lipopolysaccharides, polymers, saponins, liposomes, cytokines,ISCOMs (immunostimulating complexes), Freund's complete adjuvant, Freund's incomplete adjuvant, alums, bacterial toxins etc.,are common adjuvants under investigation. Saponin based adjuvants have the ability to stimulate the cell mediated immune system as well as to enhance antibody production and have the advantage that only a low dose is needed for adjuvant activity. In the present study the importance of adjuvants, their role and the effect of saponin in immune system is reviewed.

  11. Systemic adjuvant therapies in renal cell carcinoma.

    Buti, Sebastiano; Bersanelli, Melissa; Donini, Maddalena; Ardizzoni, Andrea

    2012-10-01

    Renal cell carcinoma (RCC) is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to describe the results of past and ongoing phase III clinical trials in this field. We explored all the systemic treatments, including chemotherapy, immunotherapy and targeted drugs while alternative approaches have also been described. Appropriate selection of patients who would benefit from adjuvant therapies remains a crucial dilemma. Although the international guidelines do not actually recommend any adjuvant treatment after radical surgery for RCC, no conclusions have yet been drawn pending the results of the promising ongoing clinical trials with the target therapies. The significant changes that these new drugs have made on advanced disease outcome could represent the key to innovation in terms of preventing recurrence, delaying relapse and prolonging survival after radical surgery for RCC. PMID:25992216

  12. Systemic adjuvant therapies in renal cell carcinoma

    Sebastiano Buti

    2012-10-01

    Full Text Available Renal cell carcinoma (RCC is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to describe the results of past and ongoing phase III clinical trials in this field. We explored all the systemic treatments, including chemotherapy, immunotherapy and targeted drugs while alternative approaches have also been described. Appropriate selection of patients who would benefit from adjuvant therapies remains a crucial dilemma. Although the international guidelines do not actually recommend any adjuvant treatment after radical surgery for RCC, no conclusions have yet been drawn pending the results of the promising ongoing clinical trials with the target therapies. The significant changes that these new drugs have made on advanced disease outcome could represent the key to innovation in terms of preventing recurrence, delaying relapse and prolonging survival after radical surgery for RCC.

  13. Beyond antigens and adjuvants: formulating future vaccines.

    Moyer, Tyson J; Zmolek, Andrew C; Irvine, Darrell J

    2016-03-01

    The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next-generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines. PMID:26928033

  14. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    Payne, Richard; McDonald, David; Byrne, Scott

    2015-10-01

    Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.

  15. The interaction between aromatase, metalloproteinase 2,9 and cd44 in breast cancer A interação entre aromatase, metalloproteinase 2, 9 e cd44 no câncer de mama

    Fábio Bagnoli

    2010-01-01

    Full Text Available OBJECTIVE: This study intends to verify the expression levels and correlation of aromatase, matrix metalloproteinase 2 (MMP-2, matrix metalloproteinase 9 (MMP-9 and CD44 in ductal carcinoma in situ (DCIS and infiltrating ductal carcinoma (IDC when both are found in the same breast. METHODS: One hundred and ten cases were evaluated by tissue microarray (TMA and immunohistochemically screened with anti-aromatase polyclonal antibodies, anti-MMP-2 monoclonal antibodies, anti-MMP-9 policlonal antibodies and anti-CD44 monoclonal antibodies. RESULTS: Aromatase was expressed in IDC and DCIS in 63 (57.3% and 60 (67% of the cases respectively; MMP-2 was similarly expressed in IDC and DCIS in 15 (13.60% cases; MMP-9 was positively expressed in IDC and DCIS in 83 (75.50% and 82 (74.50% cases, respectively; CD44 was positively expressed in IDC and DCIS in 49 (44.50% and 48 (42.60% of the cases, respectively; all of them were highly correlated (pOBJETIVO: O objetivo desse estudo é verificar as expressões e correlações da aromatase, metalloproteinase 2 da matriz (MMP2, metalloproteinase 9 da matriz (MMP-9 e CD44 no carcinoma ductal in situ (CDIS e carcinoma ductal infiltrativo (CDI quando ambos estão presentes simultaneamente na mesma mama. MÉTODOS: Foram avaliados 110 casos pelo método de tissue microarray (TMA e através da utilização de anticorpos policlonais antiaromatase, anticorpos monoclonais anti-MMP-2, anticorpos policlonais anti-MMP-9 e anticorpos monoclonais anti-CD44. RESULTADOS: A aromatase estava expressa de forma positiva no CDI e CDIS em 63 (57,3% e 60 (67% casos, respectivamente. A expressão de MMP-2 estava expressa de forma positiva em 15 (13,6% casos tanto no CDI, quanto no CDIS. A expressão da MMP-9 estava expressa de forma positiva em 83 (75,5% e 82 (74,5% casos de CDI e CDIS, respectivamente. A expressão de CD44 estava expressa de forma positiva em 49 (44,5% e 48 (42,6% casos de CDI e CDIS, respectivamente. Todos eles

