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Sample records for genotype-guided tamoxifen therapy

  1. Cost-utility analysis of genotype-guided antiplatelet therapy in patients with moderate-to-high risk acute coronary syndrome and planned percutaneous coronary intervention

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    Patel V

    2014-09-01

    Full Text Available Background: Prasugrel is recommended over clopidogrel in poor/intermediate CYP2C19 metabolizers with acute coronary syndrome (ACS and planned percutaneous coronary intervention (PCI, reducing the risk of ischemic events. CYP2C19 genetic testing can guide antiplatelet therapy in ACS patients. Objective: The purpose of this study was to evaluate the cost-utility of genotype-guided treatment, compared with prasugrel or generic clopidogrel treatment without genotyping, from the US healthcare provider’s perspective. Methods: A decision model was developed to project lifetime economic and humanistic burden associated with clinical outcomes (myocardial infarction [MI], stroke and major bleeding for the three strategies in patients with ACS. Probabilities, costs and age-adjusted quality of life were identified through systematic literature review. Incremental cost-utility ratios (ICURs were calculated for the treatment strategies, with quality-adjusted life years (QALYs as the primary effectiveness outcome. Relative risk of developing myocardial infarction and stroke between patients with and without variant CYP2C19 when receiving clopidogrel were estimated to be 1.34 and 3.66, respectively. One-way and probabilistic sensitivity analyses were performed. Results: Clopidogrel cost USD19,147 and provided 10.03 QALYs versus prasugrel (USD21,425, 10.04 QALYs and genotype-guided therapy (USD19,231, 10.05 QALYs. The ICUR of genotype-guided therapy compared with clopidogrel was USD4,200. Genotype-guided therapy provided more QALYs at lower costs compared with prasugrel. Results were sensitive to the cost of clopidogrel and relative risk of myocardial infarction and stroke between CYP2C19 variant vs. non-variant. Net monetary benefit curves showed that genotype-guided therapy had at least 70% likelihood of being the most cost-effective alternative at a willingness-to-pay of USD100,000/QALY. In comparison with clopidogrel, prasugrel therapy was more cost

  2. Tamoxifen

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    Tamoxifen is also used sometimes to induce ovulation (egg production) in women who do not produce eggs but wish to become pregnant. Tamoxifen is also ... as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant ...

  3. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer

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    Mouridsen, H.; Giobbie-Hurder, A.; Goldhirsch, A.

    2009-01-01

    BACKGROUND: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone. METHODS:...

  4. Identification of a putative protein-profile associating with tamoxifen therapy-resistance in breast cancer

    NARCIS (Netherlands)

    A. Umar (Arzu); J.W.M. Martens (John); J.A. Foekens (John); L. Paša-Tolić (Ljiljana); H. Kang; A.M. Timmermans (Mieke); M.P. Look (Maxime); M.E. Meijer van Gelder (Marion); N. Jaitly (Navdeep); M.A. den Bakker (Michael)

    2009-01-01

    textabstractTamoxifen-resistance is a major cause of death in patients with recurrent breast cancer. Current clinical parameters can correctly predict therapy response in only half of the treated patients. Identification of proteins that associate with tamoxifen-resistance is a first step towards

  5. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy.

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    Azuma, Junichi; Ohno, Masako; Kubota, Ryuji; Yokota, Soichiro; Nagai, Takayuki; Tsuyuguchi, Kazunari; Okuda, Yasuhisa; Takashima, Tetsuya; Kamimura, Sayaka; Fujio, Yasushi; Kawase, Ichiro

    2013-05-01

    This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis. In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2 4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2 4: intermediate acetylators; 2.5 mg/kg, patients without NAT2 4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the 8th week. One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen. Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.

  6. A Platelet Acquired Storage Pool Disorder Associated with Tamoxifen Therapy

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    Lalitha Nayak

    2012-01-01

    Full Text Available The antiestrogenic drug tamoxifen, used in patients with breast cancer, is associated with an increase in arterial and venous thrombotic events, the mechanism of which is not clearly understood. We report a case of a lady who presented with new bruising and prolonged bleeding following a tooth extraction 4–6 weeks after starting tamoxifen. Investigations were consistent with an acquired platelet storage pool disorder. Repeat platelet function analysis was normal, performed 3 months after discontinuation of tamoxifen. We present a previously clinically unreported effect of tamoxifen on platelet function.

  7. Identification of a putative protein profile associated with tamoxifen therapy resistance in breast cancer.

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    Umar, Arzu; Kang, Hyuk; Timmermans, Annemieke M; Look, Maxime P; Meijer-van Gelder, Marion E; den Bakker, Michael A; Jaitly, Navdeep; Martens, John W M; Luider, Theo M; Foekens, John A; Pasa-Tolić, Ljiljana

    2009-06-01

    Tamoxifen resistance is a major cause of death in patients with recurrent breast cancer. Current clinical factors can correctly predict therapy response in only half of the treated patients. Identification of proteins that are associated with tamoxifen resistance is a first step toward better response prediction and tailored treatment of patients. In the present study we intended to identify putative protein biomarkers indicative of tamoxifen therapy resistance in breast cancer using nano-LC coupled with FTICR MS. Comparative proteome analysis was performed on approximately 5,500 pooled tumor cells (corresponding to approximately 550 ng of protein lysate/analysis) obtained through laser capture microdissection (LCM) from two independently processed data sets (n = 24 and n = 27) containing both tamoxifen therapy-sensitive and therapy-resistant tumors. Peptides and proteins were identified by matching mass and elution time of newly acquired LC-MS features to information in previously generated accurate mass and time tag reference databases. A total of 17,263 unique peptides were identified that corresponded to 2,556 non-redundant proteins identified with > or = 2 peptides. 1,713 overlapping proteins between the two data sets were used for further analysis. Comparative proteome analysis revealed 100 putatively differentially abundant proteins between tamoxifen-sensitive and tamoxifen-resistant tumors. The presence and relative abundance for 47 differentially abundant proteins were verified by targeted nano-LC-MS/MS in a selection of unpooled, non-microdissected discovery set tumor tissue extracts. ENPP1, EIF3E, and GNB4 were significantly associated with progression-free survival upon tamoxifen treatment for recurrent disease. Differential abundance of our top discriminating protein, extracellular matrix metalloproteinase inducer, was validated by tissue microarray in an independent patient cohort (n = 156). Extracellular matrix metalloproteinase inducer levels were

  8. Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades.

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    Brosius, Stephanie N; Turk, Amy N; Byer, Stephanie J; Longo, Jody Fromm; Kappes, John C; Roth, Kevin A; Carroll, Steven L

    2014-11-01

    Chemotherapeutic agents effective against malignant peripheral nerve sheath tumors (MPNSTs) are urgently needed. We recently found that tamoxifen potently impedes xenograft growth. In vitro, tamoxifen inhibits MPNST proliferation and survival in an estrogen receptor-independent manner; these effects are phenocopied by the calmodulin inhibitor trifluoperazine. The present study was performed to establish the mechanism of action of tamoxifen in vivo and optimize its therapeutic effectiveness. To determine if tamoxifen has estrogen receptor-dependent effects in vivo, we grafted MPNST cells in castrated and ovariectomized mice; xenograft growth was unaffected by reductions in sex hormones. To establish whether tamoxifen and trifluoperazine additively or synergistically impede MPNST growth, mice xenografted with neurofibromatosis type 1-associated or sporadic MPNST cells were treated with tamoxifen, trifluoperazine, or both drugs for 30 days. Both monotherapies inhibited graft growth by 50%, whereas combinatorial treatment maximally reduced graft mass by 90% and enhanced decreases in proliferation and survival. Kinomic analyses showed that tamoxifen and trifluoperazine have both shared and distinct targets in MPNSTs. In addition, trifluoperazine prevented tamoxifen-induced increases in serum/glucocorticoid regulated kinase 1, a protein linked to tamoxifen resistance. These findings suggest that combinatorial therapy with tamoxifen and trifluoperazine is effective against MPNSTs because these agents target complementary pathways that are essential for MPNST pathogenesis.

  9. Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole.

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    Carlson, Robert W; Henderson, I Craig

    2003-01-01

    The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that

  10. Tamoxifen-induced hirsutism.

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    Al-Niaimi, Firas; Lyon, C

    2011-07-01

    Tamoxifen, a triphenylethylethylene, is an adjuvant therapy used for the treatment of oestrogen-receptor positive breast carcinoma due to its oestrogen receptor antagonist effect.1 We report here a case of rapid onset of hirsutism following administration of tamoxifen.

  11. Does tamoxifen therapy affect the hormone receptor expression and cell proliferation indices of endometrial polyps? An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen.

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    McGurgan, P; Taylor, L J; Duffy, S R; O'Donovan, P J

    2006-06-20

    This study set out to test the null hypothesis that tamoxifen therapy would not affect the hormone receptor expression (oestrogen and progesterone receptors-ER and PR) or markers of cell proliferation/apoptosis (Ki67 and Bcl-2) of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen. Endometrial polyps were prospectively obtained from women presenting with abnormal bleeding attending an out-patient hysteroscopy clinic who subsequently underwent endometrial polypectomy (16 from postmenopausal women not exposed to tamoxifen, 9 from women exposed to tamoxifen). Immunohistochemical staining for ER, PR, Ki67 and Bcl-2 was performed on polyps from both groups of women. Non-parametric statistical analysis was used (Mann-Whitney and Spearmans rank correlation). Endometrial polyps from tamoxifen users had significantly lower oestrogen receptor but increased progesterone receptor and Bcl-2 expression. There were no significant differences for proliferation markers (Ki67) between postmenopausal endometrial polyps exposed and not exposed to tamoxifen. Tamoxifen has a significant affect on hormone receptor expression and markers of apoptosis in endometrial polyps. The results support the hypothesis that tamoxifen promotes polyp growth by inhibiting apoptosis. The mechanism for this does not appear to be oestrogen receptor mediated.

  12. Ultrasound tomography imaging with waveform sound speed: parenchymal changes in women undergoing tamoxifen therapy

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    Sak, Mark; Duric, Neb; Littrup, Peter; Sherman, Mark; Gierach, Gretchen

    2017-03-01

    Ultrasound tomography (UST) is an emerging modality that can offer quantitative measurements of breast density. Recent breakthroughs in UST image reconstruction involve the use of a waveform reconstruction as opposed to a raybased reconstruction. The sound speed (SS) images that are created using the waveform reconstruction have a much higher image quality. These waveform images offer improved resolution and contrasts between regions of dense and fatty tissues. As part of a study that was designed to assess breast density changes using UST sound speed imaging among women undergoing tamoxifen therapy, UST waveform sound speed images were then reconstructed for a subset of participants. These initial results show that changes to the parenchymal tissue can more clearly be visualized when using the waveform sound speed images. Additional quantitative testing of the waveform images was also started to test the hypothesis that waveform sound speed images are a more robust measure of breast density than ray-based reconstructions. Further analysis is still needed to better understand how tamoxifen affects breast tissue.

  13. Tamoxifen- Induced Dermatomyositis

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    Bandyopadhyay Debabrata

    1997-01-01

    Full Text Available A 38 year old woman developed dermatomyositis after radical mastectomy and tamoxifen therapy for metastatic breast carcinoma. The possibility of the drug as the underlying cause of the connective tissue disease is discussed.

  14. Virginal Breast Hypertrophy: Different Presentations of 2 Cases and the Role of Tamoxifen as an Adjuvant Therapy.

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    Karagüzel, Gülay; Bilen, Sevcan; Karaçal, Naci; Yıldız, Kadriye; Livaoğlu, Murat

    2016-10-01

    Virginal breast hypertrophy is a rapid and massive enlargement of one or both breasts. There are several proposed causes and treatment options for virginal breast hypertrophy, but the investigations to support these theories are lacking. We report two premenarchal girls with virginal breast hypertrophy who presented as different clinical cases. After their surgical interventions, their clinical courses were followed for more than 2 years with tamoxifen as an adjuvant therapy. Breast size and shape disorders can be a disturbing cosmetic problem for adolescents who worry about their body image. A combination treatment of breast reduction surgery and tamoxifen is reasonable and can eliminate the need for repeated surgeries for girls with virginal breast hypertrophy. Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

  15. Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy

    DEFF Research Database (Denmark)

    Elias, D; (Hansen) Vever, Henriette; Lænkholm, A-V;

    2015-01-01

    To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were...... an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.Oncogene advance online publication, 2 June 2014; doi:10.1038/onc.2014.138.......To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were...... functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF...

  16. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study

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    Bergmeijer, Thomas O.; Janssen, Paul W.A.; Schipper, Jurjan C.; Qaderdan, Khalid; Ishak, Maycel; Ruitenbeek, Rianne S.; Asselbergs, Folkert W.; van 't Hof, Arnoud W.J.; Dewilde, Willem J.M.; Spanó, Fabrizio; Herrman, Jean-Paul R.; Kelder, Johannes C.; Postma, Maarten J.; de Boer, Anthonius; Deneer, Vera H.M.; ten Berg, Jurriën M.

    2014-01-01

    RATIONALE: In patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (pPCI), the use of dual antiplatelet therapy is essential to prevent atherothrombotic complications. Therefore, patients are treated with acetylsalicylic acid and clo

  17. Tamoxifen and ovarian function.

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    Martine Berliere

    Full Text Available BACKGROUND: Some studies suggest that the clinical parameter "amenorrhea" is insufficient to define the menopausal status of women treated with chemotherapy or tamoxifen. In this study, we investigated and compared the ovarian function defined either by clinical or biological parameters in pre-menopausal breast cancer patients treated with tamoxifen administered as adjuvant therapy. MATERIALS AND METHODS: Between 1999 and 2003, 138 premenopausal patients consecutively treated for early breast cancer were included. Sixty-eight received tamoxifen in monotherapy as the only adjuvant systemic treatment (Group I and 70 were treated with tamoxifen after adjuvant chemotherapy (Group II. All patients had a confirmed premenopausal status based on clinical parameters and hormonal values at study entry. They were followed prospectively every 3 months for 3 years: menses data, physical examination and blood tests (LH, FSH, 17-beta-estradiol. Vaginal ultrasonography was carried out every 6 months. After 3 years, prospective evaluation was completed and monitoring of ovarian function was performed as usual in our institution (1x/year. All data were retrospectively evaluated in 2011. RESULTS: Three patients were excluded from the study in group I and 2 were excluded in group II. Patients were divided into 4 subgroups according to clinical data, i.e. menses patterns. These patterns were assessed by questionnaires. a: Regular menses (>10 cycles/year b: Oligomenorrhea (5 to 9 cycles/year c: Severe oligomenorrhea (1 to 4 cycles/year d: Complete amenorrhea Estrogen levels did not appear to have any impact on disease-free survival rates after 3 or 8 years. FSH values were also documented and analyzed. They exhibited the same profile as estradiol values. CONCLUSIONS: Amenorrhea is an insufficient parameter to define menopausal status in patients receiving tamoxifen. Low estradiol levels must be coupled with other biological parameters to characterize endocrine status

  18. Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant tamoxifen mono-therapy: a DBCG study.

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    Maria B Lyng

    Full Text Available PURPOSE: Despite the benefits of estrogen receptor (ER-targeted endocrine therapies in breast cancer, many tumors develop resistance. MicroRNAs (miRNAs have been suggested as promising biomarkers and we here evaluated whether a miRNA profile could be identified, sub-grouping ER+ breast cancer patients treated with adjuvant Tamoxifen with regards to probability of recurrence. EXPERIMENTAL DESIGN: Global miRNA analysis was performed on 152 ER+ primary tumors from high-risk breast cancer patients with an initial discovery set of 52 patients, followed by two independent test sets (N = 60 and N = 40. All patients had received adjuvant Tamoxifen as mono-therapy (median clinical follow-up: 4.6 years and half had developed distant recurrence (median time-to-recurrence: 3.5 years. MiRNA expression was examined by unsupervised hierarchical clustering and supervised analysis, including clinical parameters as co-variables. RESULTS: The discovery set identified 10 highly significant miRNAs that discriminated between the patient samples according to outcome. However, the subsequent two independent test sets did not confirm the predictive potential of these miRNAs. A significant correlation was identified between miR-7 and the tumor grade. Investigation of the microRNAs with the most variable expression between patients in different runs yielded a list of 31 microRNAs, eight of which are associated with stem cell characteristics. CONCLUSIONS: Based on the large sample size, our data strongly suggests that there is no single miRNA profile predictive of outcome following adjuvant Tamoxifen treatment in a broad cohort of ER+ breast cancer patients. We identified a sub-group of Tamoxifen-treated breast cancer patients with miRNA-expressing tumors associated with cancer stem cell characteristics.

  19. Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant tamoxifen mono-therapy: a DBCG study.

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    Lyng, Maria B; Lænkholm, Anne-Vibeke; Søkilde, Rolf; Gravgaard, Karina H; Litman, Thomas; Ditzel, Henrik J

    2012-01-01

    Despite the benefits of estrogen receptor (ER)-targeted endocrine therapies in breast cancer, many tumors develop resistance. MicroRNAs (miRNAs) have been suggested as promising biomarkers and we here evaluated whether a miRNA profile could be identified, sub-grouping ER+ breast cancer patients treated with adjuvant Tamoxifen with regards to probability of recurrence. Global miRNA analysis was performed on 152 ER+ primary tumors from high-risk breast cancer patients with an initial discovery set of 52 patients, followed by two independent test sets (N = 60 and N = 40). All patients had received adjuvant Tamoxifen as mono-therapy (median clinical follow-up: 4.6 years) and half had developed distant recurrence (median time-to-recurrence: 3.5 years). MiRNA expression was examined by unsupervised hierarchical clustering and supervised analysis, including clinical parameters as co-variables. The discovery set identified 10 highly significant miRNAs that discriminated between the patient samples according to outcome. However, the subsequent two independent test sets did not confirm the predictive potential of these miRNAs. A significant correlation was identified between miR-7 and the tumor grade. Investigation of the microRNAs with the most variable expression between patients in different runs yielded a list of 31 microRNAs, eight of which are associated with stem cell characteristics. Based on the large sample size, our data strongly suggests that there is no single miRNA profile predictive of outcome following adjuvant Tamoxifen treatment in a broad cohort of ER+ breast cancer patients. We identified a sub-group of Tamoxifen-treated breast cancer patients with miRNA-expressing tumors associated with cancer stem cell characteristics.

  20. Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time.

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    Cluze, C; Rey, D; Huiart, L; BenDiane, M K; Bouhnik, A D; Berenger, C; Carrieri, M P; Giorgi, R

    2012-04-01

    In premenopausal women with hormone receptor-positive breast cancer (BC), 5 years of tamoxifen is recommended. Little is known about reasons for interruption in this population. The aim was to estimate the incidence of tamoxifen interruption and its correlates among younger women. Using a prospective cohort Elippse 40 of women with BC aged ≤ 40 diagnosed between 2005 and 2008, we studied 196 women. Tamoxifen interruption was defined as two or more consecutive months without dispensed prescription of tamoxifen, based on pharmacy refill database. Two periods were studied: between tamoxifen initiation and 16 months after BC diagnosis, and between 16 and 28 months. Among women treated with tamoxifen, 42% interrupted within the first 2 years of treatment. During the first period, treatment interruptions were associated with a lack of understandable information about endocrine treatment and insufficient social support. During the second period, another set of factors were associated with interruption: treatment side-effects, no longer fearing cancer relapse, lack of social support, no opportunity to ask questions at the time of diagnosis, and fewer treatment modalities. Improving information and patient-provider relationship might prevent interruption. Particular attention should be paid to women with little social support.