  16. Does lipophilicity per se induce adjuvant effects?

    Hansen, Jitka Stilund; Larsen, Søren Thor; Poulsen, Lars K.;

    2007-01-01

    ) or on lung function parameters. Thus, MP did not possess irritant or inflammatory properties, which may be a precursive stimulus for adjuvant effects. Second, mice were exposed to aerosols of MP, 6 or 323 mg/m3, for 1 h followed by a 20-min low-dose ovalbumin (OVA) inhalation. OVA only and OVA + Al......Anthopogenically introduced substances and pollutants are suspected to promote sensitization and development of allergic airway diseases, that is, acting as adjuvants. Lipophilicity may serve as an immunological warning signal, promoting adjuvant effects. Whether the lipophilicity of an inhaled...... compound induces immunomodulatory effects was investigated in a murine inhalation model with the highly lipophilic methyl palmitate (MP) as model substance. First, studies of acute effects following a 1-h exposure of up to 348 mg/m3 MP showed no effects on cell composition in bronchoalveolar lavage (BAL...

  17. Mycophenolate mofetil as adjuvant in pemphigus vulgaris

    Sarma Nilendu

    2007-01-01

    Full Text Available Pemphigus vulgaris (PV is a life threatening autoimmune blistering disease of skin and mucous membranes. Advent of systemic steroids has greatly reduced the mortality rate. However, steroids and adjuvant immunosuppressive therapy are nowadays frequent contributory agents of morbidity and mortality of PV. Mycophenolate mofetil (MMF has been reported to be an effective adjuvant to systemic steroids. It helps in increasing the immunosuppressive effect and minimizing the toxicities by steroid sparing effect. However, its efficacy in refractory cases of PV is not well documented. The lowest possible dose with satisfactory therapeutic efficacy and least side effects is known. We used MMF 1 g/day and systemic steroids in 3 Indian patients with pemphigus vulgaris who were resistant to systemic steroid monotherapy or combination treatment with azathioprine. In our experience, MMF offers an effective adjuvant with minimal side-effects in the treatment of resistant PV.

  18. Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma

    Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial. This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies

  19. Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma

    Fairfax BP

    2012-12-01

    Full Text Available Abstract Background Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC and hepatocellular carcinoma (HCC. Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. Case presentation Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial. Conclusion This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies.

  20. [Adjuvant chemotherapy of adults soft tissue sarcomas].

    Bui-Nguyen, B; Italiano, A; Delva, F; Toulmond, M

    2010-06-01

    The main progress in the management of soft tissue sarcomas have been obtained in the field of local control. Although the main evolutive, vital, risk of these diseases is metastatic dissemination, efficacy of adjuvant chemotherapy remains a controversial issue. Thus, adjuvant chemotherapy cannot be considered as a standard for any situation. The last results of clinical trials, meta-analysis and population studies are presented and discussed in this article. New therapeutic strategies are to be developed to prevent metastases in soft tissue sarcomas. This needs a better understanding of the biology of those tumors, of metastases risk factors and of the determinants of systemic therapies efficacy in these tumors. PMID:20547481

  1. Frequency of Polymorphism in Aromatase Enzyme Coding Gene with Prostate Cancer Risk in North Indian Population

    KH Onsory

    2015-10-01

    Full Text Available Background: A series of biochemical reactions are involved in the endogenous production of estrogens. Their final and rate-limiting step is catalyzed by aromatase belonging to the class XIX of cytochrome P450. CYP19 is a key enzyme for estrogen synthesis in males. It catalyzes the irreversible conversion of androstenedione and testosterone to estrone and estradiol-17β, respectively. Aromatase P450 is present in the endoplasmic reticulum of estrogen-reproducing cells in which it is expressed. The effects of the resulting estrogens are mediated through the estrogen receptor. One of the most important polymorphism, is a C to T variation in exon 7 resulting in an Arg264Cys amino acid exchange, has been shown to be very common in Asia. The purpose of this study was to determine the association of CYP19 gene polymorphism with the prostate cancer risk among the studied population. Methods: PCR-RFLP analysis of CYP19 gene was on 100 prostate cancer patients and an equal number of matching controls. The data was analyzed using the computer software SPSS for windows (version 19. Results: The frequency of CT genotype was higher in patients (37% as compared to controls (21.2% and this incidence was statistically significant (OR, 2.10; 95 % CI, 1.02-4.34; P=0.044. Stratification of patients according to the risk factors, resulted in a slightly improved OR in individuals carrying CT compared to CC genotype (OR, 2.35 95% CI, 1.11-4.96; P=0.024. The TT genotype was not significantly associated with prostate cancer risk (OR, 0.63; 95% CI, 0.16-2.50; P=0.519. Conclusion: It seems that CT genotype is more associated with cancer prostate compare with other genotypes. It appears to be an increased risk of prostate cancer associated with the Arg264Cys substitution in the CYP19 gene.

  2. New insights about the evaluation of human sperm quality: the aromatase example.

    A Saad

    2010-01-01

    Full Text Available Male contribution to the couple's infertility is at first evaluated by the routine examination of semen parameters upon optical microscopy providing valuable information for a rational initial diagnosis and for a clinical management of infertility. But the different forms of infertility defined according to the WHO criteria especially teratozoospermia are not always related to the chromatin structure or to the fertilization capacity. New investigations at the molecular level (transcript and protein could be developed in order to understand the nature of sperm malformation responsible of human infertility and thus to evaluate the sperm quality. The profile analysis of spermatozoal transcripts could be considered as a fingerprint of the past spermatogenic events. The selection of representative transcripts of normal spermatozoa remains complex because a differential expression (increased, decreased or not modified levels of specific transcripts has been revealed between immotile and motile sperm fractions issued from normozoospermic donors. Microarrays tests or real-time quantitative PCR could be helpful for the identification of factors involved in the male infertility. Differences in the expression of specific transcripts have been reported between normal and abnormal semen samples. With the aromatase example, we have noted a negative strong correlation between the amount of transcript and the percentage of abnormal forms especially in presence of head defects. Immunocytochemical procedures using fluorescent probes associated with either confocal microscopy or flow cytometry can be also helpful to proceed with further investigations about the localization of proteins in the compartmentalized spermatozoa or the acrosome reaction. The dual location of aromatase both in the equatorial segment, the mid-piece and the tail could explain the double role of this enzyme in acrosome reaction and motility.

  3. Sex Differences in Brain Aromatase Activity: Genomic and Non-Genomic Controls

    Balthazart, Jacques; Charlier, Thierry D.; Cornil, Charlotte A.; Dickens, Molly J.; Harada, Nobuhiro; Konkle, Anne T. M.; Voigt, Cornelia; Ball, Gregory F.

    2011-01-01

    Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months), brain aromatase activity (AA), and transcription are markedly (four- to sixfold) increased by genomic actions of sex steroids. Initial work indicated that the preoptic AA is higher in males than in females and it was hypothesized that this differential production of estrogen could be a critical factor responsible for the lack of behavioral activation in females. Subsequent studies revealed, however, that this enzymatic sex difference might contribute but is not sufficient to explain the sex difference in behavior. Studies of AA, immunoreactivity, and mRNA concentrations revealed that sex differences observed when measuring enzymatic activity are not necessarily observed when one measures mRNA concentrations. Discrepancies potentially reflect post-translational controls of the enzymatic activity. AA in quail brain homogenates is rapidly inhibited by phosphorylation processes. Similar rapid inhibitions occur in hypothalamic explants maintained in vitro and exposed to agents affecting intracellular calcium concentrations or to glutamate agonists. Rapid changes in AA have also been observed in vivo following sexual interactions or exposure to short-term restraint stress and these rapid changes in estrogen production modulate expression of male sexual behaviors. These data suggest that brain estrogens display most if not all characteristics of neuromodulators if not neurotransmitters. Many questions remain however concerning the mechanisms controlling these rapid changes in estrogen production and their behavioral significance. PMID:22645508

  4. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    Davor Stanić; Sydney Dubois; Hui Kheng Chua; Bruce Tonge; Nicole Rinehart; Malcolm K Horne; Wah Chin Boon

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, in...