  1. Severe Acute Pancreatitis Due to Tamoxifen-Induced Hypertriglyceridemia with Positive Rechallenge

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    Jaballah Sakhri

    2010-07-01

    Full Text Available Context Pancreatitis is a very rare adverse effect of tamoxifen with only six cases of tamoxifen-associated pancreatitis reported in the English literature until now. In these cases, rechallenge with tamoxifen was not carried out. Case report We report a case of recurrent severe acute pancreatitis in a 44-year-old female induced by tamoxifen therapy and review the literature with regards to tamoxifen-associated pancreatitis. Conclusion Clinicians should be aware of the risks of developing severe acute pancreatitis when using tamoxifen therapy. If tamoxifen is suspected as the probable causative agent, rechallenge with this drug should be prohibited.

  2. Preparation and characterization of Tamoxifen citrate loaded nanoparticles for breast cancer therapy

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    Maji R

    2014-06-01

    Full Text Available Ruma Maji, Niladri Shekhar Dey, Bhabani Sankar Satapathy, Biswajit Mukherjee, Subhasish MondalDepartment of Pharmaceutical Technology, Jadavpur University, Kolkata (Calcutta, IndiaBackground: Four formulations of Tamoxifen citrate loaded polylactide-co-glycolide (PLGA based nanoparticles (TNPs were developed and characterized. Their internalization by Michigan Cancer Foundation-7 (MCF-7 breast cancer cells was also investigated.Methods: Nanoparticles were prepared by a multiple emulsion solvent evaporation method. Then the following studies were carried out: drug-excipients interaction using Fourier transform infrared spectroscopy (FTIR, surface morphology by field emission scanning electron micro­scopy (FESEM, zeta potential and size distribution using a Zetasizer Nano ZS90 and particle size analyzer, and in vitro drug release. In vitro cellular uptake of nanoparticles was assessed by confocal microscopy and their cell viability (% was studied.Results: No chemical interaction was observed between the drug and the selected excipients. TNPs had a smooth surface, and a nanosize range (250–380 nm with a negative surface charge. Drug loadings of the prepared particles were 1.5%±0.02% weight/weight (w/w, 2.68%±0.5% w/w, 4.09%±0.2% w/w, 27.16%±2.08% w/w for NP1–NP4, respectively. A sustained drug release pattern from the nanoparticles was observed for the entire period of study, ie, up to 60 days. Further, nanoparticles were internalized well by the MCF-7 breast cancer cells on a concentration dependent manner and were present in the cytoplasm. The nucleus was free from nanoparticle entry. Drug loaded nanoparticles were found to be more cytotoxic than the free drug.Conclusion: TNPs (NP4 showed the highest drug loading, released the drug in a sustained manner for a prolonged period of time and were taken up well by the MCF-7 breast cancer cell line in vitro. Thus the formulation may be suitable for breast cancer treatment due to the

  3. Combination goserelin and tamoxifen therapy in premenopausal advanced breast cancer: a multicentre study by the ITMO group. Italian Trials in Medical Oncology.

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    Buzzoni, R.; Biganzoli, L.; Bajetta, E.; Celio, L.; Fornasiero, A.; Mariani, L.; Zilembo, N.; Di Bartolomeo, M.; Di Leo, A.; Arcangeli, G.

    1995-01-01

    It has been suggested that tamoxifen may improve the efficacy of medical castration with luteinising hormone-releasing hormone analogues, but very few data have so far been published concerning the clinical and endocrinological activity of this therapeutic modality. In this phase II multicentre trial conducted by the Italian Trials in Medical Oncology group (ITMO), 64 premenopausal patients with hormone receptor-positive or unknown breast cancer were treated with monthly s.c. injections of goserelin 3.6 mg, in association with a tamoxifen daily dose of 20 mg, as first-line therapy for their advanced disease. All of the patients were evaluable for efficacy and there was an overall response rate of 41% (95% confidence interval 28-52%), with 7 of the 26 responders achieving complete remission. The median time to response was 4 months (range 2-17), and the median response duration was 13 months (range 6-37 +). Better responses were observed in soft tissues (51%); the response in visceral and bone metastases was respectively 19% and 37%. Serum concentrations of gonadotrophins and oestradiol were significantly decreased by the treatment, oestrogen levels being constantly suppressed to within the range observed in post-menopausal women. No significant change was detected in serum testosterone levels. In our experience, although it was not associated with any increased clinical efficacy, the concurrent use of goserelin and tamoxifen proved to be a feasible approach in the management of premenopausal advanced breast cancer. PMID:7734310

  4. MiR-4653-3p and its target gene FRS2 are prognostic biomarkers for hormone receptor positive breast cancer patients receiving tamoxifen as adjuvant endocrine therapy.

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    Zhong, XiaoRong; Xie, GuiQin; Zhang, Zhang; Wang, Zhu; Wang, Yu; Wang, YanPing; Qiu, Yan; Li, Li; Bu, Hong; Li, JiaYuan; Zheng, Hong

    2016-09-20

    Long-term tamoxifen treatment significantly improves the survival of hormone receptor-positive (HR+) breast cancer (BC) patients. However, tamoxifen resistance remains a challenge. We aimed to identify prognostic biomarkers for tamoxifen resistance and reveal the underlying mechanism. From March 2001 to September 2013, 400 HR+ BC women (stage I~III) were treated with adjuvant tamoxifen for 5 years or until relapse in West China Hospital. We included a discovery set of 6 patients who were refractory to tamoxifen, and a validation cohort of 88 patients including 35 cases with relapse. In the discovery set, microRNA microarray showed that miR-4653-3p decreased in recurrent/metastatic lesions compared to the matched primary lesions. In the validation cohort, real-time RT-PCR demonstrated that, following tamoxifen treatment, miR-4653-3p overexpression in the primary tumors decreased the risk of relapse (adjusted hazard ratio [HR] = 0.17, 95% confidence interval [CI] = 0.05~0.57, P = 0.004). Conversely, high expression of FRS2, the key adaptor protein required by FGFR signaling, predicted poor disease-free survival (DFS) (adjusted HR = 2.70, 95% CI = 1.11~6.56, P = 0.03). MiR-4653-3p down regulated FRS2 by binding to its 3' untranslated region. Either overexpressing miR-4653-3p or attenuating FRS2 expression could restore TAM sensitivity in two tamoxifen-resistant BC cell lines. In conclusion, high miR-4653-3p level was the potential predictor for favorable DFS, while FRS2 overexpression was potential high-risk factor for relapse in HR+ BC patients receiving TAM adjuvant therapy. FGFR/FRS2 signaling might be a promising target for reversing tamoxifen resistance.

  5. Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863).

    NARCIS (Netherlands)

    Beex, L.V.A.M.; Rose, C.; Mouridsen, H.; Jassem, J.; Nooij, M.; Estape, J.; Paridaens, R.; Piccart, M.; Gorlia, T.; Lardenoije, S.; Baila, L.

    2006-01-01

    BACKGROUND: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross

  6. Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer : An EORTC phase III study (10863)

    NARCIS (Netherlands)

    Beex, L.; Rose, C.; Mouridsen, H.; Jassem, J.; Nooij, M.; Estape, J.; Paridaens, R.; Piccart, M.; Gorlia, T.; Lardenoije, S.; Baila, L.

    2006-01-01

    Background: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross res

  7. Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863).

    NARCIS (Netherlands)

    Beex, L.V.A.M.; Rose, C.; Mouridsen, H.; Jassem, J.; Nooij, M.; Estape, J.; Paridaens, R.; Piccart, M.; Gorlia, T.; Lardenoije, S.; Baila, L.

    2006-01-01

    BACKGROUND: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross res

  8. Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

    Energy Technology Data Exchange (ETDEWEB)

    Arruda Viani, Gustavo, E-mail: gusviani@gmail.com [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil); Bernardes da Silva, Lucas Godoi; Stefano, Eduardo Jose [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil)

    2012-07-15

    Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

  9. Identification of functional networks of estrogen- and c-Myc-responsive genes and their relationship to response to tamoxifen therapy in breast cancer.

    Science.gov (United States)

    Musgrove, Elizabeth A; Sergio, C Marcelo; Loi, Sherene; Inman, Claire K; Anderson, Luke R; Alles, M Chehani; Pinese, Mark; Caldon, C Elizabeth; Schütte, Judith; Gardiner-Garden, Margaret; Ormandy, Christopher J; McArthur, Grant; Butt, Alison J; Sutherland, Robert L

    2008-08-20

    Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis), cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes) in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature was predictive independent of the cell cycle and cell growth

  10. Identification of functional networks of estrogen- and c-Myc-responsive genes and their relationship to response to tamoxifen therapy in breast cancer.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Musgrove

    Full Text Available BACKGROUND: Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. METHODOLOGY/PRINCIPAL FINDINGS: With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis, cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature

  11. Combination treatment of tamoxifen with risperidone in breast cancer.

    Directory of Open Access Journals (Sweden)

    Wei-Lan Yeh

    Full Text Available Tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. Tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP. Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. Risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients, providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer.

  12. Tamoxifen-induced hypertriglyceridemia causing acute pancreatitis

    Directory of Open Access Journals (Sweden)

    Hemant Kumar Singh

    2016-01-01

    Full Text Available Tamoxifen has both antagonistic and agonistic tissue-specific actions. It can have a paradoxical estrogenic effect on lipid metabolism resulting in elevated triglyceride and chylomicron levels. This can cause life-threatening complications like acute pancreatitis. To our knowledge, very few cases of tamoxifen-induced pancreatitis have been reported in the literature. We report a case of severe hypertriglyceridemia and acute pancreatitis following tamoxifen use. A 50-year-old diabetic lady was on tamoxifen (20mg/day hormonal therapy for breast cancer. Within 3 months of starting therapy, she developed hypertriglyceridemia and acute pancreatitis. Laboratory values include: Serum amylase 778 IU/L, total cholesterol 785 mg/dL, triglycerides 4568 mg/dL and high-density lipoproteins (HDL 12 mg/dL. Tamoxifen was substituted with letrozole and atorvastatin started. There was a prompt reversal of the adverse effects. Effects on lipid profile must be considered while initiating tamoxifen in predisposed individuals as the consequences are life threatening.

  13. Anastrozole versus tamoxifen as adjuvant therapy for Japanese postmenopausal patients with hormone-responsive breast cancer: efficacy results of long-term follow-up data from the N-SAS BC 03 trial.

    Science.gov (United States)

    Aihara, Tomohiko; Yokota, Isao; Hozumi, Yasuo; Aogi, Kenjiro; Iwata, Hiroji; Tamura, Motoshi; Fukuuchi, Atsushi; Makino, Haruhiko; Kim, Ryungsa; Andoh, Masashi; Tsugawa, Koichiro; Ohno, Shinji; Yamaguchi, Takuhiro; Ohashi, Yasuo; Watanabe, Toru; Takatsuka, Yuichi; Mukai, Hirofumi

    2014-11-01

    Aromatase inhibitors are superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. We report the follow-up efficacy results from the N-SAS BC 03 trial (UMIN CTRID: C000000056) where anastrozole was compared with tamoxifen as adjuvant therapy in postmenopausal Japanese patients with hormone-responsive early breast cancer. The full analysis set contained 696 patients (anastrozole arm, n = 345; tamoxifen arm, n = 351). The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS); Kaplan-Meier estimates were calculated. The treatment effects were estimated by Cox's proportional hazards model. To examine time-varying effect of hazard ratios, we estimated time-varying hazard ratios at time t [HR(t)] using data from time t up to 12 months. After a median follow-up of 98.5 months, hazard ratios (95% CIs) were 0.90 (0.65-1.24; log-rank p = 0.526) for DFS and 0.83 (0.56-1.23; log-rank p = 0.344) for RFS. Hazard ratios (95% CIs) for DFS and RFS up to 36 months were 0.69 (0.40-1.17) and 0.54 (0.27-1.06) and those after 36 months were 1.06 (0.70-1.59) and 1.05 (0.64-1.73), respectively. Time-varying hazard ratios for both DFS and RFS showed that hazard ratios were initially in favor of anastrozole and approached 1.0 at around 36 months. Superior efficacy of anastrozole to tamoxifen suggested by the initial analysis was not confirmed in the present analysis after a long-term follow-up period. Advantage of anastrozole was the greatest immediately after switching from tamoxifen and then decreased thereafter.

  14. Metabolism and transport of tamoxifen in relation to its effectiveness

    DEFF Research Database (Denmark)

    Cronin-Fenton, Deirdre P; Damkier, Per; Lash, Timothy L

    2014-01-01

    Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review ta...... effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline endocrine therapy.......Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review...... tamoxifen's clinical pharmacology and use meta-analyses to evaluate the clinical epidemiology studies conducted to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Our findings indicate that the effect of both drug-induced and/or gene-induced inhibition of CYP2D6 activity...

  15. Hormone therapy with tamoxifen reduces plasma levels of NT-B-type natriuretic peptide but does not change ventricular ejection fraction after chemotherapy in women with breast cancer

    Directory of Open Access Journals (Sweden)

    F.B. Silva

    2015-02-01

    Full Text Available The objective of this study was to evaluate the effect of tamoxifen on the plasma concentration of NT-pro-B-type natriuretic peptide (NT-proBNP in women undergoing chemotherapy for breast cancer and to correlate changes in NT-proBNP with the left ventricular ejection fraction (LVEF. Over a period of 12 months, we followed 60 women with a diagnosis of breast cancer. The patients were separated into a group that received only chemotherapy (n=23, a group that received chemotherapy + tamoxifen (n=21, and a group that received only tamoxifen (n=16. Plasma levels of NT-proBNP were assessed at 0 (T0, 6 (T6, and 12 (T12 months of treatment, and echocardiography data were assessed at T0 and T12. Plasma NT-proBNP levels were increased in the chemotherapy-only group at T6 and T12, whereas elevated NT-proBNP levels were only found at T6 in the chemotherapy + tamoxifen group. At T12, the chemotherapy + tamoxifen group exhibited a significant reduction in the peptide to levels similar to the group that received tamoxifen alone. The chemotherapy-only group exhibited a significant decrease in LVEF at T12, whereas the chemotherapy + tamoxifen and tamoxifen-only groups maintained levels similar to those at the beginning of treatment. Treatment with tamoxifen for 6 months after chemotherapy significantly reduced the plasma levels of NT-proBNP and did not change LVEF in women with breast cancer.

  16. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer

    DEFF Research Database (Denmark)

    Regan, Meredith M; Leyland-Jones, Brian; Bouzyk, Mark;

    2012-01-01

    Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated...

  17. Integrative "omic" analysis for tamoxifen sensitivity through cell based models.

    Directory of Open Access Journals (Sweden)

    Liming Weng

    Full Text Available It has long been observed that tamoxifen sensitivity varies among breast cancer patients. Further, ethnic differences of tamoxifen therapy between Caucasian and African American have also been reported. Since most studies have been focused on Caucasian people, we sought to comprehensively evaluate genetic variants related to tamoxifen therapy in African-derived samples. An integrative "omic" approach developed by our group was used to investigate relationships among endoxifen (an active metabolite of tamoxifen sensitivity, SNP genotype, mRNA and microRNA expressions in 58 HapMap YRI lymphoblastoid cell lines. We identified 50 SNPs that associate with cellular sensitivity to endoxifen through their effects on 34 genes and 30 microRNA expression. Some of these findings are shared in both Caucasian and African samples, while others are unique in the African samples. Among gene/microRNA that were identified in both ethnic groups, the expression of TRAF1 is also correlated with tamoxifen sensitivity in a collection of 44 breast cancer cell lines. Further, knock-down TRAF1 and over-expression of hsa-let-7i confirmed the roles of hsa-let-7i and TRAF1 in increasing tamoxifen sensitivity in the ZR-75-1 breast cancer cell line. Our integrative omic analysis facilitated the discovery of pharmacogenomic biomarkers that potentially affect tamoxifen sensitivity.

  18. Impact of Fertility Concerns on Tamoxifen Initiation and Persistence.

    Science.gov (United States)

    Llarena, Natalia C; Estevez, Samantha L; Tucker, Susan L; Jeruss, Jacqueline S

    2015-10-01

    Adjuvant tamoxifen reduces breast cancer recurrence risk and mortality; however, initiation and treatment persistence are poor for younger patients. We hypothesized that a unique set of factors, including fertility concerns, would contribute to the poor tamoxifen use among premenopausal patients. From 2007 to 2012, 515 premenopausal patients younger than age 45 years, with stage 0 to III hormone receptor-positive breast cancer, for whom tamoxifen was recommended, were identified. Clinical and pathologic tumor characteristics, treatment regimens, and fertility concerns were recorded. Clinical factors associated with tamoxifen noninitiation and discontinuation were identified using univariate and multivariable analysis. After the recommendation for tamoxifen, patient reasons for tamoxifen noninitiation or discontinuation were also documented. All statistical tests were two-sided. Based on multivariable analysis, fertility concerns were statistically associated with both noninitiation (odds ratio = 5.04, 95% confidence interval (CI) = 2.29 to 11.07) and early discontinuation (hazard ratio = 1.78, 95% CI = 1.09 to 3.38) of tamoxifen. Other independent predictors of noninitiation included a diagnosis of ductal carcinoma in situ, declining radiation, and not receiving chemotherapy (stage I-III). Additionally, smoking and not receiving radiation therapy were statistically significant predictors of early withdrawal from therapy. Primary patient reasons for noninitiation and early discontinuation included concerns about side effects and fertility. This study provided insight into factors associated with tamoxifen use for reproductive-aged breast cancer survivors, with a new focus on fertility. Fertility concerns negatively impacted tamoxifen initiation and continuation among premenopausal patients. Interventions to optimize treatment initiation and persistence for young cancer patients should include access to fertility preservation options. © The Author 2015. Published by

  19. Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Nicholes R Candelaria

    Full Text Available Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. Alcohol consumption is a modifiable behavior that is linked to increased breast cancer risks and is associated with the development of hormone-dependent breast cancers as well as disease progression and recurrence following endocrine treatment. In this study we examined the molecular mechanisms of action of alcohol by applying molecular, genetic, and genomic approaches in characterizing its effects on estrogen receptor (ER-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1 but not the canonical target TFF1/pS2. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, including those which function in apoptotic and cell proliferation pathways. Furthermore, expression profiles of the responsive gene sets in tumors were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics.

  20. Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome.

    Science.gov (United States)

    Frasor, Jonna; Chang, Edmund C; Komm, Barry; Lin, Chin-Yo; Vega, Vinsensius B; Liu, Edison T; Miller, Lance D; Smeds, Johanna; Bergh, Jonas; Katzenellenbogen, Benita S

    2006-07-15

    The beneficial effect of the selective estrogen receptor (ER) modulator tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here, we report that, in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene in ERalpha-positive MCF-7 human breast cancer cells. This gene regulation by tamoxifen is mediated by ERalpha and reversed by E2 or ICI 182,780. Introduction of ERbeta into MCF-7 cells reverses tamoxifen action on approximately 75% of these genes. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, their expression level was examined in breast cancers of women who had received adjuvant therapy with tamoxifen. High expression of two of the tamoxifen-stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive cancers and hence seem to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy.

  1. 4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer

    NARCIS (Netherlands)

    T. de Marchi (Tommaso); N.Q. Liu (Ning Qing); C. Stingl (Christoph); A.M. Timmermans (Mieke); M. Smid (Marcel); M.P. Look (Maxime); M. Tjoa (Mila); R.B.H. Braakman (René); M. Opdam (Mark); S.C. Linn (Sabine); F.C. Sweep (Fred); P.N. Span (Paul); M. Kliffen (Mike); T.M. Luider (Theo); J.A. Foekens (John); J.W.M. Martens (John); A. Umar (Arzu)

    2016-01-01

    textabstractEstrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in the recurrent disease resistance to tamoxifen therapy is common and a major cause of death. In recent years, in-depth

  2. Obesity and risk of recurrence or death after adjuvant endocrine therapy with letrozole or tamoxifen in the breast international group 1-98 trial

    DEFF Research Database (Denmark)

    Ewertz, Marianne; Gray, Kathryn P; Regan, Meredith M

    2012-01-01

    To examine the association of baseline body mass index (BMI) with the risk of recurrence or death in postmenopausal women with early-stage breast cancer receiving adjuvant tamoxifen or letrozole in the Breast International Group (BIG) 1-98 trial at 8.7 years of median follow-up....