  5. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    2010-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Adjuvants for pesticide chemicals. 582.99...

  6. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    2010-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide chemicals. 182.99...

  7. Effectiveness of spray adjuvants on reduction of spray drift

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Five new drift control adjuvants were sele...

  8. Doxorubicin and deracoxib adjuvant therapy for canine splenic hemangiosarcoma: a pilot study.

    Kahn, S Anthony; Mullin, Christine M; de Lorimier, Louis-Philippe; Burgess, Kristine E; Risbon, Rebecca E; Fred, Rogers M; Drobatz, Kenneth; Clifford, Craig A

    2013-03-01

    Canine hemangiosarcoma (HSA) is a highly malignant tumor for which standard chemotherapy has done little to substantially improve survival. Cyclooxygenase-2 (Cox-2) plays a role in the formation, growth, and metastasis of tumors and inhibitors have demonstrated therapeutic benefit with certain canine cancers. In this prospective study, 21 dogs received adjuvant therapy combining the selective Cox-2 inhibitor deracoxib with doxorubicin, following splenectomy for HSA. The combination was well-tolerated with only low-grade gastrointestinal and hematologic toxicities noted. An overall median survival of 150 days (range; 21 to 1506 days) was noted. Although there was no significant difference in survival based upon stage of disease, dogs with stage III HSA (n = 11) had a median survival of 149 days, which appears to be longer than previously reported. Further studies are warranted to evaluate the potential benefit of Cox-2 inhibitors in the treatment of canine HSA. PMID:23997259

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

    Diamond Michael P; Casper Robert F; Mitwally Mohamed FM

    2005-01-01

    Abstract 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...

  10. Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita; Tod J Merkel

    2014-01-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax a...

  11. Dietary Polyphenols Suppress Elevated Levels of Proinflammatory Mediators and Aromatase in the Mammary Gland of Obese Mice

    Subbaramaiah, Kotha; Sue, Erika; Bhardwaj, Priya; Du, Baoheng; Hudis, Clifford A.; Giri, Dilip; Kopelovich, Levy; Zhou, Xi Kathy; Dannenberg, Andrew J.

    2013-01-01

    In postmenopausal women, obesity is a risk factor for the development of hormone receptor-positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity-inflammation-aromatase axis. This obesity induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose...

  12. Farnesoid X Receptor, through the Binding with Steroidogenic Factor 1-responsive Element, Inhibits Aromatase Expression in Tumor Leydig Cells*

    Catalano, Stefania; Malivindi, Rocco; Giordano, Cinzia; Gu, Guowei; Panza, Salvatore; Bonofiglio, Daniela; Lanzino, Marilena; Sisci, Diego; Panno, Maria Luisa; Andò, Sebastiano

    2009-01-01

    The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. It is expressed in the liver and the gastrointestinal tract, but also in several non-enterohepatic tissues including testis. Recently, FXR was identified as a negative modulator of the androgen-estrogen-converting aromatase enzyme in human breast cancer cells. In the present study we detected the expression of FXR in Leydig normal and tumor cell lines and in rat testes tissue. ...

  13. Brain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner

    Dickens, M.J.; Balthazart, J.; Cornil, C. A.

    2012-01-01

    Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in the control of sexual behaviour, sexual or stressfull stimuli induce respectively a rapid inhibition or increase in preoptic aromatase activity (AA). Here, we tested quail that were either non-stressed or acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with s...

  14. New generation adjuvants--from empiricism to rational design.

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability. PMID:26022561

  15. The effect of oral contraceptives on aromatase and Cox-2 expression in the endometrium of patients with idiopathic menorrhagia or adenomyosis

    Maia H Jr

    2013-06-01

    Full Text Available Hugo Maia Jr,1–3 Clarice Haddad,3 Nathaniel Pinheiro,4 Julio Casoy31School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil; 2Itaigara Memorial Day Hospital, Salvador, Bahia, Brazil; 3CEPARH (Centro de Pesquisas e Assistência em Reprodução Humana, Salvador, Bahia, Brazil; 4Imagepat Pathology Laboratory, Federal University of Bahia, Salvador, Bahia, BrazilBackground: The presence of aromatase and cyclooxygenase-2 (Cox-2 expression was investigated in the endometrium of patients with idiopathic menorrhagia or adenomyosis. The effect of oral contraceptives administered in extended regimens on the endometrial expression of these enzymes was also investigated.Methods and results: Aromatase expression was detected by immunohistochemistry in the endometrial glands and stroma of patients with idiopathic menorrhagia or adenomyosis. There was no difference in the percentage of aromatase expression in the endometria between the two groups. The mean intensity of Cox-2 expression in the glandular epithelium also did not differ significantly between the groups. Among the patients using oral contraceptives in extended regimens, the relative decrease in both aromatase and Cox-2 expression was significantly greater in amenorrheic patients compared with those who were experiencing breakthrough bleeding.Conclusion: The presence of aromatase expression in the endometrium is associated with the occurrence of menorrhagia, irrespective of the presence of adenomyosis. Continuous expression of these enzymes in the endometrium of users of oral contraceptives in extended regimens is positively associated with the presence of breakthrough bleeding. This suggests a role for both aromatase and Cox-2 in the etiology of abnormal uterine bleeding.Keywords: menorrhagia, aromatase, endometrium, Cox-2, adenomyosis

  16. The adjuvancy of silicones: dependency on compartmentalization.

    Klykken, P C; White, K L

    1996-01-01

    Studies have been conducted in mice (B6C3F1) and rats (Sprague Dawley, Fischer 344) to investigate the adjuvancy potential of silicone mammary gel and the low molecular weight silicone fluid, octamethylcyclotetrasiloxane (D4). Dependent on the experimental conditions employed, a divergent data profile emerges. If the antigen (bovine serum albumin, BSA) is emulsified with either the gel or the D4 prior to intramuscular immunization, an amplified anti-BSA IgG antibody response, as measured by multipoint ELISA methodology, is noted over the 8 week measurement period. In parallel studies, a variety of non-silicone personal care ingredients (lanolin, white mineral oil, isopropyl palmitate) were also capable of amplifying this humoral response relative to the non-adjuvant phosphate buffered saline control. These observations are consistent with the empirical knowledge that hydrophobic substances tend to augment immune responses. However, under conditions in which the antigen is not blended with the silicone prior to immunization, normal immune responses are noted. In short (10 day) and long (180 day) term gel implant studies, the optimal IgM and IgG antibody responses, as determined in the antibody forming cell assay, were equivalent between the gel implanted and control animals. Moreover, under similar exposure conditions, no adjuvancy was noted in the three Host Resistance models (B16F10 Melanoma, Listeria monocytogenes, and Streptococcus pneumoniae) tested. Antibody forming cell studies conducted after 28 days of oral or inhalation exposure to D4 have also yielded responses similar to the non-silicone exposed vehicle controls. Collectively, these data suggest that in the absence of premixing the antigen with the silicone test material, there does not appear to be any silicone induced adjuvant response. PMID:8565549

  17. Impact of adjuvant chemotherapy for gliomatosis cerebri

    Gliomatosis cerebri (GC) is characterized by a diffuse infiltration of tumor cells throughout CNS, however, few details are available about the chemotherapeutic effect on GC. The aim of this study was to investigate its clinical course and to determine the efficacy of chemotherapy for GC. Between Jan. 1999 and Dec. 2004, 37 GC patients were diagnosed by biopsy and treated with radiotherapy in a single institution. To determine the efficacy of chemotherapy for GC, we retrospectively reviewed their clinical courses. The study cohort was divided into 2 groups, those with and without receiving post-radiotherapy adjuvant chemotherapy such as temozolomide or nitrosourea-based chemotherapy. Nineteen patients with adjuvant chemotherapy were assigned to the chemotreatment group and 18 with radiotherapy alone were assigned to the control group. Mean survival for chemotreatment group and control group were 24.2 and 13.1 months, respectively (p = 0.045). Time to progression for these groups were 16.0 and 6.0 months, respectively (p = 0.007). Overall review of the clinical course of patients with GC provided that early appearance of new contrast-enhancing lesions within 6 months from the initial diagnosis and higher histological grade were closely associated with poor survival (p < 0.001 and p = 0.008). Adjuvant chemotherapy following radiotherapy could prolong the survival in patients with GC. In addition, newly developed contrast-enhanced lesions on the follow-up MR images indicate the progression of GC