  3. Sox2 promotes tamoxifen resistance in breast cancer cells

    Science.gov (United States)

    Piva, Marco; Domenici, Giacomo; Iriondo, Oihana; Rábano, Miriam; Simões, Bruno M; Comaills, Valentine; Barredo, Inmaculada; López-Ruiz, Jose A; Zabalza, Ignacio; Kypta, Robert; Vivanco, Maria d M

    2014-01-01

    Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells. PMID:24178749

  4. Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance.

    Science.gov (United States)

    Jordan, V C

    1982-01-01

    Over the past decade, the non-steroidal antiestrogen tamoxifen has gained general acceptance for the palliative treatment of breast cancer. Although there has been much interest in the pharmacology of tamoxifen, our knowledge of its metabolism in laboratory animals and patients is incomplete and the precise mechanism of action within target tissue and breast tumor cells is unknown. This review briefly describes the pharmacology of tamoxifen in various laboratory species and patients. Several metabolites of tamoxifen are known and their relative potencies as estrogens and antiestrogens are compared with the parent compound. Apart from monohydroxytamoxifen, none of tamoxifen's metabolites are more potent antiestrogens, but a metabolite in the dog, Metabolite E, is fully estrogenic. Routine assays (tlc, HPLC, glc/ms) are available to detect tamoxifen, N-desmethyltamoxifen, monohydroxytamoxifen, and a newly identified metabolite, designated Metabolite Y, in biological fluids. Continuous therapy with tamoxifen (10 mg bid) produces steady-state levels (100-200 ng/ml serum) within 4 weeks. Levels of N-desmethyltamoxifen are often up to twice the levels achieved with tamoxifen, while levels of monohydroxytamoxifen and Metabolite Y are below 10 ng/ml. Although monohydroxytamoxifen has a high binding affinity for the estrogen receptor, the metabolic activation of tamoxifen is an advantage rather than a requirement for antiestrogenic activity. The action of tamoxifen in vivo is the net result of the individual actions of the parent compound and its metabolites competing for the occupation of receptors within target tissues and tumors.

  5. Tamoxifen treatment for intracerebral hemorrhage.

    Science.gov (United States)

    Xie, Qing; Guan, Jian; Wu, Gang; Xi, Guohua; Keep, Richard F; Hua, Ya

    2011-01-01

    Tamoxifen is a selective estrogen receptor modulator. In this study we investigated whether or not tamoxifen reduces intracerebral hemorrhage (ICH)-induced brain injury in rats. In all experiments, adult male Sprague-Dawley rats received an injection of 100 μL autologous whole blood into the right basal ganglia. In the first set of experiments, rats were treated with tamoxifen (2.5 mg/kg or 5 mg/kg, i.p.) or vehicle 2 and 24 h after ICH and were killed at day 3 for brain edema measurement. In the second set of experiments, rats were treated with tamoxifen (5 mg/kg) or vehicle and magnetic resonance imaging (MRI), and behavior tests were performed at days 1, 7, 14 and 28. Rats were killed at day 28 for brain histology. We found that tamoxifen at 5 but not at 2.5 mg/kg reduced perihematomal brain edema at day 3 (ptamoxifen reduced caudate atrophy at day 28 (pTamoxifen also improved functional outcome (ptamoxifen-treated rats. However, two out of five rats treated with tamoxifen developed hydrocephalus. These results suggest that tamoxifen has neuroprotective effects in ICH, but the cause of hydrocephalus development following tamoxifen treatment needs to be examined further.

  6. CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy.

    Science.gov (United States)

    Teft, Wendy A; Gong, Inna Y; Dingle, Brian; Potvin, Kylea; Younus, Jawaid; Vandenberg, Theodore A; Brackstone, Muriel; Perera, Francisco E; Choi, Yun-Hee; Zou, Guangyong; Legan, Robin M; Tirona, Rommel G; Kim, Richard B

    2013-05-01

    Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4*22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4*22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4*22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.

  7. Endometrial cancer survival after breast cancer in relation to tamoxifen treatment : Pooled results from three countries

    NARCIS (Netherlands)

    Jones, Michael E.; van Leeuwen, Flora E.; Hoogendoorn, Wilhelmina E.; Mourits, Marian J. E.; Hollema, Harry; van Boven, Hester; Press, Michael F.; Bernstein, Leslie; Swerdlow, Anthony J.

    2012-01-01

    Introduction: Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subs

  8. Endometrial cancer survival after breast cancer in relation to tamoxifen treatment : Pooled results from three countries

    NARCIS (Netherlands)

    Jones, Michael E.; van Leeuwen, Flora E.; Hoogendoorn, Wilhelmina E.; Mourits, Marian J. E.; Hollema, Harry; van Boven, Hester; Press, Michael F.; Bernstein, Leslie; Swerdlow, Anthony J.

    2012-01-01

    Introduction: Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subs

  9. Five Years of Tamoxifen Continues to Benefit Women 15 Years after Treatment

    Science.gov (United States)

    In a large randomized clinical trial, women with early-stage breast cancer who received 5 years of adjuvant treatment with tamoxifen had better outcomes up to 15 years after the start of treatment than those who received 2 years of tamoxifen therapy.

  10. Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat

    Directory of Open Access Journals (Sweden)

    Goldstein Irwin

    2006-09-01

    Full Text Available Abstract Background Tamoxifen, a selective estrogen receptor modulator with both estrogenic and anti-estrogenic activity, is widely used as adjuvant therapy in breast cancer patients. Treatment with tamoxifen is associated with sexual side effects, such as increased vaginal dryness and pain/discomfort during sexual activity. There have been limited investigations of the effect of tamoxifen on estrogen-dependent peripheral genital arousal responses. The objective of this study was to investigate the effects of tamoxifen on vaginal physiology in the rat. Methods Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy. After 2 weeks, sham-operated rats were implanted with subcutaneous osmotic infusion pumps containing vehicle (control or tamoxifen (150 μg/day. Ovariectomized rats were similarly infused with vehicle. After an additional 2 weeks, vaginal blood flow responses to pelvic nerve stimulation were measured by laser Doppler flowmetry and vaginal tissue was collected for histological and biochemical assay. Results Tamoxifen treatment did not change plasma estradiol concentrations relative to control animals, while ovariectomized rats exhibited a 60% decrease in plasma estradiol. Tamoxifen treatment caused a significant decrease in mean uterine weight, but did not alter mean vaginal weight. Vaginal blood flow was significantly decreased in tamoxifen-infused rats compared to controls. Similar to ovariectomized animals, estrogen receptor binding was increased and arginase enzyme activity was decreased in tamoxifen-infused rats. However, different from control and ovariectomized animals, the vaginal epithelium in tamoxifen-infused rats appeared highly mucified. Periodic acid-Schiff staining confirmed a greater production of carbohydrate-rich compounds (e.g. mucin, glycogen by the vaginal epithelium of tamoxifen-infused rats. Conclusion The observations suggest that tamoxifen exerts both anti-estrogenic and pro

  11. Tamoxifen in the rat prevents estrogen-deficiency bone loss elicited with the LHRH agonist buserelin.

    Science.gov (United States)

    Goulding, A; Gold, E; Feng, W

    1992-08-01

    In young women chronic use of luteinizing hormone releasing hormone (LHRH) agonists such as buserelin to treat endometriosis leads to estrogen-deficiency bone loss. Tamoxifen citrate is an estrogen agonist/antagonist which protects the skeleton from osteopenia when ovarian hormones are depleted. The present study was undertaken to determine whether tamoxifen citrate (20 mg/kg body wt/week s.c.) could prevent the osteopenic effect of buserelin (25 micrograms/kg body wt/day s.c.). Four groups of rats with 45Ca-labelled bones were studied for 4 weeks: group A--placebo controls; group B--buserelin; Group C--tamoxifen; group D--buserelin+tamoxifen. Bone resorption was monitored by measuring the urinary excretion of 45Ca and hydroxyproline. Interestingly buserelin lowered both blood 17 beta-estradiol values and uterine weights in the presence and absence of tamoxifen. However, tamoxifen slowed bone breakdown and inhibited the bone-thinning effects of buserelin. Total body calcium values (mg; means +/- S.D.) were: 2227 +/- 137; 1926 +/- 124; 2233 +/- 94 and 2268 +/- 163, in groups A to D respectively. Osteopenia was thus present only in group B (P less than 0.001). Because tamoxifen inhibits estrogen-deficiency bone loss in buserelin-treated rats without depressing the hypoestrogenic actions of this LHRH-agonist, we suggest that use of tamoxifen to protect the skeleton during LHRH-agonist therapy in young women should be explored. Tamoxifen citrate might also help to prevent postmenopausal osteoporosis.

  12. Annexin-A1 and caldesmon are associated with resistance to tamoxifen in estrogen receptor positive recurrent breast cancer

    NARCIS (Netherlands)

    T. de Marchi (Tommaso); A.M. Timmermans (Anne M.); M. Smid (Marcel); M.P. Look (Maxime); C. Stingl (Christoph); M. Opdam (Mark); S.C. Linn (Sabine); F.C. Sweep (Fred); P.N. Span (Paul); M. Kliffen (Mike); C.H.M. van Deurzen (Carolien); T.M. Luider (Theo); J.A. Foekens (John); J.W.M. Martens (John); A. Umar (Arzu)

    2016-01-01

    textabstractTamoxifen therapy resistance constitutes a major cause of death in patients with recurrent estrogen receptor (ER) positive breast cancer. Through high resolution mass spectrometry (MS), we previously generated a 4-protein predictive signature for tamoxifen therapy outcome in recurrent

  13. Genotype-guided coumarin dosing: Where are we now and where do we need to go next?

    NARCIS (Netherlands)

    Baranova, Ekaterina V.; Verhoef, Talitha I; Asselbergs, Folkert W.; De Boer, Anthonius; Maitland-Van Der Zee, Anke-Hilse

    2015-01-01

    Introduction: A large proportion of the coumarin dose variability is explained by environmental factors and by common genetic variants in the VKORC1 and CYP2C9 genes. Genotype-guided coumarin dosing has been proposed for a more accurate prediction of the coumarin dose in order to reduce the incidenc

  14. Genotype-guided coumarin dosing : where are we now and where do we need to go next?

    NARCIS (Netherlands)

    Baranova, Ekaterina V; Verhoef, Talitha I; Asselbergs, Folkert W; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse

    2015-01-01

    INTRODUCTION: A large proportion of the coumarin dose variability is explained by environmental factors and by common genetic variants in the VKORC1 and CYP2C9 genes. Genotype-guided coumarin dosing has been proposed for a more accurate prediction of the coumarin dose in order to reduce the incidenc

  15. Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance.

    Science.gov (United States)

    Hirokawa, Yumiko; Arnold, Melissa; Nakajima, Hidenori; Zalcberg, John; Maruta, Hiroshi

    2005-09-01

    PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for both neurofibromatosis (NF) and RAS transformation in vivo. FK228, a histone deacetylase (HDAC) inhibitor, activates a very specific set of genes such as the tumor suppressor WAF1, an inhibitor of cyclin-dependent kinases (CDKs), and suppresses the growth of these tumors. In addition, this drug downregulates cyclin D1, which is upregulated by RAS through PAK1, in breast cancers. In this study, we demonstrate that FK228 at 0.1-1 nM significantly reduces the kinase activity of PAK1 in these cells, without affecting the protein level of PAK1. Interestingly, estrogen receptor (ER) and PAK1 mutually activate each other in breast cancers. Here we provide an evidence suggesting that breast cancers require PAK1 for their estrogen-dependent growth. Moreover, the treatment with FK228 strongly inhibits the estrogen-dependent growth of human breast cancers (both tamoxifen-sensitive and resistant cell lines) in vivo, suggesting that FK228 and other anti-PAK1 drugs would be useful for the treatment of breast cancers which become resistant to currently used estrogen antagonists such as tamoxifen.

  16. Evaluation of adverse effects in tamoxifen exposed healthy female dogs.

    Science.gov (United States)

    Tavares, Wanessa L F; Lavalle, Gleidice E; Figueiredo, Mariana S; Souza, Aline G; Bertagnolli, Angelica C; Viana, Fernando A B; Paes, Paulo R O; Carneiro, Rubens A; Cavalcanti, Guilherme A O; Melo, Marilia M; Cassali, Geovanni D

    2010-12-22

    Mammary tumors are among the most frequent neoplasms in female dogs, but the strategies employed in animal treatment are limited. In human medicine, hormone manipulation is used in cancer therapy. Tamoxifen citrate is a selective inhibitor of oestrogen receptors and exerts a potent anti-oestrogen effect on the mammary gland. The aim of this study was to evaluate the adverse effects when exposing healthy female dogs to tamoxifen. Tamoxifen was administered for 120 days at a dose of 0.5 or 0.8 mg/kg/day to either intact or spayed female dogs. The effects were assessed through clinical examination, haematology, serum biochemistry, ophthalmology and bone marrow aspirate examination. Ovariohysterectomy was performed and the uterus examined by histopathology. Vulva oedema and purulent vaginal discharge developed with 10 days of tamoxifen exposure in all groups. Pyometra was diagnosed after around 90 days of exposure in intact females with frequencies increasing during the following 30 days of exposure. Up to 50% of dogs within the groups developed retinitis but none of the dogs had signs of reduced visual acuity. The prevalence of retinitis in each group was similar after 120 days of exposure. Haematological, biochemical and bone marrow changes were not observed. Due to the high risk of developing pyometra after prolonged exposure to tamoxifen, only spayed animals should be given this medication. A dose of 0.8 mg tamoxifen/kg body weight/day is recommended when treating tamoxifen-responsive canine mammary tumors. Due to the high risk of developing pyometra, ovariohysterectomy is recommended.

  17. Evaluation of adverse effects in tamoxifen exposed healthy female dogs

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    Cavalcanti Guilherme AO

    2010-12-01

    Full Text Available Abstract Background Mammary tumors are among the most frequent neoplasms in female dogs, but the strategies employed in animal treatment are limited. In human medicine, hormone manipulation is used in cancer therapy. Tamoxifen citrate is a selective inhibitor of oestrogen receptors and exerts a potent anti-oestrogen effect on the mammary gland. The aim of this study was to evaluate the adverse effects when exposing healthy female dogs to tamoxifen. Methods Tamoxifen was administered for 120 days at a dose of 0.5 or 0.8 mg/kg/day to either intact or spayed female dogs. The effects were assessed through clinical examination, haematology, serum biochemistry, ophthalmology and bone marrow aspirate examination. Ovariohysterectomy was performed and the uterus examined by histopathology. Results Vulva oedema and purulent vaginal discharge developed with 10 days of tamoxifen exposure in all groups. Pyometra was diagnosed after around 90 days of exposure in intact females with frequencies increasing during the following 30 days of exposure. Up to 50% of dogs within the groups developed retinitis but none of the dogs had signs of reduced visual acuity. The prevalence of retinitis in each group was similar after 120 days of exposure. Haematological, biochemical and bone marrow changes were not observed. Due to the high risk of developing pyometra after prolonged exposure to tamoxifen, only spayed animals should be given this medication. Conclusions A dose of 0.8 mg tamoxifen/kg body weight/day is recommended when treating tamoxifen-responsive canine mammary tumors. Due to the high risk of developing pyometra, ovariohysterectomy is recommended.

  18. Valor da ultra-sonografia na avaliação das alterações endometriais em pacientes tratadas com tamoxifeno Value of sonographic endometrial findings in patients under tamoxifen therapy

    Directory of Open Access Journals (Sweden)

    Arildo Corrêa Teixeira

    2007-12-01

    Full Text Available OBJETIVO: Avaliar as alterações endometriais por meio da ultra-sonografia transvaginal e correlacioná-las com os achados da histeroscopia e histologia, em pacientes submetidas a tratamento com tamoxifeno. MATERIAIS E MÉTODOS: No período de janeiro de 2003 a dezembro de 2005, foram incluídas pacientes com câncer de mama usuárias de tamoxifeno que apresentaram espessamento endometrial acima de 5 mm. Os achados foram correlacionados com os dados de histeroscopia e anatomopatologia. RESULTADOS: Foram selecionadas 25 pacientes com idade média de 62,6 anos. O tempo médio do diagnóstico do câncer foi de 4,3 anos e do uso de tamoxifeno, três anos. Vinte pacientes eram assintomáticas (80% e as demais apresentaram sangramento (20%. À ultra-sonografia, 16% apresentaram espessamento endometrial entre 5 mm e 8 mm, 40% entre 9 mm e 15 mm, e 44% acima de 15 mm. Ao estudo com a histeroscopia, 40% apresentaram atrofia, 16% atrofia cística, 28% pólipos, e 16% lesão hiperplásica. O estudo anatomopatológico apresentou-se normal em 35,2% dos casos e mostrou atrofia em 5,8%, pólipo em 29,4% e hiperplasia em 11,7%. Foi observado um caso de adenocarcinoma (5,8%. CONCLUSÃO: A ultra-sonografia associada à histeroscopia apresentam-se como importantes aliados na avaliação de pacientes usuárias de tamoxifeno. A detecção de espessamento endometrial à ultra-sonografia apresenta baixa especificidade, enquanto a histeroscopia é mais acurada na detecção de pólipos, hiperplasia e alterações neoplásicas.OBJECTIVE: To evaluate endometrial alterations by means of transvaginal ultrasound and to correlate them with hysteroscopic and histological findings in patients under tamoxifen therapy. MATERIALS AND METHODS: The present study was developed in the period between January 2003 and December 2005, including patients under tamoxifen therapy for breast cancer, and presenting with endometrial thickening > 5 mm. The sonographic findings were correlated

  19. The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha.

    Science.gov (United States)

    Lichtenfels, Martina; Dornelles, Arethuza da Silva; Petry, Fernanda Dos Santos; Blank, Martina; de Farias, Caroline Brunetto; Roesler, Rafael; Schwartsmann, Gilberto

    2017-09-02

    Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.

  20. Tamoxifen Resistance: Emerging Molecular Targets

    Directory of Open Access Journals (Sweden)

    Milena Rondón-Lagos

    2016-08-01

    Full Text Available 17β-Estradiol (E2 plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer.

  1. Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy.

    Science.gov (United States)

    Cronin-Fenton, Deirdre P; Damkier, Per; Lash, Timothy L

    2014-01-01

    Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review tamoxifen's clinical pharmacology and use meta-analyses to evaluate the clinical epidemiology studies conducted to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Our findings indicate that the effect of both drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline endocrine therapy.

  2. The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy.

    Science.gov (United States)

    Dorchies, Olivier M; Reutenauer-Patte, Julie; Dahmane, Elyes; Ismail, Heham M; Petermann, Olivier; Patthey- Vuadens, Ophélie; Comyn, Sophie A; Gayi, Elinam; Piacenza, Tony; Handa, Robert J; Décosterd, Laurent A; Ruegg, Urs T

    2013-02-01

    Duchenne muscular dystrophy (DMD) is a severe disorder characterized by progressive muscle wasting,respiratory and cardiac impairments, and premature death. No treatment exists so far, and the identification of active substances to fight DMD is urgently needed. We found that tamoxifen, a drug used to treat estrogen-dependent breast cancer, caused remarkable improvements of muscle force and of diaphragm and cardiac structure in the mdx(5Cv) mouse model of DMD. Oral tamoxifen treatment from 3 weeks of age for 15 months at a dose of 10 mg/kg/day stabilized myofiber membranes, normalized whole body force, and increased force production and resistance to repeated contractions of the triceps muscle above normal values. Tamoxifen improved the structure of leg muscles and diminished cardiac fibrosis by~ 50%. Tamoxifen also reduced fibrosis in the diaphragm, while increasing its thickness,myofiber count, and myofiber diameter, thereby augmenting by 72% the amount of contractile tissue available for respiratory function. Tamoxifen conferred a markedly slower phenotype to the muscles.Tamoxifen and its metabolites were present in nanomolar concentrations in plasma and muscles,suggesting signaling through high-affinity targets. Interestingly, the estrogen receptors ERa and ERb were several times more abundant in dystrophic than in normal muscles, and tamoxifen normalized the relative abundance of ERb isoforms. Our findings suggest that tamoxifen might be a useful therapy for DMD.

  3. Differential response to α-oxoaldehydes in tamoxifen resistant MCF-7 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Norbert Nass

    Full Text Available Tamoxifen is the standard adjuvant endocrine therapy for estrogen-receptor positive premenopausal breast cancer patients. However, tamoxifen resistance is frequently observed under therapy. A tamoxifen resistant cell line has been generated from the estrogen receptor positive mamma carcinoma cell line MCF-7 and was analyzed for putative differences in the aldehyde defence system and accumulation of advanced glycation end products (AGE. In comparison to wt MCF-7 cells, these tamoxifen resistant cells were more sensitive to the dicarbonyl compounds glyoxal and methylglyoxal and displayed increased caspase activity, p38-MAPK- and IκBα-phosphorylation. However, mRNA accumulation of the aldehyde- and AGE-defence enzymes glyoxalase-1 and -2 (GLO1, GLO2 as well as fructosamine-3-kinase (FN3K was not significantly altered. Tamoxifen resistant cells contained less free sulfhydryl-groups (glutathione suggesting that the increased sensitivity towards the dicarbonyls was due to a higher sensitivity towards reactive oxygen species which are associated with dicarbonyl stress. To further analyse, if these data are of more general importance, key experiments were replicated with tamoxifen resistant MCF-7 cell lines from two independent sources. These cell lines were also more sensitive to aldehydes, especially glyoxal, but were different in their cellular signalling responses to the aldehydes. In conclusion, glyoxalases and other aldehyde defence enzymes might represent a promising target for the therapy of tamoxifen resistant breast cancers.

  4. Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

    DEFF Research Database (Denmark)

    Joshi, Tejal; Elias, Daniel; Stenvang, Jan

    2016-01-01

    Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of mi...... and siRNAmediated gene knockdown, we showed that both SNAI2 and FYN significantly affect the growth of TamR cell lines. Finally, we show that a combination of 2 miRNAs (miR-190b and miR-516a-5p) exhibiting altered expression in TamR cell lines were predictive of treatment outcome in a cohort of ER......+ breast cancer patients receiving adjuvant tamoxifen mono-therapy. Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer....

  5. Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer*

    Science.gov (United States)

    Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh; Nirujogi, Raja Sekhar; Kim, Min-Sik; Manda, Srikanth S.; Stearns, Vered; Gabrielson, Edward; Sukumar, Saraswati; Pandey, Akhilesh

    2015-01-01

    Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers. PMID:26330541

  6. Pigment Epithelium-Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia.

    Science.gov (United States)

    Goldberg, Keren; Bar-Joseph, Hadas; Grossman, Hadas; Hasky, Noa; Uri-Belapolsky, Shiri; Stemmer, Salomon M; Chuderland, Dana; Shalgi, Ruth; Ben-Aharon, Irit

    2015-12-01

    Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro- and anti-angiogenic factors. VEGF is a pro-angiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-α and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

  7. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen

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    Daidone Maria G

    2008-05-01

    Full Text Available Abstract Background Estrogen receptor positive (ER+ breast cancers (BC are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30–40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings. Results We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29–3.13; p = 0.002. Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response. Conclusion We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

  8. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.

    Science.gov (United States)

    Loi, Sherene; Haibe-Kains, Benjamin; Desmedt, Christine; Wirapati, Pratyaksha; Lallemand, Françoise; Tutt, Andrew M; Gillet, Cheryl; Ellis, Paul; Ryder, Kenneth; Reid, James F; Daidone, Maria G; Pierotti, Marco A; Berns, Els Mjj; Jansen, Maurice Phm; Foekens, John A; Delorenzi, Mauro; Bontempi, Gianluca; Piccart, Martine J; Sotiriou, Christos

    2008-05-22

    Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings. We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response. We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

  9. Gene expression signatures that predict outcome of tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients

    DEFF Research Database (Denmark)

    Lyng, Maria Bibi; Lænkholm, Anne-Vibeke; Tan, Qihua;

    2013-01-01

    Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy....

  10. Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant tamoxifen mono-therapy

    DEFF Research Database (Denmark)

    Lyng, Maria Bibi; Lænkholm, Anne-Vibeke; Søkilde, Rolf

    2012-01-01

    Despite the benefits of estrogen receptor (ER)-targeted endocrine therapies in breast cancer, many tumors develop resistance. MicroRNAs (miRNAs) have been suggested as promising biomarkers and we here evaluated whether a miRNA profile could be identified, sub-grouping ER+ breast cancer patients...

  11. Tamoxifen-associated vasculitis in a breast cancer patient

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    Vargas-Viveros Pablo

    2007-01-01

    Full Text Available Abstract Background Estrogen plays a critical role in breast cancer. Thereafter, endocrine therapy is a standard of care in patients with breast carcinoma, expressing ER or PR. Case presentation Herein we report the case of a 53-year old patient, who developed cholestasis and vasculitis during the treatment with tamoxifen. This toxicity was reversable after the removal of the drug. Thereafter she continued adjuvant treatment for breast carcinoma with anastrazole. Since tamoxifen has been widely indicated for patients with breast carcinoma, we did a literature review, looking for other cases with this type of toxicity. Conclusion This case is the third with vasculitis informed in the literature, but the first one that additionally developed cholestasis and arthritis. Although it is rare, we discuss the indication of this drug in the actual era, where aromatase inhibitors offer a better security profile.

  12. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer.

    Science.gov (United States)

    Ingle, J N; Krook, J E; Green, S J; Kubista, T P; Everson, L K; Ahmann, D L; Chang, M N; Bisel, H F; Windschitl, H E; Twito, D I

    1986-02-01

    A randomized clinical trial was performed to compare the efficacy of bilateral oophorectomy with that of tamoxifen at a dose of 10 mg twice daily in premenopausal women with metastatic breast cancer, and to examine the efficacy of each as a crossover treatment. Initial treatment responses were seen in ten of 27 patients (37%) treated with oophorectomy and seven of 26 patients (27%) treated with tamoxifen. The difference was not statistically significant. Crossover responses were seen in five of 15 patients (33%) treated with oophorectomy, including three responses in ten prior tamoxifen nonresponders; and two of 18 patients (11%) treated with tamoxifen. Time to progression distributions were not significantly different during initial treatment, and no significant differences in survival were noted. Thus, there was no overall disadvantage to the use of tamoxifen as opposed to oophorectomy as initial hormonal therapy, and a failure to respond to tamoxifen did not preclude a response to subsequent oophorectomy. Exploratory data analysis within subsets indicated consistent differential treatment effects in the visceral dominant patients. Of the 16 such patients treated with oophorectomy, eight (50%) experienced objective responses but there were no responses in the 14 patients treated with tamoxifen. In the nine visceral dominant crossover patients who had not responded to initial tamoxifen, three (33%) subsequently responded to oophorectomy. Time to progression distributions within the visceral dominant subset appeared to be better for the patients treated initially with oophorectomy. However, one must be very cautious in drawing conclusions from exploratory subset analyses, especially with the small sample size. Further studies would be required to test any hypothesis of differential organ site responsiveness.

  13. Factors Promoting Tamoxifen Resistance in Breast Cancer via Stimulating Breast Cancer Stem Cell Expansion.

    Science.gov (United States)

    Ojo, Diane; Wei, Fengxiang; Liu, Yun; Wang, Enli; Zhang, Hongde; Lin, Xiaozeng; Wong, Nicholas; Bane, Anita; Tang, Damu

    2015-01-01

    Estrogen receptor-alpha positive (ER(+)) breast cancer constitutes 70-75% of the disease incidence. Tamoxifen has been the basis of endocrine therapy for patients with ER(+) breast cancer for more than three decades. The treatment reduces the annual mortality rate of breast cancer by 31%, and remains the most effective targeted cancer therapy. However, approximately one-third of patients treated with adjuvant tamoxifen suffer from aggressive recurrent disease. Resistance to tamoxifen, thus, remains a major challenge in providing effective treatments for these patients. In an effort to overcome the resistance, intensive research has been conducted to understand the underlying mechanisms; this has resulted in the identification of complex factors/pathways contributing to tamoxifen resistance, including modulations of the ERsignaling, upregulation of a set of growth factor receptor networks (HER2, EGFR, FGFR, and IGF1R), alterations of the PI3K-PTEN/AKT/mTOR pathway, and an elevation of the NF-κB signaling. Despite these advances, our understanding of the acquired resistance remains fragmented and there is a lack of a platform to integrate these diversified molecular factors/ pathways into a cohesive mechanistic model. Nonetheless, at the cellular level, it is becoming increasingly recongnized that cancer stem cells (CSCs) are key in driving cancer metastasis and therapy resistance. Likewise, evidence is emerging for the critical contributions of breast cancer stem cells (BCSCs) to tamoxifen resistance. In this review, we will discuss these recent developments of BCSC-mediated resistance to tamoxifen and the contributions of those demonstrated molecular factors/pathways to BCSC expansion during the emergency of tamoxifen resistance.

  14. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer.

    Science.gov (United States)

    Ingle, J N; Ahmann, D L; Green, S J; Edmonson, J H; Bisel, H F; Kvols, L K; Nichols, W C; Creagan, E T; Hahn, R G; Rubin, J; Frytak, S

    1981-01-01

    Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

  15. Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Kai [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of Life Science and Technology, Jinan University, Guangzhou (China); Chen, Maoyun [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of pharmacy, Jinan University, Guangzhou (China); Xiang, Yangfei; Ma, Kaiqi [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); Jin, Fujun [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of pharmacy, Jinan University, Guangzhou (China); Wang, Xiao [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China); Wang, Xiaoyan; Wang, Shaoxiang [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); Wang, Yifei, E-mail: twang-yf@163.com [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China)

    2014-04-18

    Highlights: • We analyze the anti-HSV potential of chloride channel inhibitors. • Tamoxifen and NPPB show anti-HSV-1 and anti-ACV-resistant HSV-1 activities. • HSV-1 infection induces intracellular chloride concentration increasing. • Tamoxifen and NPPB inhibit HSV-1 early infection. • Tamoxifen and NPPB prevent the fusion process of HSV-1. - Abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.

  16. Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation: A systematic review and meta-analysis

    NARCIS (Netherlands)

    Belley-Cote, Emilie P.; Hanif, Hasib; D’Aragon, Frederick; Eikelboom, John W.; Anderson, Jeffrey L.; Borgman, Mark; Jonas, Daniel E.; Kimmel, Stephen E.; Manolopoulos, Vangelis G.; Baranova, Ekaterina; Maitland-van der Zee, Anke H.; Pirmohamed, Munir; Whitlock, Richard P.

    2015-01-01

    Variability in vitamin K antagonist (VKA) dosing is partially explained by genetic polymorphisms. We performed a meta-analysis to determine whether genotype-guided VKA dosing algorithms decrease a composite of death, thromboembolic events and major bleeding (primary outcome) and improve time in ther

  17. The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Clausen, Mathias Porsmose; Bennetzen, Martin

    2009-01-01

    -glycoprotein in cancer cells. In this study, we have investigated the effect of chlorpromazine on tamoxifen response of human breast cancer cells. We found that chlorpromazine worked synergistically together with tamoxifen with respect to reduction of cell growth and metabolic activity, both in the antiestrogen......-sensitive breast cancer cell line, MCF-7, and in a tamoxifen-resistant cell line, established from the MCF-7 cells. Tamoxifen-sensitive and tamoxifen-resistant cells were killed equally well by combined treatment with chlorpromazine and tamoxifen. This synergistic effect could be prevented by addition of estrogen...

  18. Is tamoxifen associated with an increased risk for thromboembolic complications in patients undergoing microvascular breast reconstruction? [Ist die Einnahme von Tamoxifen zum Zeitpunkt der mikrovaskulären Brustrekonstruktion mit einer erhöhten Rate an thrombembolischen Komplikationen assoziiert?

    Directory of Open Access Journals (Sweden)

    Krämer, Robert

    2013-02-01

    Full Text Available [english] Introduction: Tamoxifen is associated with a twofold increased risk of thromboembolic events. Third generation aromatase inhibitors (AIs, such as letrozole, anastrozole, and exemestane have therefore replaced tamoxifen in the adjuvant therapy of hormone receptor-positive breast cancer. A retrospective review was performed in patients who underwent delayed microvascular breast reconstruction and received tamoxifen at the time of surgery in order to assess the risk of both minor and major flap complications including thromboembolic events.Patients and methods: Twenty-nine patients who underwent delayed microsurgical breast reconstruction with autologous tissue between 2006 and 2012 were included in the study. The overall complication rates were compared between patients who did versus those who did not receive tamoxifen at the time of microsurgical breast reconstruction. Results: Breast reconstruction was performed with a DIEP flap in and with a TRAM flap in 4 patients. Overall, the complication rate was 37.9% (n=11 consisting of 5 major (including one total flap loss and 6 minor complications. In patients receiving tamoxifen (n=5, we observed one minor complication and one major complication with a total flap loss due to thrombus formation at the anastomosis site. In one patient pulmonary embolism occurred without association to tamoxifen. The number of thromboembolic events was equivalent in both groups (p=0.642. No increase of major (p=0.858 or minor (p=0.967 complications in the tamoxifen group could be observed. Taking the overall complication rate into account there was no statistically difference between the two groups (p=0.917.Conclusion: In our study we could not observe an increased risk for thromobembolic events in patients receiving tamoxifen while undergoing autologous microvascular breast reconstruction.[german] Aromatasehemmer der dritten Generation haben mittlerweile Tamoxifen in der neoadjuvanten und adjuvanten Therapie

  19. Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women with Breast Cancer

    Science.gov (United States)

    Zafra-Ceres, Mercedes; de Haro, Tomas; Farez-Vidal, Esther; Blancas, Isabel; Bandres, Fernando; de Dueñas, Eduardo Martinez; Ochoa-Aranda, Enrique; Gomez-Capilla, Jose A.; Gomez-Llorente, Carolina

    2013-01-01

    Background Estrogen receptor-positive breast cancer tumors depend on estrogen signaling for their growth and replication and can be treated by anti-estrogen therapy with tamoxifen. Polymorphisms of the CYP2D6 and CYP2C19 genes are associated with an impaired response to tamoxifen. The study objective was to investigate the impact of genetic polymorphisms in CYP2D6 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Spanish women with estrogen receptor-positive breast cancer who were candidates for tamoxifen therapy. Methods: We studied 90 women with estrogen receptor-positive breast cancer, using the AmpliChip CYP450 test to determine CYP2D6 and CYP2C19 gene variants. Plasma levels of tamoxifen and its metabolites were quantified by high-performance liquid chromatography. Results The CYP2D6 phenotype was extensive metabolizer in 80%, intermediate metabolizer in 12.2%, ultra-rapid metabolizer in 2.2%, and poor metabolizer in 5.6% of patients, and the allele frequency was 35.0% for allele *1, 21.0% for *2, and 18.9% for *4. All poor metabolizers in this series were *4/*4, and their endoxifen and 4-hydroxy tamoxifen levels were 25% lower than those of extensive metabolizers. CYP2C19*2 allele, which has been related to breast cancer outcomes, was detected in 15.6% of the studied alleles. Conclusion CYP2D6*4/*4 genotype was inversely associated with 4-hydroxy tamoxifen and endoxifen levels. According to these results, CYP2D6 and CYP2C19 genotyping appears advisable before the prescription of tamoxifen therapy. PMID:23781139

  20. Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer.

    Science.gov (United States)

    Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh; Nirujogi, Raja Sekhar; Kim, Min-Sik; Manda, Srikanth S; Stearns, Vered; Gabrielson, Edward; Sukumar, Saraswati; Pandey, Akhilesh

    2015-11-01

    Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer.

    Science.gov (United States)

    Kimura, Morihiko; Tominaga, Takeshi; Kimijima, Izo; Takatsuka, Yuichi; Takashima, Shigemitsu; Nomura, Yasuo; Kasumi, Fujio; Yamaguchi, Akihiro; Masuda, Norikazu; Noguchi, Shinzaburo; Eshima, Nobuoki

    2014-05-01

    Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen. The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events. A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated. Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

  2. Physiologically Based Pharmacokinetic Modeling of Tamoxifen and its Metabolites in Women of Different CYP2D6 Phenotypes Provides New Insight into the Tamoxifen Mass Balance

    Science.gov (United States)

    Dickschen, Kristin; Willmann, Stefan; Thelen, Kirstin; Lippert, Jörg; Hempel, Georg; Eissing, Thomas

    2012-01-01

    Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+) mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6). It is widely accepted that CYP2D6 poor metabolizers exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved. In this study, physiologically based pharmacokinetic (PBPK)-modeling was applied to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy. A PBPK-model of tamoxifen and its pharmacologically important metabolites N-desmethyltamoxifen (NDM-TAM), 4-hydroxytamoxifen (4-OH-TAM), and endoxifen was developed and validated. This model is able to simulate the pharmacokinetics (PK) after single and repeated oral tamoxifen doses in female breast cancer patients in dependence of the CYP2D6 phenotype. A detailed model-based analysis of the mass balance offered support for a recent hypothesis stating a more prominent role for endoxifen formation from 4-OH-TAM. In the future this model provides a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity, or co-treatment with CYP2D6 inhibitors. PMID:22661948

  3. Physiologically-based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

    Directory of Open Access Journals (Sweden)

    Kristin eDickschen

    2012-05-01

    Full Text Available Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+ mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6. It is widely accepted that CYP2D6 poor metabolizers (PM exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers (EM. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved.In this context, physiologically-based pharmacokinetic (PBPK-modeling provides a useful tool to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy.It has long been thought that only a minor percentage of endoxifen is formed via 4-hydroxytamoxifen. However, the current investigation supports very recently published data that postulates a contribution of 4-hydroxytamoxifen above 20 % to total endoxifen formation. The developed PBPK-model describes tamoxifen PK in rats and humans. Moreover, tamoxifen metabolism in dependence of CYP2D6 phenotype in populations of European female individuals is well described, thus providing a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity or co-treatment with CYP2D6 inhibitors.

  4. Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen.

    Science.gov (United States)

    Mendes-Pereira, Ana M; Sims, David; Dexter, Tim; Fenwick, Kerry; Assiotis, Ioannis; Kozarewa, Iwanka; Mitsopoulos, Costas; Hakas, Jarle; Zvelebil, Marketa; Lord, Christopher J; Ashworth, Alan

    2012-02-21

    Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.

  5. Compound list: tamoxifen [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available tamoxifen TMX 00054 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/tamox...ifen.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/tamox...ifen.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/tamox...open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/tamoxifen.Rat.in_vivo.Liver.Repeat.zip ...

  6. Tamoxifen citrate loaded ethosomes for transdermal drug delivery system: preparation and characterization.

    Science.gov (United States)

    Sarwa, Khomendra Kumar; Suresh, Preeti K; Debnath, Manabendra; Ahmad, Mohammad Zaki

    2013-08-01

    Long term tamoxifen citrate therapy is imperative to treat several dermatological and hormonal sensitive disorders. Successful oral and parenteral administration of tamoxifen citrate has been challenging since it undergoes enzymatic degradation and has poor aqueous solubility issues. In the present work, tamoxifen citrate loaded ethosomes were prepared and characterized for transdermal applications. The prepared formulations were characterized for morphological features, particle size distribution, calorimetric attributes, zeta potential and drug entrapment. Permeation profile of prepared ethosomes was compared with liposomes and hydroethonalic solution across cellophane membrane and human cadaver skin. Results of the permeation studies indicate that ethosomes were able to deliver >90% drug within 24 hours of application, while liposomes and hydroethanolic solution delivered only 39.04% and 36.55% respectively. Skin deposition and stability studies are also reported.