  18. Adjuvant and neoadjuvant treatment in pancreatic cancer

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic adenocarcinoma is one of the most aggressive human malignancies,ranking 4th among causes for cancer-related death in the Western world including the United States.Surgical resection offers the only chance of cure,but only 15 to 20 percent of cases are potentially resectable at presentation.Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy.Currently there is no consensus around the world on what constitutes "standard"adjuvant therapy for pancreatic cancer.This controversy derives from several studies,each fraught with its own limitations.Standards of care also vary somewhat with regard to geography and economy,for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe.Regardless of the efforts in adjuvant and neoadjuvant improved therapy,the major goal to combat pancreatic cancer is to find diagnostic markers,identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients.In this review,authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients.

  19. Chitosan as an adjuvant for poliovaccine.

    Ghendon, Y; Markushin, S; Akopova, I; Koptiaeva, I; Krivtsov, G

    2011-05-01

    The use of inactivated poliomyelitis vaccine is very important for eradicating poliomyelitis. However, this vaccine is not available readily in underdeveloped countries due to the high cost. Adjuvants can improve the immunogenicity of a vaccine and reduce the antigen dose required for vaccination, thus lowering the cost of the vaccine. Chitosan glutamate solution and a chitosan sulfate micro/nanoparticle suspension were tested as adjuvants for Imovax-inactivated poliovaccine and for inactivated monovalent poliovirus type 1, 2, and 3 vaccines obtained by inactivation of the attenuated Sabin poliovirus strains. Inactivated vaccines admixed with either chitosan glutamate or chitosan sulfate micro/nanoparticles and administered to mice showed significantly enhanced immunogenicity to poliovirus type 1, 2, and 3 strains compared to the respective vaccines administered without chitosan. Chitosan preparations increased the immunogenicity of 1:2 and 1:4 diluted inactivated Sabin strain preparations in mice 8- to 16-fold, so that the neutralizing antibody titers after vaccination with adjuvanted diluted vaccine were equal to those obtained after vaccination with undiluted vaccine administered without chitosan. Neutralizing antibodies could be detected in sera of rats vaccinated with undiluted, 1:10, and 1:100 diluted Imovax vaccine admixed with chitosan sulfate micro/nanoparticles, although in the control group, vaccination only with the undiluted vaccine resulted in antibody production. These results show that the chitosan glutamate solution and chitosan sulfate micro/nanoparticle suspension can significantly improve the immunogenicity of various poliovaccines, and reduce the effective antigen dose. PMID:21412793

  20. Molecular Markers Predict Distant Metastases After Adjuvant Chemoradiation for Rectal Cancer

    Kim, Jun Won; Kim, Yong Bae [Department of Radiation Oncology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Choi, Jun Jeong [Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Koom, Woong Sub [Department of Radiation Oncology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Hoguen [Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Nam-Kyu [Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Ahn, Joong Bae [Department of Medical Oncology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lee, Ikjae; Cho, Jae Ho [Department of Radiation Oncology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Keum, Ki Chang, E-mail: kckeum@yuhs.ac [Department of Radiation Oncology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-12-01

    Purpose: The outcomes of adjuvant chemoradiation for locally advanced rectal cancer are nonuniform among patients with matching prognostic factors. We explored the role of molecular markers for predicting the outcome of adjuvant chemoradiation for rectal cancer patients. Methods and Materials: The study included 68 patients with stages II to III rectal adenocarcinoma who were treated with total mesorectal excision and adjuvant chemoradiation. Chemotherapy based on 5-fluorouracil and leucovorin was intravenously administered each month for 6-12 cycles. Radiation therapy consisted of 54 Gy delivered in 30 fractions. Immunostaining of surgical specimens for COX-2, EGFR, VEGF, thymidine synthase (TS), and Raf kinase inhibitor protein (RKIP) was performed. Results: The median follow-up was 65 months. Eight locoregional (11.8%) and 13 distant (19.1%) recurrences occurred. Five-year locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates for all patients were 83.9%, 78.7%, 66.7%, and 73.8%, respectively. LRFFS was not correlated with TNM stage, surgical margin, or any of the molecular markers. VEGF overexpression was significantly correlated with decreased DMFS (P=.045), while RKIP-positive results were correlated with increased DMFS (P=.025). In multivariate analyses, positive findings for COX-2 (COX-2+) and VEGF (VEGF+) and negative findings for RKIP (RKIP-) were independent prognostic factors for DMFS, DFS, and OS (P=.035, .014, and .007 for DMFS; .021, .010, and <.0001 for DFS; and .004, .012, and .001 for OS). The combination of both COX-2+ and VEGF+ (COX-2+/VEGF+) showed a strong correlation with decreased DFS (P=.007), and the combinations of RKIP+/COX-2- and RKIP+/VEGF- showed strong correlations with improved DFS compared with the rest of the patients (P=.001 and <.0001, respectively). Conclusions: Molecular markers can be valuable in predicting treatment outcome of adjuvant