  7. Increased Lipiodol uptake in hepatocellular carcinoma possibly due to increased membrane fluidity by dexamethasone and tamoxifen

    Energy Technology Data Exchange (ETDEWEB)

    Becker, Stephanie, E-mail: stephanie.becker@rouen.fnclcc.f [Department of Nuclear Medicine, Centre E. Marquis, F-35042 Rennes (France); INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France); Department of Nuclear Medicine, Centre H. Becquerel, F-76038 Rouen (France); Ardisson, Valerie; Lepareur, Nicolas [Department of Nuclear Medicine, Centre E. Marquis, F-35042 Rennes (France); INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France); Sergent, Odile [European University of Brittany, F-35000 Rennes (France); UPRES EA SeRAIC, IFR 140, University of Rennes 1, F-35043 Rennes (France); Bayat, Sahar [INSERM U936 Department of Biostatistics, CHRU Pontchaillou, F-35033 Rennes (France); Noiret, Nicolas [European University of Brittany, F-35000 Rennes (France); Ecole Nationale Superieure de Chimie de Rennes, UMR CNRS 6226, F-35708 Rennes (France); Gaboriau, Francois; Clement, Bruno [INSERM U 991, Rennes, F-35033 France (France); Boucher, Evelyne [INSERM U 991, Rennes, F-35033 France (France); Department of Medical Oncology, Centre E. Marquis, F-35042 Rennes (France); Raoul, Jean-Luc [INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France); Department of Medical Oncology, Centre E. Marquis, F-35042 Rennes (France); Garin, Etienne [Department of Nuclear Medicine, Centre E. Marquis, F-35042 Rennes (France); INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France)

    2010-10-15

    Introduction: Lipiodol is used as a vector for chemoembolization or internal radiotherapy in unresectable hepatocellular carcinomas (HCCs). The aim of this study is to improve the tumoral uptake of Lipiodol by modulating membrane fluidizing agents to optimize the effectiveness of Lipiodol vectorized therapy. Methods: The effect of dexamethasone and tamoxifen on membrane fluidity was studied in vitro by electron paramagnetic resonance applied to rat hepatocarcinoma cell line N1S1. The tumoral uptake of Lipiodol was studied in vivo on rats with HCC, which had been previously treated by dexamethasone and/or tamoxifen, after intra-arterial administration of {sup 99m}Tc-SSS-Lipiodol. Results: The two molecules studied here exhibit a fluidizing effect in vitro which appears dependent on time and dose, with a maximum fluidity obtained after 1 hr at concentrations of 20 {mu}M for dexamethasone and 200 nM for tamoxifen. In vivo, while the use of dexamethasone or tamoxifen alone tends to lead to increased tumoral uptake of Lipiodol, this effect does not reach levels of significance. On the other hand, there is a significant increase in the tumoral uptake of {sup 99m}Tc-SSS-Lipiodol in rats pretreated by both dexamethasone and tamoxifen, with a tumoral uptake (expressed in % of injected activity per g of tumor) of 13.57{+-}3.65% after treatment, as against 9.45{+-}4.44% without treatment (P<.05). Conclusions: Dexamethasone and tamoxifen fluidify the N1S1 cells membrane, leading to an increase in the tumoral uptake of Lipiodol. These drugs could be combined with chemo-Lipiodol-embolization or radiolabeled Lipiodol, with a view to improving the effectiveness of HCCs therapy.

  8. Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells.

    Science.gov (United States)

    Kim, Sangmin; Lee, Jeongmin; Oh, Soo Jin; Nam, Seok Jin; Lee, Jeong Eon

    2015-09-01

    Although tamoxifen is the most common and effective therapy for treatment of estrogen receptor-α (ER-α) breast cancer patients, resistance of endocrine therapy occurs, either de novo or acquired during therapy. Here, we investigated the clinical value of epidermal growth factor receptor (EGFR) in tamoxifen-resistant (TamR) patients and the differential effect of EGFR inhibitors, neratinib and gefitinib, on TamR breast cancer cell model. The morphology of TamR MCF7 cells showed mesenchymal phenotypes and did not induce cell death by tamoxifen treatment compared with tamoxifen‑sensitive (TamS) MCF7 cells. In addition, mesenchymal marker proteins, including N-cadherin (N-cad), fibronectin (FN), and Slug, significantly increased in TamR cells. In contrast, ER-α and E-cadherin (E-cad) were greatly decreased. We also found that the levels of EGFR and HER2 expression were increased in TamR cells. Furthermore, we observed that EGFR expression was directly involved with poor prognosis of tamoxifen-treated breast cancer patients using the GSE1378 date set. Thus, we treated TamR and TamS cells with EGFR inhibitors, neratinib and gefitinib, respectively. Interestingly, neratinib induced apoptotic cell death of TamR but not gefitinib. Cleaved PARP-1 expression was also increased by neratinib treatment in TamR cells. Therefore, we suggest that neratinib may be a potential therapeutic drug for treating TamR breast cancer.

  9. Signaling by estrogens and tamoxifen in the human endometrium.

    Science.gov (United States)

    Gielen, Susanne C J P; Santegoets, Lindy A M; Hanifi-Moghaddam, Payman; Burger, Curt W; Blok, Leen J

    2008-04-01

    Tamoxifen is used as adjuvant treatment for postmenopausal breast cancer patients. The mechanism of action of tamoxifen in breast cancer patients is that tamoxifen inhibits growth of cancer cells by competitive antagonism for estrogens at the estrogen receptor (ER). In the endometrium, tamoxifen has an effect that varies with the ambient concentration of estrogen: in premenopausal women (high estrogen levels), tamoxifen displays an estrogen-antagonistic effect, while in postmenopausal women (low estrogen levels), tamoxifen displays an estrogen-agonistic mode of action. Here, using microarray technology we have compared estrogen signaling with tamoxifen signaling in the human endometrium. It was observed that on the one hand tamoxifen-treatment results in modulation of expression of specific genes (370 genes) and on the other hand tamoxifen-treatment results in modulation of a set of genes which are also regulated by estrogen treatment (142 genes). Upon focusing on regulation of proliferation, we found that tamoxifen-induced endometrial proliferation is largely accomplished by using the same set of genes as are regulated by estradiol. So, as far as regulation of proliferation goes, tamoxifen seems to act as estrogen agonist. Furthermore, tamoxifen-specific gene regulation may explain why tamoxifen-induced endometrial tumors behave more aggressively than sporadic endometrial tumors.

  10. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single [14C]-Labeled Therapeutic Dose.

    Energy Technology Data Exchange (ETDEWEB)

    Brown, K; Tompkins, E M; Boocock, D J; Martin, E A; Farmer, P B; Turteltaub, K W; Ubick, E; Hemingway, D; Horner-Glister, E; White, I H

    2007-05-23

    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single [{sup 14}C]-labeled therapeutic (20 mg) dose, {approx}18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N{sup 2}-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/10{sup 9} nucleotides. No [{sup 14}C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to {alpha}-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was {approx}10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  11. Hyper-reactivity of cerebral arteries from ovariectomized rats: therapeutic benefit of tamoxifen.

    Science.gov (United States)

    Thorin, Eric; Pham-Dang, Mylan; Clement, Robert; Mercier, Isabelle; Calderone, Angelino

    2003-12-01

    1. An increased incidence of systemic hypertension has been documented in postmenopausal women and identified as an independent risk factor in the development of cerebrovascular stroke. The present study examined whether cerebrovascular reactivity was increased in the hypertensive ovariectomized rat, and explored the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen. 2. Female Sprague-Dawley rats were subjected to bilateral ovariectomy (OVX, n=16) or a sham operation (n=8). At 6-week postsurgery, rats were anesthetized to assess ventricular contractility and blood pressure. In a second series of experiments, OVX rats (n=8) were given tamoxifen starting 3 weeks postsurgery, and continued for 3 weeks. At the end of each protocol, the middle cerebral artery was harvested and rings were mounted in wire-myographs to measure isometric tension. 3. Systolic arterial pressure (SAP) was significantly increased (PEmax), whereas a significant (PEmax). Lastly, vascular sensitivity (pD2) to sodium nitroprusside was significantly increased (P<0.05) in OVX rats, as compared to sham. 4. Tamoxifen therapy normalized the resting tension of isolated cerebral arteries from OVX rats, abrogated phenylephrine-mediated contraction, and modestly reduced SAP. By contrast, tamoxifen treatment of OVX rats did not attenuate L-NNA-mediated contractile response of cerebral arteries. 5. These data demonstrate that the cerebral artery isolated from the OVX rat was associated with an exaggerated vasoconstrictor response to phenylephrine, and altered NO-dependent vascular reactivity. The administration of tamoxifen to OVX rats normalized cerebral artery reactivity to phenylephrine. These findings provide the impetus to examine the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen to reduce the incidence of cerebrovascular stroke in postmenopausal women.

  12. The role of Nanog expression in tamoxifen-resistant breast cancer cells

    Directory of Open Access Journals (Sweden)

    Arif K

    2015-06-01

    Full Text Available Khalid Arif,1 Issam Hussain,1 Carol Rea,1 Mohamed El-Sheemy2 1School of Life Sciences, University of Lincoln, Brayford Pool, 2Lincoln County Hospital, Greetwell Road, Lincoln, Lincolnshire, UK Abstract: There is an accumulation of evidence that shows a significant role of cancer stem cells in tumor initiation, proliferation, relapse, and metastasis. Nanog is the most important core transcription marker of stem cells, known by its role in maintaining pluripotency, proliferation, and differentiation. Therefore, this study aimed to examine the role of Nanog in breast cancer cell tamoxifen resistance and its implications in breast cancer treatment. In this study, the expression of the three core transcription markers Nanog, Oct3/4, and Sox2 were quantitatively evaluated using flow cytometry. Then, small interfering RNA (siRNA against human Nanog was transfected into tamoxifen-resistant breast cancer cells via Lipofectamine 2000. Nanog gene expression in the cells was detected using reverse transcription polymerase chain reaction (RT-PCR. The change in cell proliferation was evaluated using the tetrazolium bromide method. An enzyme-linked immunosorbent assay was used to detect apoptosis of the transfected cells alone and in combination with 4-hydroxytamoxifen. The results showed a high level expression of Nanog, Oct3/4, and Sox2 in MDA-MB-231 and MCF7/tamoxifen resistant cells compared with MCF7/wild-type. siRNA-mediated Nanog gene silencing can efficiently inhibit cell proliferation and induce apoptosis of tamoxifen-resistant breast cancer cells. This study provides a basis for further study of the role of Nanog in developing resistance to tamoxifen, its implication in breast cancer management, and as a new strategy to enhance response to endocrine therapy. Keywords: breast cancer, cancer stem cell, Nanog, tamoxifen, estrogen receptor

  13. Relevance of breast cancer antiestrogen resistance genes in human breast cancer progression and tamoxifen resistance.

    Science.gov (United States)

    van Agthoven, Ton; Sieuwerts, Anieta M; Meijer-van Gelder, Marion E; Look, Maxime P; Smid, Marcel; Veldscholte, Jos; Sleijfer, Stefan; Foekens, John A; Dorssers, Lambert C J

    2009-02-01

    We have previously identified a set of breast cancer antiestrogen resistance (BCAR) genes causing estrogen independence and tamoxifen resistance in vitro using a functional genetic screen. Here, we explored whether these BCAR genes provide predictive value for tamoxifen resistance and prognostic information for tumor aggressiveness in breast cancer patients. mRNA levels of 10 BCAR genes (AKT1, AKT2, BCAR1, BCAR3, EGFR, ERBB2, GRB7, SRC, TLE3, and TRERF1) were measured in estrogen receptor-positive breast tumors using quantitative reverse-transcriptase polymerase chain reaction. Normalized mRNA levels were evaluated for association with progression-free survival (PFS) in 242 patients receiving tamoxifen as first-line monotherapy for recurrent disease, and with distant metastasis-free survival (MFS) in 413 lymph node-negative (LNN) primary breast cancer patients who did not receive systemic adjuvant therapy. Concerning tamoxifen resistance, BCAR3, ERBB2, GRB7, and TLE3 mRNA levels were predictive for PFS, independent of traditional predictive factors. By combining GRB7 (or ERBB2) and TLE3 mRNA levels, patients could be classified in three subgroups with distinct PFS. For the evaluation of tumor aggressiveness, AKT2, EGFR, and TRERF1 mRNA levels were all significantly associated with MFS, independent of traditional prognostic factors. Using the combined AKT2 and EGFR mRNA status, four prognostic groups were identified with different MFS outcomes. The majority of BCAR genes, which were revealed to confer tamoxifen resistance and estrogen independence in vitro by functional screening, have clinical relevance, and associate with tamoxifen resistance and/or tumor aggressiveness in breast cancer patients.

  14. Ovarian cysts in women receiving tamoxifen for breast cancer

    NARCIS (Netherlands)

    Mourits, MJE; de Vries, EGE; Willemse, PHB; ten Hoor, KA; Hollema, H; Sluiter, WJ; de Bruijn, HWA; van der Zee, AGJ

    1999-01-01

    Tamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast ca

  15. CCNA2 is a prognostic biomarker for ER+ breast cancer and tamoxifen resistance.

    Science.gov (United States)

    Gao, Tian; Han, Yong; Yu, Ling; Ao, Sheng; Li, Ziyu; Ji, Jiafu

    2014-01-01

    Identification of effective prognostic biomarkers and targets are of crucial importance to the management of estrogen receptor positive (ER+) breast cancer. CCNA2 (also known as CyclinA2) belongs to the highly conserved cyclin family and is significantly overexpressed in various cancer types. In this study, we demonstrated that CCNA2 had significant predictive power in distant metastasis free survival, disease free survival, recurrence free survival and overall survival of ER+ breast cancer patients. We also found that CCNA2 was closely associated with tamoxifen resistance. In addition, gene set enrichment analysis (GSEA) revealed that its expression was positively associated with genes overexpressed in endocrine therapy resistant samples. Finally, though CCNA2-Drug interaction network, we demonstrated the interactions between CCNA2 and several available cancer drugs. Overall, we suggest that CCNA2 is a biomarker for the prognosis of ER+ breast cancer and monitoring of tamoxifen efficacy. It's also a promising target for developing new strategies to prevent or even reverse tamoxifen resistance. Moreover, CCNA2 expression may help monitoring tamoxifen efficacy and directing personalized therapies. Nevertheless, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed before its application in clinical settings.

  16. CCNA2 is a prognostic biomarker for ER+ breast cancer and tamoxifen resistance.

    Directory of Open Access Journals (Sweden)

    Tian Gao

    Full Text Available Identification of effective prognostic biomarkers and targets are of crucial importance to the management of estrogen receptor positive (ER+ breast cancer. CCNA2 (also known as CyclinA2 belongs to the highly conserved cyclin family and is significantly overexpressed in various cancer types. In this study, we demonstrated that CCNA2 had significant predictive power in distant metastasis free survival, disease free survival, recurrence free survival and overall survival of ER+ breast cancer patients. We also found that CCNA2 was closely associated with tamoxifen resistance. In addition, gene set enrichment analysis (GSEA revealed that its expression was positively associated with genes overexpressed in endocrine therapy resistant samples. Finally, though CCNA2-Drug interaction network, we demonstrated the interactions between CCNA2 and several available cancer drugs. Overall, we suggest that CCNA2 is a biomarker for the prognosis of ER+ breast cancer and monitoring of tamoxifen efficacy. It's also a promising target for developing new strategies to prevent or even reverse tamoxifen resistance. Moreover, CCNA2 expression may help monitoring tamoxifen efficacy and directing personalized therapies. Nevertheless, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed before its application in clinical settings.

  17. Faktor Yang Mempengaruhi Kepatuhan Berobat Pasien Yang Diterapi Dengan Tamoxifen Setelah Operasi Kanker Payudara

    Directory of Open Access Journals (Sweden)

    Arif Budiman

    2013-01-01

    . Period of research carried out for 3 months. Analysis univariat, bivariat and multivariat performed by using SPSS version 18.00.Results. Of the 61 patients we found 9 patients not adherent tamoxifen therapy, the results bivariant a significant association between adherence to the age, level of education, familyIncome, availability of health insurance and medical care (p<0.05. Multivariate analysis found that the most influential factor is the care of medical personnel with p=0.06. Discussion. It can be concluded that the medical services are the most influential factor on treatment compliance of patients receiving tamoxifen after breast cancer surgery, other factors are age, education level, family income and the availability of health insurance. The results of this study can be suggestion on the medical staff so as to improve treatment compliance of patients.Keywords:Compliance, tamoxifen, breast cancer.

  18. A candidate molecular signature associated with tamoxifen failure in primary breast cancer.

    Science.gov (United States)

    Vendrell, Julie A; Robertson, Katherine E; Ravel, Patrice; Bray, Susan E; Bajard, Agathe; Purdie, Colin A; Nguyen, Catherine; Hadad, Sirwan M; Bieche, Ivan; Chabaud, Sylvie; Bachelot, Thomas; Thompson, Alastair M; Cohen, Pascale A

    2008-01-01

    Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer. Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified. Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERalpha, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-alpha, gamma-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERalpha, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERalpha, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression

  19. Tamoxifen is not effective in good prognosis patients with hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Daniele Bruno

    2006-07-01

    Full Text Available Abstract Background Large randomised clinical trials and systematic reviews substantiate that tamoxifen is ineffective in improving survival of patients with hepatocellular carcinoma (HCC. However, a recent report suggested that the drug might prolong survival among patients with well preserved liver function. The aim of this paper is to validate this hypothesis. Methods We used the updated database of the phase 3 randomised CLIP-1 trial that compared tamoxifen with supportive therapy. Primary endpoint was overall survival. Treatment arms were compared within strata defined according to the Okuda stage and the CLIP-score. Survival differences were tested by the Log-rank test. Results Tamoxifen was not effective in prolonging survival in Okuda I-II subgroup (p = 0.501. Median survival times were equal to 16.8 (95%CI 12.7–18.5 months for tamoxifen and 16.8 (95%CI 13.5–22.4 months for the control arms; 1-year survival probabilities were equal to 58.8% (95%CI 51.7–65.8 and 59.4 (95%CI 52.5–66.2, respectively. Similar results were observed in the better CLIP subgroup (score 0/1, without evidence of difference between the two treatment arms (p = 0.734. Median survival times were equal to 29.2 (95%CI 20.1–36.4 months with tamoxifen and 29.0 (95%CI 23.3–35.2 months without; 1-year survival probabilities were equal to 80.9% (95%CI 72.5–89.3 with tamoxifen and 77.1% (95%CI 68.6–85.7 for the control arm. Conclusion The recent suggestion that tamoxifen might be effective in the subgroup of patients with better prognosis is not supported by a reanalysis of the CLIP-1 trial. Tamoxifen should no longer be considered for the treatment of HCC patients and future trials of medical treatment should concentrate on different drugs.

  20. Gamma shielding properties of Tamoxifen drug

    Science.gov (United States)

    Kanberoglu, Gulsah Saydan; Oto, Berna; Gulebaglan, Sinem Erden

    2017-02-01

    Tamoxifen (MW=371 g/mol) is an endocrine therapeutic drug widely prescribed as chemopreventive in women to prevent and to treat all stages of breast cancer. It is also being studied for other types of cancer. In this study, we have calculated some gamma shielding parameters such as mass attenuation coefficient (μρ), effective atomic number (Zeff) and electron density (Nel) for Tamoxifen drug. The values of μρ were calculated using WinXCom computer program and then the values of Zeff and Nel were derived using μρ values in the wide energy range (1 keV - 100 GeV).

  1. Tamoxifen integromics and personalized medicine: dynamic modular transformations underpinning response to tamoxifen in breast cancer treatment.

    Science.gov (United States)

    Dimitrakopoulou, Konstantina; Dimitrakopoulos, Georgios N; Sgarbas, Kyriakos N; Bezerianos, Anastasios

    2014-01-01

    Recent advances in pharmacogenomics technologies allow bold steps to be taken towards personalized medicine, more accurate health planning, and personalized drug development. In this framework, systems pharmacology network-based approaches offer an appealing way for integrating multi-omics data and set the basis for defining systems-level drug response biomarkers. On the road to individualized tamoxifen treatment in estrogen receptor-positive breast cancer patients, we examine the dynamics of the attendant pharmacological response mechanisms. By means of an "integromics" network approach, we assessed the tamoxifen effect through the way the high-order organization of interactome (i.e., the modules) is perturbed. To accomplish that, first we integrated the time series transcriptome data with the human protein interaction data, and second, an efficient module-detecting algorithm was applied onto the composite graphs. Our findings show that tamoxifen induces severe modular transformations on specific areas of the interactome. Our modular biomarkers in response to tamoxifen attest to the immunomodulatory role of tamoxifen, and further reveal that it deregulates cell cycle and apoptosis pathways, while coordinating the proteasome and basal transcription factors. To the best of our knowledge, this is the first report that informs the fields of personalized medicine and clinical pharmacology about the actual dynamic interactome response to tamoxifen administration.

  2. Construction of a Nanodiamond–Tamoxifen Complex as a Breast Cancer Drug Delivery Vehicle

    Directory of Open Access Journals (Sweden)

    Linda-Lucila Landeros-Martínez

    2016-01-01

    Full Text Available According to the World Health Organization, breast cancer represents 16% of all cancer cases in women and is the second most common cancer. In the past decades, the mortality among patients with metastasis breast cancer has been reduced significantly via drug delivery by means of nanodiamond therapies, which are both biocompatible and scalable. In this study, we determined a theoretical pathway for the construction of a nanodiamond–tamoxifen complex that will act as a drug delivery vehicle for targeting tumor tissues of breast cancer. The tamoxifen pharmacophore was defined and the binding zone was identified for the electrostatic interaction between tamoxifen and a functionalized site of a nanodiamond particle allowing for attachment of the payload (this drug to the surface of the nanodiamond particle. In addition, an analysis of the intermolecular interaction between the nanodiamond and tamoxifen was conducted, showing three hydrogen bonds complying fully with Lipinski’s rule of five, which states that a compound should have five or fewer hydrogen bonds to be permeating and easily absorbed by the body (qualitative prediction. All calculations were performed using the conceptual Density Functional Theory with the M06 functional and the basis set 6-31G(d. The solvent effect has been taken into account by an implicit model, the conductor like polarizable continuum model.

  3. ATLAS: Adjuvant Tamoxifen Longer Against Shorter

    Science.gov (United States)

    1998-09-01

    tamoxifen duration in early breast cancer Davies C Peto R Gray R 3rd Portuguese -Brazilian Mastology Congress - Recife, Brazil November 1996 ATLAS: An...van Leeuwenhoek Huis Oficina ATLAS (Espana) Inst. Portugues de Oncologia Antoninlvan Leeuwenhoek HuisCEPSS - FPT Av. Bissaia Barreto Plesmanlaan 121

  4. Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases.

    Science.gov (United States)

    Sommer, Ann-Katrin; Hermawan, Adam; Mickler, Frauke Martina; Ljepoja, Bojan; Knyazev, Pjotr; Bräuchle, Christoph; Ullrich, Axel; Wagner, Ernst; Roidl, Andreas

    2016-08-02

    Luminal A breast cancer is the most common breast cancer subtype which is usually treated with selective estrogen receptor modulators (SERMS) like tamoxifen. Nevertheless, one third of estrogen receptor positive breast cancer patients initially do not respond to endocrine therapy and about 40% of luminal A breast tumors recur in five years. In this study, we investigated an alternative treatment approach by combining tamoxifen and salinomycin in luminal A breast cancer cell lines. We have found that salinomycin induces an additional cytotoxic effect by inhibiting the ligand independent activation of ERα. Thereby salinomycin increases the intracellular calcium level. This leads to a premature fusion of endosomes with lysosomes and thus to the degradation of Egfr family members. Since this process is essential for luminal A breast cancer cells to circumvent tamoxifen treatment, the combination of both drugs induces cytotoxicity in tamoxifen sensitive as well as resistant luminal A breast cancer cell lines.

  5. Relationship Between Quantitative Estrogen and Progesterone Receptor Expression and Human Epidermal Growth Factor Receptor 2 (HER-2) Status With Recurrence in the Arimidex, Tamoxifen, Alone or in Combination Trial

    National Research Council Canada - National Science Library

    Mitch Dowsett; Craig Allred; Jill Knox; Emma Quinn; Janine Salter; Chris Wale; Jack Cuzick; Joan Houghton; Norman Williams; Elizabeth Mallon; Hugh Bishop; Ian Ellis; Denis Larsimont; Hironobu Sasano; Pauline Carder; Antonio Llombart Cussac; Fiona Knox; Valerie Speirs; John Forbes; Aman Buzdar

    2008-01-01

    ...) expression and human epidermal growth factor 2 (HER-2) status with time to recurrence (TTR) in postmenopausal women with hormone receptor-positive primary breast cancer treated with anastrozole or tamoxifen as adjuvant therapy...

  6. Prior Adjuvant Tamoxifen Treatment in Breast Cancer Is Linked to Increased AIB1 and HER2 Expression in Metachronous Contralateral Breast Cancer

    Science.gov (United States)

    Alkner, Sara; Bendahl, Pär-Ola; Ehinger, Anna; Lövgren, Kristina; Rydén, Lisa; Fernö, Mårten

    2016-01-01

    Aim The estrogen receptor coactivator Amplified in Breast Cancer 1 (AIB1) has been associated with an improved response to adjuvant tamoxifen in breast cancer, but also with endocrine treatment resistance. We hereby use metachronous contralateral breast cancer (CBC) developed despite prior adjuvant tamoxifen for the first tumor as an “in vivo”-model for tamoxifen resistance. AIB1-expression in the presumable resistant (CBC after prior tamoxifen) and naïve setting (CBC without prior tamoxifen) is compared and correlated to prognosis after CBC. Methods From a well-defined population-based cohort of CBC-patients we have constructed a unique tissue-microarray including >700 patients. Results CBC developed after adjuvant tamoxifen more often had a HER2-positive/triple negative-subtype and a high AIB1-expression (37% vs. 23%, p = 0.009), than if no prior endocrine treatment had been administered. In patients with an estrogen receptor (ER) positive CBC, a high AIB1-expression correlated to an inferior prognosis. However, these patients seemed to respond to tamoxifen, but only if endocrine therapy had not been administered for BC1. Conclusions Metachronous CBC developed after prior endocrine treatment has a decreased ER-expression and an increased HER2-expression. This is consistent with endocrine treatment escape mechanisms previously suggested, and indicates metachronous CBC to be a putative model for studies of treatment resistance “in vivo”. The increased AIB1-expression in CBC developed after prior tamoxifen suggests a role of AIB1 in endocrine treatment resistance. In addition, we found indications that the response to tamoxifen in CBC with a high AIB1-expression seem to differ depending on previous exposure to this drug. A different function for AIB1 in the tamoxifen treatment naïve vs. resistant setting is suggested, and may explain previously conflicting results where a high AIB1-expression has been correlated to both a good response to adjuvant

  7. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial

    DEFF Research Database (Denmark)

    Crivellari, D.; Sun, Z.; Coates, A.S.;

    2008-01-01

    PURPOSE: To explore potential differences in efficacy, treatment completion, and adverse events (AEs) in elderly women receiving adjuvant tamoxifen or letrozole for five years in the Breast International Group (BIG) 1-98 trial. METHODS: This report includes the 4,922 patients allocated to 5 years...... of letrozole or tamoxifen in the BIG 1-98 trial. The median follow-up was 40.4 months. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to examine the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categoric age groups were...... had superior efficacy (DFS) compared with tamoxifen in all age groups. On the basis of a small number of patients older than 75 years (6%), age per se should not unduly affect the choice of adjuvant endocrine therapy Udgivelsesdato: 2008/4/20...

  8. Clinical evidence on the magnitude of change in growth pathway activity in relation to Tamoxifen resistance is required.

    Science.gov (United States)

    Mansouri, Sepideh; Farahmand, Leila; Teymourzadeh, Azin; Majidzadeh-A, Keivan

    2017-08-08

    Despite prolonged disease-free survival and overall survival rates in estrogen receptor (ER)-positive patients undergoing adjuvant treatment, Tamoxifen therapy tends to fail due to eventual acquisition of resistance. Although numerous studies have emphasized the role of receptor tyrosine kinases (RTKs) in the development of Tamoxifen resistance, inadequate clinical evidence is available regarding the alteration of biomarker expression during acquired resistance, thus undermining the validity of the findings. Results of two meta-analyses investigating the effect of HER2 status on the prognosis of Tamoxifen-receiving patients have demonstrated that despite HER2-negative patients having longer disease-free survival; there is no difference in overhaul survival between the two groups. Furthermore, due to the intricate molecular interactions among estrogen receptors including ERα36, ERα66, and also RTKs, it is not surprising that RTK suppression does not restore Tamoxifen sensitivity. In considering such a complex network, we speculate that by the time HER2/EGFR is suppressed via targeted therapies, activation of ERα66 and ERα36 initiate molecular signaling pathways downstream of RTKs, thereby enhancing cell proliferation even in the presence of both Tamoxifen and RTK inhibitors. Although clinical findings regarding the molecular pathways downstream of RTKs have been thoroughly discussed in this review, further clinical studies are required in determining a consistency between preclinical and clinical findings. Discovering the best targets in preventing tumor progression requires thorough comprehension of estrogen-dependent and estrogen-independent pathways during Tamoxifen resistance development. Indeed, exploring additional clinically-proven targets would allow for better characterized treatments being available for breast cancer patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Estimation of tamoxifen metabolite concentrations in the blood of breast cancer patients through CYP2D6 genotype activity score.

    Science.gov (United States)

    Wu, Alan H B; Lorizio, Wendy; Tchu, Simone; Lynch, Kara; Gerona, Roy; Ji, Wuyang; Ruan, Weiming; Ruddy, Kathryn J; Desantis, Stephen D; Burstein, Harold J; Ziv, Elad

    2012-06-01

    Tamoxifen, a prodrug used for adjuvant breast cancer therapy, requires conversion to the active metabolite endoxifen through CYP 2D6. We aimed to construct an algorithm to predict endoxifen concentrations based on a patient’s CYP 2D6 genotype, demographic factors, and co-medication use. Eighty-eight women enrolled in the UCSF TamGen II study and 81 women enrolled in a prospective study at Dana-Farber Cancer Institute were included in this analysis. All the women had been on tamoxifen for at least 3 months before blood collection. Demographic information included the patient’s age, race/ethnicity, body mass index (where available), and self-reported and measured medications and herbals that affect 2D6 activity. DNA was extracted and genotyped for 2D6 (Amplichip, Roche Diagnostics). An activity score was calculated based on genotypes and adjusted for use of medications known to inhibit 2D6. Serum was tested for tamoxifen and metabolite concentrations and for the presence of drugs by liquid chromatography/mass spectrometry. Univariate and multivariate regression analysis were computed for age, body mass index, ethnicity, and adjusted activity score to predict tamoxifen metabolite concentrations in the training data-set of UCSF patients, and the resulting algorithm was validated in the Dana-Farber patients. For the training set, the correlation coefficient (r2) for log endoxifen and N-desmethyltamoxifen:endoxifen ratio to activity score, age, and race, were 0.520 and 0.659, respectively; 0.324 and 0.567 for the validation; and 0.396 and 0.615 for both the datasets combined. An algorithm that incorporates genotype and demographic variables can be used to predict endoxifen concentrations for women on tamoxifen therapy. If endoxifen levels are confirmed to be predictive of tamoxifen benefit, then this algorithm may be helpful to determine which women warrant endoxifen testing.

  10. Molecular classification of tamoxifen-resistant breast carcinomas by gene expression profiling.

    Science.gov (United States)

    Jansen, Maurice P H M; Foekens, John A; van Staveren, Iris L; Dirkzwager-Kiel, Maaike M; Ritstier, Kirsten; Look, Maxime P; Meijer-van Gelder, Marion E; Sieuwerts, Anieta M; Portengen, Henk; Dorssers, Lambert C J; Klijn, Jan G M; Berns, Els M J J

    2005-02-01

    To discover a set of markers predictive for the type of response to endocrine therapy with the antiestrogen tamoxifen using gene expression profiling. The study was performed on 112 estrogen receptor-positive primary breast carcinomas from patients with advanced disease and clearly defined types of response (ie, 52 patients with objective response v 60 patients with progressive disease) from start of first-line treatment with tamoxifen. Main clinical end points are the effects of therapy on tumor size and time until tumor progression (progression-free survival [PFS]). RNA isolated from tumor samples was amplified and hybridized to 18,000 human cDNA microarrays. Using a training set of 46 breast tumors, 81 genes were found to be differentially expressed (P tamoxifen-responsive and -resistant tumors. These genes were involved in estrogen action, apoptosis, extracellular matrix formation, and immune response. From the 81 genes, a predictive signature of 44 genes was extracted and validated on an independent set of 66 tumors. This 44-gene signature is significantly superior (odds ratio, 3.16; 95% CI, 1.10 to 9.11; P = .03) to traditional predictive factors in univariate analysis and also significantly related with a longer PFS in univariate (hazard ratio, 0.54; 95% CI, 0.31 to 0.94; P = .03) as well as in multivariate analyses (P = .03). Our data show that gene expression profiling can be used to discriminate between breast cancer patients with progressive disease and objective response to tamoxifen. Additional studies are needed to confirm if the predictive signature might allow identification of individual patients who could benefit from other (adjuvant) endocrine therapies.

  11. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer

    Science.gov (United States)

    Law, Emily K.; Sieuwerts, Anieta M.; LaPara, Kelly; Leonard, Brandon; Starrett, Gabriel J.; Molan, Amy M.; Temiz, Nuri A.; Vogel, Rachel Isaksson; Meijer-van Gelder, Marion E.; Sweep, Fred C. G. J.; Span, Paul N.; Foekens, John A.; Martens, John W. M.; Yee, Douglas; Harris, Reuben S.

    2016-01-01

    Breast tumors often display extreme genetic heterogeneity characterized by hundreds of gross chromosomal aberrations and tens of thousands of somatic mutations. Tumor evolution is thought to be ongoing and driven by multiple mutagenic processes. A major outstanding question is whether primary tumors have preexisting mutations for therapy resistance or whether additional DNA damage and mutagenesis are necessary. Drug resistance is a key measure of tumor evolvability. If a resistance mutation preexists at the time of primary tumor presentation, then the intended therapy is likely to fail. However, if resistance does not preexist, then ongoing mutational processes still have the potential to undermine therapeutic efficacy. The antiviral enzyme APOBEC3B (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3B) preferentially deaminates DNA C-to-U, which results in signature C-to-T and C-to-G mutations commonly observed in breast tumors. We use clinical data and xenograft experiments to ask whether APOBEC3B contributes to ongoing breast tumor evolution and resistance to the selective estrogen receptor modulator, tamoxifen. First, APOBEC3B levels in primary estrogen receptor–positive (ER+) breast tumors inversely correlate with the clinical benefit of tamoxifen in the treatment of metastatic ER+ disease. Second, APOBEC3B depletion in an ER+ breast cancer cell line results in prolonged tamoxifen responses in murine xenograft experiments. Third, APOBEC3B overexpression accelerates the development of tamoxifen resistance in murine xenograft experiments by a mechanism that requires the enzyme’s catalytic activity. These studies combine to indicate that APOBEC3B promotes drug resistance in breast cancer and that inhibiting APOBEC3B-dependent tumor evolvability may be an effective strategy to improve efficacies of targeted cancer therapies. PMID:27730215

  12. The role of the expression of bcl-2, p53 gene in tamoxifen-induced apoptosis of breast cancer cells and its relationship with hormone receptor status

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Woo Chul; Ham, Yong Ho [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1998-01-01

    To investigate the relationship of bcl-2, p53, ER and tamoxifen-induced apoptosis of breast cancer cells, MCF-7 (ER+/bcl-2+/p53-) and MB MDA 468 (ER-/bcl-2-/p53+) cell line were cultured in estrogen-free condition. E2(10`-`9M) and tamoxifen (10`-`5M) were added to the media. The changes of bcl-2 and mutant p53 protein were checked by Western blot and apoptosis were measured by flowcytometry. In MCF-7 cells, we found that treatment with tamoxifen resulted in a decrease in bcl-2 protein level, but produced no change in mutant p53. In MB MDA 468 cell however, there were no changes of bcl-2 and mutant p53 protein level when E2 or tamoxifen were added. Apoptotic cells increased with time-dependent pattern when tamoxifen was added to MCF-7 cells. According to these result, ER+/blc-2+/mutant p53- cells, when treated with tamoxifen, were converted into bcl-2/mutant p53- cells which were more prone to apoptosis than bcl-2-/mutant p53+ cells. The paradoxical correlation of bcl-2 and ER which had been observed in clinical studies might be explained with this results and bcl-2 protein seems to be one of important factors that can predict the effect of hormone therapy. (author). 26 refs., 5 figs

  13. “Iron-saturated” bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice

    Directory of Open Access Journals (Sweden)

    Sun Xueying

    2012-12-01

    Full Text Available Abstract Background Tamoxifen is used in hormone therapy for estrogen-receptor (ER-positive breast cancer, but also has chemopreventative effects against ER-negative breast cancers. This study sought to investigate whether oral iron-saturated bovine lactoferrin (Fe-Lf, a natural product which enhances chemotherapy, could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers. Methods In a model of breast cancer prevention, female Balb/c mice treated with tamoxifen (5 mg/Kg were fed an Fe-Lf supplemented diet (5 g/Kg diet or the base diet. At week 2, 4T1 mammary carcinoma cells were injected into an inguinal mammary fat pad. In a model of breast cancer treatment, tamoxifen treatment was not started until two weeks following tumor cell injection. Tumor growth, metastasis, body weight, and levels of interleukin 18 (IL-18 and interferon γ (IFN-γ were analyzed. Results Tamoxifen weakly (IC50 ~ 8 μM inhibited the proliferation of 4T1 cells at pharmacological concentrations in vitro. In the tumor prevention study, a Fe-Lf diet in combination with tamoxifen caused a 4 day delay in tumor formation, and significantly inhibited tumor growth and metastasis to the liver and lung by 48, 58, and 66% (all P P  Conclusions The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen. It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors.

  14. An integrated bioinformatics approach identifies elevated cyclin E2 expression and E2F activity as distinct features of tamoxifen resistant breast tumors.

    Directory of Open Access Journals (Sweden)

    Lei Huang

    Full Text Available Approximately half of estrogen receptor (ER positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers.

  15. An integrated bioinformatics approach identifies elevated cyclin E2 expression and E2F activity as distinct features of tamoxifen resistant breast tumors.

    Science.gov (United States)

    Huang, Lei; Zhao, Shuangping; Frasor, Jonna M; Dai, Yang

    2011-01-01

    Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers.