  1. Adjuvant Therapy of Colon Cancer: Current Status and Future Developments

    Morse, Michael A.

    2005-01-01

    Options for the adjuvant therapy of resected stage III colon cancer have expanded beyond the previously well-accepted standard of 5-fluorouracil (5-FU) combined with leucovorin. The Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study confirmed that capecitabine (Xeloda) is at least as effective and is less toxic than a bolus 5-FU and leucovorin regimen for patients with stage III colon cancer. This study, in addition to National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06, which...

  2. [Recent advance in adjuvant therapy for breast cancer].

    Shimizu, Chikako; Watanabe, Toru

    2002-12-01

    Adjuvant systemic therapy has contributed to a significant improvement of disease-free and overall survival in addition to surgery and irradiation to the local disease. The adjuvant therapy to a patient is determined integrating the information on estimated risk of recurrence, benefit and harm of the therapy and the patient's value. In this review, the state of the art of adjuvant therapy is discussed from several aspects, such as interpretation and evaluation of risk, the best available evidences on adjuvant systemic therapy, the future direction of primary therapy for breast cancer, and patient-oriented decision making. PMID:12506467

  3. Modern Vaccines/Adjuvants Formulation Session 6: Vaccine & Adjuvant Formulation & Production 15-17 May 2013, Lausanne, Switzerland

    Fox, Christopher B.

    2013-01-01

    The Modern Vaccines/Adjuvants Formulation meeting aims to fill a critical gap in current vaccine development efforts by bringing together formulation scientists and immunologists to emphasize the importance of rational formulation design in order to optimize vaccine and adjuvant bioactivity, safety, and manufacturability. Session 6 on Vaccine and Adjuvant Formulation and Production provided three examples of this theme, with speakers emphasizing the need for extensive physicochemical characte...

  4. CpG ODN and ISCOMATRIX Adjuvant: A Synergistic Adjuvant Combination Inducing Strong T-Cell IFN-γ Responses

    Michael J. McCluskie; Weeratna, Risini D.; Evans, Dana M.; Shawn Makinen; Debbie Drane; Heather L. Davis

    2013-01-01

    For the induction of robust humoral and cellular immune responses, a strong rationale exists to use vaccine-adjuvant combinations possessing both immune modulatory and enhanced delivery capabilities. Herein, we evaluated the combination of 2 different adjuvants, a TLR9 agonist, composed of synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs (CpG), and ISCOMATRIX adjuvant (ISCOMATRIX), composed of saponin, phospholipid, and cholesterol, which possesses both immunostim...

  5. Rapid increase in aggressive behavior precedes the decrease in brain aromatase activity during socially mediated sex change in Lythrypnus dalli

    Black, Michael P; Balthazart, Jacques; Baillien, Michelle; Grober, Matthew S.

    2010-01-01

    In the bluebanded goby, Lythrypnus dalli, removal of the male from a social group results in a rapid behavioral response where one female becomes dominant and changes sex to male. In a previous study, within hours of male removal, aromatase activity in the brain (bAA) of dominant females was almost 50% lower than that of control females from a group in which the male had not been removed. For those females that displayed increased aggressive behavior after the male was removed, the larger the...

  6. Corrosion inhibitors

    In this paper, we briefly describe the characteristics, cost and electrochemical nature of the corrosion phenomena as well as some of the technologies that are currently employed to minimize its effect. The main subject of the paper however, deals with the description, classification and mechanism of protection of the so-called corrosion inhibitors. Examples of the use of these substances in different aggressive environments are also presented as means to show that these compounds, or their combination, can in fact be used as excellent and relatively cheap technologies to control the corrosion of some metals. In the last part of the paper, the most commonly used techniques to evaluate the efficiency and performance of corrosion inhibitors are presented as well as some criteria to make a careful and proper selection of a corrosion inhibitor technology in a given situation. (Author) 151 refs

  7. Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice.