  16. CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study

    Directory of Open Access Journals (Sweden)

    Wickramage I

    2017-03-01

    Full Text Available Ishani Wickramage,1 Kamani Hemamala Tennekoon,1 Merenchi Arachchige Yasantha Ariyaratne,2 Asanka Sudeshini Hewage,1 Tharmini Sundralingam,1 1Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB, University of Colombo, Colombo, Sri Lanka; 2National Cancer Institute, Maharagama, Sri Lanka Introduction and aims: Tamoxifen is an adjuvant drug effective in treating hormone ­receptor – positive breast cancer. However, 30%–50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between CYP2D6 polymorphisms and recurrence of breast cancer in patients on tamoxifen had been reported, little evidence exists on association between these polymorphisms and adverse effects to tamoxifen. This study explored the association between CYP2D6 polymorphisms and tamoxifen effects, hitherto not studied in Sri Lanka. Methods: A retrospective preliminary study was carried out on 24 breast cancer patients on tamoxifen for minimally 3 months attending National Cancer Institute, Maharagama, Sri Lanka. They were not on CYP2D6-inhibiting drugs, chemotherapy or other endocrine therapy, and had no conditions that could occur as adverse effects to tamoxifen before starting the therapy. Their blood samples were collected, DNA was extracted and genotyped using SNaPshot Multiplex sequencing based single-nucleotide polymorphism (SNP assay. Results: SNP/allele frequencies detected: 1846G>A (confirmatory of *4 null allele=8.3%; 2549delA (confirmatory of *3 null allele=50%; 100C>T (suggestive of *10 reduced functional allele, in addition to other alleles=0%; combination of 2988G>A, -1584C and 2850C>T (strongly suggestive of *41 or other reduced functional allele=4.8%. Occurrence of heterozygous 2988G>A SNP with

  17. Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers.

    Science.gov (United States)

    Chew, G L; Huo, C W; Huang, D; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M C; Hopper, J L; Britt, K; Henderson, M A; Haviv, I; Thompson, E W

    2014-11-01

    Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other

  18. A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer.

    Science.gov (United States)

    Mihály, Zsuzsanna; Kormos, Máté; Lánczky, András; Dank, Magdolna; Budczies, Jan; Szász, Marcell A; Győrffy, Balázs

    2013-07-01

    To date, three molecular markers (ER, PR, and CYP2D6) have been used in clinical setting to predict the benefit of the anti-estrogen tamoxifen therapy. Our aim was to validate new biomarker candidates predicting response to tamoxifen treatment in breast cancer by evaluating these in a meta-analysis of available transcriptomic datasets with known treatment and follow-up. Biomarker candidates were identified in Pubmed and in the 2007-2012 ASCO and 2011-2012 SABCS abstracts. Breast cancer microarray datasets of endocrine therapy-treated patients were downloaded from GEO and EGA and RNAseq datasets from TCGA. Of the biomarker candidates, only those identified or already validated in a clinical cohort were included. Relapse-free survival (RFS) up to 5 years was used as endpoint in a ROC analysis in the GEO and RNAseq datasets. In the EGA dataset, Kaplan-Meier analysis was performed for overall survival. Statistical significance was set at p tamoxifen-resistance genes in three independent platforms and identified PGR, MAPT, and SLC7A5 as the most promising prognostic biomarkers in tamoxifen treated patients.

  19. Effects of a combined treatment with tamoxifen and estrogen receptor β agonists on human breast cancer cell lines.

    Science.gov (United States)

    Lattrich, Claus; Schüler, Susanne; Häring, Julia; Skrzypczak, Maciej; Ortmann, Olaf; Treeck, Oliver

    2014-01-01

    Coexpression of estrogen receptors (ER) α and β is present in about half of all breast cancer cases. Whereas ERα is a well-established target for endocrine therapy with the selective estrogen receptor modulator tamoxifen, the applicability of ERβ as target in breast cancer therapy is unclear. In this study, we examined the effects of two synthetic ERβ agonists alone and in combination with tamoxifen on ERα/β-positive breast cancer cells. We treated MCF-7 and T-47D breast cancer cells with the ERβ agonists ERB-041 and WAY-200070 and measured the effects on cell growth. In addition, transcriptome analyses were performed by means of Affymetrix GeneChip arrays. When given alone, ERβ agonists ERB-041 and WAY-200070 did not affect the growth of MCF-7 or T-47D cells. In contrast, addition of these drugs to tamoxifen increased its growth-inhibitory effect on both cell lines. This effect was more pronounced under serum-free conditions, but was also observed in the presence of serum in T-47D cells. Transcriptome analyses revealed a set of genes regulated after addition of ERβ agonists including S100A8 and CD177. The observed enhanced growth-inhibitory effects of a combination of tamoxifen and ERβ agonists in vitro encourage further studies to test its possible use in the clinical setting.

  20. The influence of tamoxifen on normal mouse mammary gland homeostasis

    NARCIS (Netherlands)

    Shehata, M.; van Amerongen, R.; Zeeman, A.L.; Giraddi, R.R.; Stingl, J.

    2014-01-01

    Introduction: Lineage tracing using inducible genetic labelling has emerged to be a powerful method for interrogating the developmental fate of cells in intact tissues. A common induction mechanism is the use of tamoxifen-dependent Cre recombinase (CreER and CreERT2), but the effects of tamoxifen at

  1. Exemestane Following Tamoxifen Reduces Breast Cancer Recurrences and Prolongs Survival

    Science.gov (United States)

    Postmenopausal women with early-stage hormone receptor-positive breast cancer had delayed disease recurrence and longer survival after taking 2-3 years of tamoxifen followed by exemestane for a total of 5 years compared to taking tamoxifen for 5 years.

  2. Tamoxifen adherence and its relationship to mortality in 116 men with breast cancer.

    Science.gov (United States)

    Xu, Shouping; Yang, Yumei; Tao, Weiyang; Song, Yanni; Chen, Yanbo; Ren, Yanlv; Liu, Jianxin; Pang, Da

    2012-11-01

    Recent studies have revealed that many, perhaps most women with hormone-responsive breast cancer have low adherence to tamoxifen adjuvant hormonal therapy. However, limited data are available on tamoxifen adherence in male breast cancer (MBC) patients. The goal of this study was to assess tamoxifen adherence and its relationship to mortality in MBC patients. A cohort of 116 men who were diagnosed with receptor-positive breast cancer between June 1987 and July 2012 was recruited for the study using the cancer prevention and treatment system database of Heilongjiang Province. From the 116 patients who received a five-year tamoxifen prescription, only 64.6 % were still taking their medication 1 year later, and this percentage decreased to 46.4 and 28.7 % after 2 and 3 years, respectively, to 25.8 % after 4 years, and to 17.7 % in the last year. After multivariate adjustment, factors that significantly decreased tamoxifen adherence were low social support [Hazard ratio (HR) = 2.45, 95 % CI 1.32-4.55], age (HR = 1.10, 95 % CI 1.01-1.21), and adverse effects (HR = 2.19, 95 % CI 1.57-3.04). The primary endpoints in the adherence or low-adherence groups from this study were overall survival (OS) and disease-free survival (DFS) of the MBC patients. The five- and ten-year OS of the patients was 97.9 and 79.6 %, respectively, in the adherence group, and 84.7 and 50.4 %, respectively, in the low-adherence group (p = 0.008). The five- and ten-year DFS of the patients was 95.4 and 72.8 %, respectively, in the adherence group, and 72.6 and 42.3 %, respectively, in the low-adherence group (p = 0.007). The consequences of low treatment adherence in men, who have a potentially long life expectancy, may be significant. In light of these findings, there is an urgent need to acknowledge and tackle the issue of tamoxifen adherence in this patient group.

  3. Anti-thrombotic effects of selective estrogen receptor modulator tamoxifen.

    Science.gov (United States)

    Nayak, Manasa K; Singh, Sunil K; Roy, Arnab; Prakash, Vivek; Kumar, Anand; Dash, Debabrata

    2011-10-01

    Tamoxifen is a known anti-cancer drug and established estrogen receptor modulator. Few clinical studies have earlier implicated the drug in thrombotic complications attributable to lower anti-thrombin and protein S levels in plasma. However, action of tamoxifen on platelet signalling machinery has not been elucidated in detail. In the present report we show that tamoxifen is endowed with significant inhibitory property against human platelet aggregation. From a series of in vivo and in vitro studies tamoxifen was found to inhibit almost all platelet functions, prolong tail bleeding time in mouse and profoundly prevent thrombus formation at injured arterial wall in mice, as well as on collagen matrix perfused with platelet-rich plasma under arterial shear against the vehicle dimethylsulfoxide (DMSO). These findings strongly suggest that tamoxifen significantly downregulates platelet responses and holds potential as a promising anti-platelet/anti-thrombotic agent.

  4. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer

    DEFF Research Database (Denmark)

    Ejlertsen, Bent; Jensen, Maj-Britt; Elversang, Johanna

    2013-01-01

    We report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes....

  5. Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer.

    Science.gov (United States)

    Xiong, Rui; Patel, Hitisha K; Gutgesell, Lauren M; Zhao, Jiong; Delgado-Rivera, Loruhama; Pham, Thao N D; Zhao, Huiping; Carlson, Kathryn; Martin, Teresa; Katzenellenbogen, John A; Moore, Terry W; Tonetti, Debra A; Thatcher, Gregory R J

    2016-01-14

    Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth.

  6. Effect of conjugated equine estrogens and tamoxifen administration on thyroid gland histomorphology of the rat.

    Science.gov (United States)

    de Araujo, Luiz Felipe Bittencourt; Soares, José Maria; Simões, Ricardo Santos; Calió, Pedro Luiz; Oliveira-Filho, Ricardo Martins; Simões, Manuel de Jesus; Haidar, Mauro Abi; Baracat, Edmund C

    2006-08-01

    The aim of this study was to evaluate the action of the conjugated equine estrogens and tamoxifen on the morphology of thyroid gland in ovariectomized (OVx) rats. Conjugated equine estrogens (CEE), clinically used as estrogen therapy, is a complex formulation containing multiple estrogens that decrease menopausal symptoms. Thirty ovariectomized rats were randomly divided into 3 treatment groups: GI, vehicle (propylene glycol); GII, CEE 200 microg/kg per day; and GIII, tamoxifen 1 mg/kg per day. Another group of 10 rats with intact ovaries (GIV) was included, treated with the vehicle, and sacrificed during estrous. All animals were treated by gavage for 50 days, after which they were sacrificed. Blood samples were collected, and the thyroid was removed for morphological analysis and PCNA evaluation through immunohistochemical study. The thyroid follicular cell height was increased in animals treated with CEE (14.90 +/- 0.20 microm), with TAM (14.90 +/- 0.10 microm), and in rats with intact ovaries (15.10 +/- 0.50 microm) in comparison to that of the vehicle group (9.90 +/- 0.20 microm) (P estrogen and tamoxifen administration has a proliferative effect on the thyroid.

  7. THE PROFILE OF TAMOXIFEN USER DUE TO GYNECOMASTIA INDUCED BY ANABOLIC STEROIDS FOR BODYBUILDERS OR BODYBUILDING

    Directory of Open Access Journals (Sweden)

    E. Santos

    2016-09-01

    Full Text Available Due to valorization of body appearance, the seek for a good physic body gets a central importance in externalization of subjectivity and in the construction the identities of the people. Because of this, them invest time to look for devices to streamline results to get a perfect body, between mechanisms used there is the use of anabolic steroids (AS. With the rapid response this kind of treatment, there are aware concerns their side effects such as gynecomastia which is characterized by breast enlargement of man. In an attempt to prevent this effect aesthetically uncomfortable, the users seek take medicines such as tamoxifen to reverse or prevent this situation without proper prescription or monitoring of a pharmacist professional, as well as almost all treatments with EA which are made clandestinely. This work aimed to describe profile among consumers seeking the tamoxifen therapy to prevent or treat gynecomastia induced using EA. The target audience was composed of bodybuilders men that were making anabolic cycles, aiming fast muscular hypertrophy. Two questionnaires were applied, one to the drugstores that sell these drugs and one for bodybuilders who buy these drugs. Tamoxifen user profile found in this study shows that they are young people aged 18 to 35 years old, seeking muscle hypertrophy strength. As the natural results are slow, influenced by training friends, start using EA, even declaring know about the risks to health. Use along with these steroids, tamoxifen, in an attempt to prevent or treat gynecomastia, get the medication in drugstores without a prescription and without the pharmacist questioning, demonstrating that pharmaceutical care is still not fully deployed and functioning

  8. A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer.

    Science.gov (United States)

    Chanrion, Maïa; Negre, Vincent; Fontaine, Hélène; Salvetat, Nicolas; Bibeau, Frédéric; Mac Grogan, Gaëtan; Mauriac, Louis; Katsaros, Dionyssios; Molina, Franck; Theillet, Charles; Darbon, Jean-Marie

    2008-03-15

    The identification of a molecular signature predicting the relapse of tamoxifen-treated primary breast cancers should help the therapeutic management of estrogen receptor-positive cancers. A series of 132 primary tumors from patients who received adjuvant tamoxifen were analyzed for expression profiles at the whole-genome level by 70-mer oligonucleotide microarrays. A supervised analysis was done to identify an expression signature. We defined a 36-gene signature that correctly classified 78% of patients with relapse and 80% of relapse-free patients (79% accuracy). Using 23 independent tumors, we confirmed the accuracy of the signature (78%) whose relevance was further shown by using published microarray data from 60 tamoxifen-treated patients (63% accuracy). Univariate analysis using the validation set of 83 tumors showed that the 36-gene classifier is more efficient in predicting disease-free survival than the traditional histopathologic prognostic factors and is as effective as the Nottingham Prognostic Index or the "Adjuvant!" software. Multivariate analysis showed that the molecular signature is the only independent prognostic factor. A comparison with several already published signatures demonstrated that the 36-gene signature is among the best to classify tumors from both training and validation sets. Kaplan-Meier analyses emphasized its prognostic power both on the whole cohort of patients and on a subgroup with an intermediate risk of recurrence as defined by the St. Gallen criteria. This study identifies a molecular signature specifying a subgroup of patients who do not gain benefits from tamoxifen treatment. These patients may therefore be eligible for alternative endocrine therapies and/or chemotherapy.

  9. Augmentation of oxidative stress-induced apoptosis in MCF7 cells by ascorbate-tamoxifen and/or ascorbate-juglone treatments.

    Science.gov (United States)

    Sajadimajd, Soraya; Yazdanparast, Razieh; Roshanzamir, Fariba

    2016-02-01

    Since reactive oxygen species (ROS) play diverse roles in cancer, modulating the redox status of cancerous cells seems to be a promising therapeutic approach. Oxidant-targeted therapy appears logical for intervention with the acquired adaptive response to oxidative stress in cancer. In this study, we investigated the cytotoxic effects of juglone (J) and tamoxifen (T) and also the combination of each with ascorbate (A): tamoxifen/ascorbate (TA) and/or juglone/ascorbate (JA) on MCF7 cancerous cells. The results revealed that the growth inhibitory effects of juglone and tamoxifen were each associated with enhanced levels of ROS production and lipid peroxidation. These effects were markedly intensified in tamoxifen/ascorbate and juglone/ascorbate co-treatments. On the other hand, the intracellular anti-oxidant components such as reduced glutathione (GSH), catalase, superoxide dismutase (SOD), and glutathione peroxidase significantly declined in cells subjected to combination treatments compared to that in cells exposed solely to tamoxifen, juglone, and the untreated control cells. In addition, ascorbate association induced more apoptotic and necrotic or necrotic-like cell death than cells treated with each drug alone. These results were further confirmed by comparing the Bax/Bcl2 ratio in combination-treated cells. Additionally, ascorbate was able to potentiate the cytotoxic effects of combination therapy via activation of ROS-responsive factors including Foxo family members.

  10. Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy

    OpenAIRE

    Cronin-Fenton, Deirdre P.; Damkier, Per; Lash, Timothy L

    2014-01-01

    Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review tamoxifen's clinical pharmacology and use meta-analyses to evaluate the clinical epidemiology studies conducted to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Our find...

  11. 4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer.

    Science.gov (United States)

    De Marchi, Tommaso; Liu, Ning Qing; Stingl, Cristoph; Timmermans, Mieke A; Smid, Marcel; Look, Maxime P; Tjoa, Mila; Braakman, Rene B H; Opdam, Mark; Linn, Sabine C; Sweep, Fred C G J; Span, Paul N; Kliffen, Mike; Luider, Theo M; Foekens, John A; Martens, John W M; Umar, Arzu

    2016-01-01

    Estrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in the recurrent disease resistance to tamoxifen therapy is common and a major cause of death. In recent years, in-depth proteome analyses have enabled identification of clinically useful biomarkers, particularly, when heterogeneity in complex tumor tissue was reduced using laser capture microdissection (LCM). In the current study, we performed high resolution proteomic analysis on two cohorts of ER positive breast tumors derived from patients who either manifested good or poor outcome to tamoxifen treatment upon recurrence. A total of 112 fresh frozen tumors were collected from multiple medical centers and divided into two sets: an in-house training and a multi-center test set. Epithelial tumor cells were enriched with LCM and analyzed by nano-LC Orbitrap mass spectrometry (MS), which yielded >3000 and >4000 quantified proteins in the training and test sets, respectively. Raw data are available via ProteomeXchange with identifiers PXD000484 and PXD000485. Statistical analysis showed differential abundance of 99 proteins, of which a subset of 4 proteins was selected through a multivariate step-down to develop a predictor for tamoxifen treatment outcome. The 4-protein signature significantly predicted poor outcome patients in the test set, independent of predictive histopathological characteristics (hazard ratio [HR] = 2.17; 95% confidence interval [CI] = 1.15 to 4.17; multivariate Cox regression p value = 0.017). Immunohistochemical (IHC) staining of PDCD4, one of the signature proteins, on an independent set of formalin-fixed paraffin-embedded tumor tissues provided and independent technical validation (HR = 0.72; 95% CI = 0.57 to 0.92; multivariate Cox regression p value = 0.009). We hereby report the first validated protein predictor for tamoxifen treatment outcome in recurrent ER-positive breast

  12. Gene expression signatures that predict outcome of tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients: a DBCG study.

    Directory of Open Access Journals (Sweden)

    Maria B Lyng

    Full Text Available BACKGROUND: Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+ breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy. METHODOLOGY/PRINCIPAL FINDINGS: Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling. The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623. Three gene signatures were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503 confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015 and untreated patients (n = 62, p = 0.25. CONCLUSIONS/SIGNIFICANCE: A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.

  13. High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer

    NARCIS (Netherlands)

    M.P.H.M. Jansen (Maurice); E.A. Reijm (Esther); A.M. Sieuwerts (Anieta); K. Ruigrok-Ritstier (Kirsten); M.P. Look (Maxime); F.G. Rodriguez-Gonzalez (F. German); A.A.J. Heine (Anouk); J.W.M. Martens (John); S. Sleijfer (Stefan); J.A. Foekens (John); P.M.J.J. Berns (Els)

    2012-01-01

    textabstractFor patients with metastatic breast cancer, we previously described that increased EZH2 expression levels were associated with an adverse outcome to tamoxifen therapy. Main objective of the present study is to investigate miR-26a and miR-101 levels, which both target EZH2, for their

  14. Breast fibromatosis response to tamoxifen: dynamic MRI findings and review of the current treatment options.

    Science.gov (United States)

    Plaza, Michael J; Yepes, Monica

    2012-03-01

    Breast fibromatosis is a rare entity responsible for 0.2% of all solid breast tumors. It has been associated with scars, pregnancy, implants, and familial adenomatous polyposis. We present an interesting case of breast fibromatosis in a 29 year old woman which encroached upon her saline implant and subsequently filled its cavity once the implant was removed. The patient was put on tamoxifen therapy and at 14 month follow-up there was a significant decrease in the size of the mass. Dynamic MRI images are offered for review and current treatment options are discussed.

  15. The INCA trial (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites): study protocol for a randomized controlled trial.