    Michelle L Van Sinderen

    Full Text Available The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2 treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα and interleukin 6 (IL6. Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.

  8. Adjuvant chemotherapy for soft tissue sarcoma.

    Casali, Paolo G

    2015-01-01

    Adjuvant chemotherapy is not standard treatment in soft tissue sarcoma (STS). However, when the risk of relapse is high, it is an option for shared decision making with the patient in conditions of uncertainty. This is because available evidence is conflicting, even if several randomized clinical trials have been performed for 4 decades and also have been pooled into meta-analyses. Indeed, available meta-analyses point to a benefit in the 5% to 10% range in terms of survival and distant relapse rate. Some local benefit also was suggested by some trials. Placing chemotherapy in the preoperative setting may help gain a local advantage in terms of the quality of surgical margins or decreased sequelae. This may be done within a personalized approach according to the clinical presentation. Attempts to personalize treatment on the basis of the variegated pathology and molecular biology of STS subgroups are ongoing as well, according to what is done in the medical treatment of advanced STS. Thus, decision making for adjuvant and neoadjuvant indications deserves personalization in clinical research and in clinical practice, taking profit from all multidisciplinary clinical skills available at a sarcoma reference center, though with a degree of subjectivity because of the limitations of available evidence. PMID:25993233

  9. Mucosal adjuvants to improve wildlife rabies vaccination.

    Fry, Tricia; Van Dalen, Kaci; Hurley, Jerome; Nash, Paul

    2012-10-01

    RABORAL V-RG(®)a is a recombinant vaccine used in oral rabies vaccination (ORV) programs for wildlife in the United States. Vaccination rates for raccoons are substantially lower than vaccination rates for gray foxes and coyotes. Research suggests that the low viscosity of the oral vaccine may preclude animals from receiving an effective dose when biting into the vaccine bait delivery system. We evaluated the possibility of using two benign compounds, chitosan and N,N,N-trimethylated chitosan (TMC), to increase the viscosity of the vaccine and potentially act as adjuvants to improve the immune response in raccoons (Procyon lotor). Forty mildly sedated raccoons were orally vaccinated via needleless syringe with either RABORAL V-RG (n = 12), chitosan+RABORAL V-RG (n = 12), TMC+ RABORAL V-RG (n = 12), or no vaccine (n = 4), on day 0 and again on day 90. We collected sera every 2-4 wk for 4 mo and evaluated rabies virus-neutralizing antibodies (rVNA). Raccoons were considered responders if rVNA titers were ≥ 0.1 IU/mL. Eleven of 12 raccoons vaccinated with TMC+RABORAL V-RG responded after one dose of vaccine, as did eight of 12 vaccinated with RABORAL V-RG, and three of 12 vaccinated with chitosan+ RABORAL V-RG. Our results suggest that the inclusion of an adjuvant, such as TMC, could increase vaccine efficacy to aid in controlling rabies virus spread in wildlife reservoirs. PMID:23060506

  10. Adjuvant Bidirectional Chemotherapy Using an Intraperitoneal Port

    Paul H. Sugarbaker

    2012-01-01

    Full Text Available Cytoreductive surgery (CRS and hyperthermic intraperitoneal chemotherapy (HIPEC have been established as treatment options for patients with peritoneal metastases or peritoneal mesothelioma. However, this novel treatment strategy remains associated with a large percentage of local-regional treatment failures. These treatment failures are attributed to the inadequacy of HIPEC to maintain a surgical complete response. Management strategies to supplement CRS and HIPEC are indicated. A simplified approach to the intraoperative placement of an intraperitoneal port for adjuvant bidirectional chemotherapy (ABC was devised. Four different chemotherapy treatment plans were utilized depending upon the primary site of the malignancy. Thirty-one consecutive patients with an intraoperative placement of the intraperitoneal port were available for study. The incidence of adverse events that caused an early discontinuation of the bidirectional chemotherapy occurred in 75% of the 8 patients who had an incomplete cytoreduction and in 0% of patients who had a complete cytoreduction. All of the patients who had complete cytoreduction completed at least 5 of the scheduled 6 bidirectional chemotherapy treatments. Adjuvant bidirectional chemotherapy is possible following a major cytoreductive surgical procedure using a simplified method of intraoperative intraperitoneal port placement.