    Science.gov (United States)

    Casper, Markus; Mengel, Martin; Fuhrmann, Christine; Herrmann, Eva; Appenrodt, Beate; Schiedermaier, Peter; Reichert, Matthias; Bruns, Tony; Engelmann, Cornelius; Grünhage, Frank; Lammert, Frank

    2015-03-08

    Patients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP. The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms. German Clinical Trials Register DRKS00005616 . Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26 . Registered 26 January 2015.

  16. Open-label, 2-period sequential drug interaction study to evaluate the effect of a 100-mg dose of desvenlafaxine on the pharmacokinetics of tamoxifen when coadministered in healthy postmenopausal female subjects.

    Science.gov (United States)

    Nichols, Alice I; Lubaczewski, Shannon; Liang, Yali; Matschke, Kyle; Braley, Gabriel; Ramey, Tanya

    2014-10-01

    Potential drugdrug interactions are a concern for patients taking tamoxifen. This study was designed to determine the effect of coadministering desvenlafaxine on tamoxifen pharmacokinetics. This open-label, 2-period inpatient and outpatient study enrolled healthy, postmenopausal women. Period 1, day 1, subjects were administered tamoxifen 40 mg followed by 23 days of blood sampling for pharmacokinetic analyses. During period 2, subjects received desvenlafaxine 100 mg/d for 28 days; a single dose of tamoxifen 40 mg was administered with desvenlafaxine 100 mg on day 7, followed by 23 days of blood sampling. Pharmacokinetics of tamoxifen and its metabolites (AUC over infinite time (AUC(inf)), AUC to the last measurable concentration (AUC(last)), peak plasma concentration (C(max)) were compared for monotherapy vs. combination therapy using the ratio of adjusted mean differences. A superposition method was used in the statistical analysis of N-desmethyl-tamoxifen and endoxifen to address the carry-over observed for those metabolites. The test for interaction was considered negative if the 90% confidence intervals (CIs) for the ratios were within 80 - 125%. Coadministration of tamoxifen with steady-state desvenlafaxine did not alter tamoxifen AUC(inf), AUC(last), and C(max), as reflected by the ratio of adjusted geometric means (90% CIs) of 100.7% (96.7%, 104.9%), 103.5% (100.2%, 106.9%), and 99.4% (94.0%, 105.2%), respectively. Similarly, coadministration did not alter 4-hydroxy- tamoxifen and N-desmethyl-amoxifen pharmacokinetics. The 11.8% (88.2% (82.6%, 94.2%)) and 8.0% (92.0% (84.7%, 100.0%)) decreases in endoxifen AUC(last) and C(max), respectively, were not significant (90% CIs fell wholly within the prespecified acceptance range). Steady-state desvenlafaxine 100 mg did not affect tamoxifen pharmacokinetics. For women treated with tamoxifen, desvenlafaxine may represent a safe and effective treatment unlikely to alter tamoxifen efficacy.

  17. Nuclear receptor conformation, coregulators, and tamoxifen-resistant breast cancer.

    Science.gov (United States)

    Graham, J D; Bain, D L; Richer, J K; Jackson, T A; Tung, L; Horwitz, K B

    2000-01-01

    The development of tamoxifen resistance and consequent disease progression are common occurrences in breast cancers, often despite the continuing expression of estrogen receptors (ER). Tamoxifen is a mixed antagonist, having both agonist and antagonist properties. We have suggested that the development of tamoxifen resistance is associated with an increase in its agonist-like properties, resulting in loss of antagonist effects or even inappropriate tumor stimulation. Nuclear receptor function is influenced by a family of transcriptional coregulators, that either enhance or suppress transcriptional activity. Using a mixed antagonist-biased two-hybrid screening strategy, we identified two such proteins: the human homolog of the nuclear receptor corepressor, N-CoR, and a novel coactivator, L7/SPA (Switch Protein for Antagonists). In transcriptional studies, N-CoR suppressed the agonist properties of tamoxifen and RU486, and L7/SPA increased agonist effects. We speculated that the relative levels of these coactivators and corepressors may determine the balance of agonist and antagonist properties of mixed antagonists, such as tamoxifen. Using quantitative RT-PCR, we, therefore, measured the levels of transcripts encoding these coregulators, as well as the corepressor SMRT, and the coactivator SRC-1, in a small cohort of tamoxifen-resistant and sensitive breast tumors. The results suggest that tumor sensitivity to mixed antagonists may be governed by a complex set of transcription factors, which we are only now beginning to understand.

  18. Tissue selective action of tamoxifen methiodide, raloxifene and tamoxifen on creatine kinase B activity in vitro and in vivo.

    Science.gov (United States)

    Sömjen, D; Waisman, A; Kaye, A M

    1996-12-01

    We have compared the cell and tissue selective estrogenic and antiestrogenic activities of tamoxifen, raloxifene, ICI 164,384 and a permanently ionized derivative of tamoxifen--tamoxifen methiodide (TMI). This non-steroidal antiestrogen has limited ability to cross the blood brain barrier and is therefore less likely to cause the central nervous system disturbances caused by tamoxifen. We have used the stimulation of the specific activity of the "estrogen induced protein", creatine kinase BB, as a response marker in bone, cartilage, uterine and adipose cells and in rat skeletal tissues, uterus and mesometrial adipose tissue. In vitro, TMI, tamoxifen and raloxifene mimicked the agonistic action of 17beta-estradiol in ROS 17/2.8 rat osteogenic osteosarcoma, female calvaria, and SaOS2 human osteoblast cells. In Ishikawa endometrial cancer cells, tamoxifen showed reduced agonistic effects and raloxifene showed no stimulation. However, as antagonists, tamoxifen and raloxifene were equally effective in Ishikawa or SaOS2 cells. In immature rats, all four of the antiestrogens inhibited estrogen action in diaphysis, epiphysis, uterus and mesometrial adipose tissue; when administered alone, tamoxifen stimulated creatine kinase (CK) specific activity in all these tissues. Raloxifene and TMI, however, stimulated only the skeletal tissues and had no stimulatory effect in the uterus or mesometrial fat, and the pure antiestrogen ICI 164,384 showed no stimulatory effect in any of the tissues. The simultaneous injection of estrogen, plus an antiestrogen which acted as an agonist, resulted in lower CK activity than after injection of either agent alone. These differential effects, in vivo and in vitro, may point the way to a wider therapeutic choice of an appropriate antiestrogen which, although antagonizing E2 action in mammary cancer, can still protect against osteoporosis and cardiovascular disease and not stimulate the uterus with its attendant undesirable changes, or interfere

  19. Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s.

    Science.gov (United States)

    Styles, J A; Davies, A; Lim, C K; De Matteis, F; Stanley, L A; White, I N; Yuan, Z X; Smith, L L

    1994-01-01

    The clastogenicity of tamoxifen and toremifene was tested in six human lymphoblastoid cell lines each expressing increased monooxygenase activity associated with a specific transfected human cytochrome P450 cDNA (CYP1A1, CYP1A2, CYP2D6, CYP2E1 or CYP3A4). The chemicals were also tested in a cell line (MCL-5) expressing elevated native CYP1A1 and containing transfected CYP1A2, CYP2A6, CYP2E1 and CYP3A4 and epoxide hydrolase, and in a cell line containing only the viral vector (Ho1). Dose-related increases in micronuclei were observed when cells expressing 2E1, 3A4, 2D6 or MCL-5 cells were exposed to tamoxifen. The positive responses in the cell lines were in the order MCL-5 > 2E1 > 3A4 > 2D6. Toremifene also gave positive results with 2E1, 3A4 and MCL-5 cells, although the responses were less marked and the positive effects required higher doses than with tamoxifen. A synthesized epoxide of tamoxifen was also tested in these cell lines and produced similar increases in the incidences of micronucleated cells. The increases in the responses observed with the epoxide were greater than with tamoxifen or toremifene. The P450 isoenzyme activities in these cells were in a range similar to those of human tumour-derived cell lines. Microsomes (1A1, 2A2, 2A6, 2B6, 2E1, 3A4 and 2D6) from these cells all metabolized tamoxifen. The major metabolite detected by HPLC was N-desmethyltamoxifen, and 4-hydroxytamoxifen was also detected in cells with cytochrome P450 2E1 and 2D6. These results are consistent with the following conclusions. (1) Tamoxifen requires metabolic activation to DNA-reactive species by specific CYP monooxygenases in order to exert its genotoxic effects. (2) The positive clastogenic effects elicited in lymphoblastoid cells by tamoxifen epoxide suggest that the genotoxic (and possibly the carcinogenic) effects of tamoxifen may be due to one or more epoxide metabolites that are generated intracellularly, probably in close proximity to the nucleus. (3) Tamoxifen is

  20. Long-Term Data from 20 Trials Confirm Tamoxifen's Long-Lasting Benefit

    Science.gov (United States)

    Women with estrogen receptor-positive breast cancer who received about 5 years of adjuvant tamoxifen had a lower risk of recurrence in the 15 years after treatment than women who did not receive tamoxifen.

  1. Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer.

    Science.gov (United States)

    Rudraraju, Bharath; Droog, Marjolein; Abdel-Fatah, Tarek M A; Zwart, Wilbert; Giannoudis, Athina; Malki, Mohammed I; Moore, David; Patel, Hetal; Shaw, Jacqui; Ellis, Ian O; Chan, Steve; Brooke, Greg N; Nevedomskaya, Ekaterina; Lo Nigro, Christiana; Carroll, Jason; Coombes, R Charles; Bevan, Charlotte; Ali, Simak; Palmieri, Carlo

    2014-09-01

    Activating transcription factor-2 (ATF-2) has been implicated as a tumour suppressor in breast cancer (BC). c-JUN N-terminal kinase (JNK) and p38 MAPK phosphorylate ATF-2 within the activation domain (AD), which is required for its transcriptional activity. To date, the role of ATF-2 in determining response to endocrine therapy has not been explored. Effects of ATF-2 loss in the oestrogen receptor (ER)-positive luminal BC cell line MCF7 were explored, as well as its role in response to tamoxifen treatment. Genome-wide chromatin binding patterns of ATF-2 when phosphorylated within the AD in MCF-7 cells were determined using ChIP-seq. The expression of ATF-2 and phosphorylated ATF-2 (pATF-2-Thr71) was determined in a series of 1,650 BC patients and correlated with clinico-pathological features and clinical outcome. Loss of ATF-2 diminished the growth-inhibitory effects of tamoxifen, while tamoxifen treatment induced ATF-2 phosphorylation within the AD, to regulate the expression of a set of 227 genes for proximal phospho-ATF-2 binding, involved in cell development, assembly and survival. Low expression of both ATF-2 and pATF-2-Thr71 was significantly associated with aggressive pathological features. Furthermore, pATF-2 was associated with both p-p38 and pJNK1/2 (ATF-2 is not associated with outcome, pATF-2 is associated with longer disease-free (p = 0.002) and BC-specific survival in patients exposed to tamoxifen (p = 0.01). Furthermore, multivariate analysis confirmed pATF-2-Thr71 as an independent prognostic factor. ATF-2 is important for modulating the effect of tamoxifen and phosphorylation of ATF-2 within the AD at Thr71 predicts for improved outcome for ER-positive BC receiving tamoxifen.

  2. The First Electrochemical MIP Sensor for Tamoxifen

    Directory of Open Access Journals (Sweden)

    Aysu Yarman

    2014-04-01

    Full Text Available We present an electrochemical MIP sensor for tamoxifen (TAM—a nonsteroidal anti-estrogen—which is based on the electropolymerisation of an O-phenylenediamine‒resorcinol mixture directly on the electrode surface in the presence of the template molecule. Up to now only “bulk” MIPs for TAM have been described in literature, which are applied for separation in chromatography columns. Electro-polymerisation of the monomers in the presence of TAM generated a film which completely suppressed the reduction of ferricyanide. Removal of the template gave a markedly increased ferricyanide signal, which was again suppressed after rebinding as expected for filling of the cavities by target binding. The decrease of the ferricyanide peak of the MIP electrode depended linearly on the TAM concentration between 1 and 100 nM. The TAM-imprinted electrode showed a 2.3 times higher recognition of the template molecule itself as compared to its metabolite 4-hydroxytamoxifen and no cross-reactivity with the anticancer drug doxorubucin was found. Measurements at +1.1 V caused a fouling of the electrode surface, whilst pretreatment of TAM with peroxide in presence of HRP generated an oxidation product which was reducible at 0 mV, thus circumventing the polymer formation and electrochemical interferences.

  3. Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch

    NARCIS (Netherlands)

    L. Binkhorst (Lisette); M. Bannink (Marjolein); P. de Bruijn (Peter); J.B. Ruit (Jos); J. Droogendijk (Jolanda); R.J. van Alphen (Robbert); T.D. den Boer (Tilly D.); M.H. Lam (Mei); A. Jager (Agnes); T. van Gelder (Teun); A.H.J. Mathijssen (Ron)

    2016-01-01

    textabstractBackground and Objective: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. F

  4. Tamoxifen in early-stage estrogen receptor-positive breast cancer: overview of clinical use and molecular biomarkers for patient selection

    Directory of Open Access Journals (Sweden)

    Carmen Criscitiello

    2010-12-01

    Full Text Available Carmen Criscitiello1, Debora Fumagalli1, Kamal S Saini2, Sherene Loi11Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels; 2Breast Data Centre, Institut Jules Bordet, Brussels, BelgiumAbstract: Tamoxifen was the first targeted anticancer agent for breast cancer patients and its effects on reduction of breast cancer events and improvement in overall survival are undisputed. Hence, it has long been considered an essential part of patient care. Recent results of several large adjuvant hormonal trials evaluating the use of aromatase inhibitors in comparison with the previous standard of five years of tamoxifen has led to a paradigm shift, ensuring the inclusion of an aromatase inhibitor as part of standard endocrine therapy for most postmenopausal women diagnosed today with estrogen receptor-positive breast cancer. However, one could argue that despite statistically significant improvements in breast cancer events, an overall survival advantage has not been clear. In this review, we discuss recent genomic and molecular data pertaining to estrogen receptor-positive breast cancer and how this knowledge may aid clinicians to prescribe adjuvant hormonal treatment in the future. A combination of gene expression and genetic aberration markers may be most useful in discerning a population that is still appropriate for adjuvant tamoxifen treatment.Keywords: tamoxifen, aromatase inhibitors, resistance, prediction, mutation, endocrine therapy, PI3K

  5. High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer.

    Science.gov (United States)

    Jansen, M P H M; Reijm, E A; Sieuwerts, A M; Ruigrok-Ritstier, K; Look, M P; Rodríguez-González, F G; Heine, A A J; Martens, J W; Sleijfer, S; Foekens, J A; Berns, E M J J

    2012-06-01

    For patients with metastatic breast cancer, we previously described that increased EZH2 expression levels were associated with an adverse outcome to tamoxifen therapy. Main objective of the present study is to investigate miR-26a and miR-101 levels, which both target EZH2, for their association with molecular pathways and with efficacy of tamoxifen as first-line monotherapy for metastatic breast cancer. Expression levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens of 235 estrogen receptor-α (ER)-positive patients. Pathway analysis was performed on microarray data available for 65 of these tumors. Logistic regression and Cox uni- and multivariate analysis were performed to relate expression levels with clinical benefit and time to progression (TTP). Increasing levels of miR-26a were significantly (P set of markers associated with outcome on tamoxifen therapy, independently of traditional predictive factors. To summarize, only miR-26a levels are related with treatment outcome. Cell cycle regulation is the only overlapping pathway linked to miR-26a and EZH2 levels. Low mRNA levels of EZH2, CCNE1, and CDC2, and high levels of miR-26a are associated with favorable outcome on tamoxifen.

  6. A model of estrogen-related gene expression reveals non-linear effects in transcriptional response to tamoxifen

    Directory of Open Access Journals (Sweden)

    Lebedeva Galina

    2012-11-01

    Full Text Available Abstract Background Estrogen receptors alpha (ER are implicated in many types of female cancers, and are the common target for anti-cancer therapy using selective estrogen receptor modulators (SERMs, such as tamoxifen. However, cell-type specific and patient-to-patient variability in response to SERMs (from suppression to stimulation of cancer growth, as well as frequent emergence of drug resistance, represents a serious problem. The molecular processes behind mixed effects of SERMs remain poorly understood, and this strongly motivates application of systems approaches. In this work, we aimed to establish a mathematical model of ER-dependent gene expression to explore potential mechanisms underlying the variable actions of SERMs. Results We developed an equilibrium model of ER binding with 17β-estradiol, tamoxifen and DNA, and linked it to a simple ODE model of ER-induced gene expression. The model was parameterised on the broad range of literature available experimental data, and provided a plausible mechanistic explanation for the dual agonism/antagonism action of tamoxifen in the reference cell line used for model calibration. To extend our conclusions to other cell types we ran global sensitivity analysis and explored model behaviour in the wide range of biologically plausible parameter values, including those found in cancer cells. Our findings suggest that transcriptional response to tamoxifen is controlled in a complex non-linear way by several key parameters, including ER expression level, hormone concentration, amount of ER-responsive genes and the capacity of ER-tamoxifen complexes to stimulate transcription (e.g. by recruiting co-regulators of transcription. The model revealed non-monotonic dependence of ER-induced transcriptional response on the expression level of ER, that was confirmed experimentally in four variants of the MCF-7 breast cancer cell line. Conclusions We established a minimal mechanistic model of ER-dependent gene

  7. Effect of tamoxifen on spermatogenesis and tubular morphology in rats

    Institute of Scientific and Technical Information of China (English)

    UrbanJ.A.D'Souza

    2004-01-01

    Aim: To observe the effect of tamoxifen citrate on spermatogenesis and tubular morphology in rats.Methods: The effect of tamoxifen citrate i.g. at doses of 400 and 800 mg·kg-1·day-1 in 0.1 mL olive oil for 30 days on seminiferous tubular morphology, seminiferous epithelial diameter (STD), epithelial height (SEH), epididymal sperm count and percent abnormal sperm were evaluated at day 1, 12 and 36 after treatment. Controls were given the vehicle. Results: The higher dose resulted in tubular atrophy on day 31. The STD, SEH and sperm count were decreased and the abnormal spermatozoa increased in a dose-dependent manner with the maximal effect on day 36.Conclusion: Tamoxifen citrate induces tubular shrinkage and atrophy and sperm abnormality at a dose-dependent manner. (Asian J Androl 2004 Sep; 6: 223-226)

  8. Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance.

    Directory of Open Access Journals (Sweden)

    John Koren

    Full Text Available MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB. Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.

  9. Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance.

    Science.gov (United States)

    Koren, John; Miyata, Yoshinari; Kiray, Janine; O'Leary, John C; Nguyen, Lana; Guo, Jianping; Blair, Laura J; Li, Xiaokai; Li, Xiokai; Jinwal, Umesh K; Cheng, Jin Q; Gestwicki, Jason E; Dickey, Chad A

    2012-01-01

    MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.

  10. Isomers of broparoestrol and antiestrogen action: comparison with tamoxifen.

    Science.gov (United States)

    Edery, M; Barnova, A; Drosdowsky, M; Guggiari, M; Vives, C; Rudali, G

    1985-01-01

    This study compares the relative biological potencies of a known antiestrogen tamoxifen to two triarylethylene compounds which have been shown previously to be potent inhibitors of rodent mammary tumorigenesis. Based on a) uterotrophic and anti-uterotrophic tests, b) indexes of cellularity, and c) protein content, these studies indicate that the trans, as well as the cis, isomers of bromotriphenylethylene are partial estrogen antagonists with no estrogenic effects in rat uteri and partial agonists in mouse uteri, whereas tamoxifen shows partial antiestrogenic/estrogenic effects in rats and is fully estrogenic in mice.

  11. Comparative study of transvaginal ultrasonographic and diagnostic hysteroscopic findings in postmenopausal breast cancer patients treated with tamoxifen

    Institute of Scientific and Technical Information of China (English)

    GAO Wan-li; ZHANG Lu-ping; FENG Li-min

    2011-01-01

    Background There is an association between postmenopausal tamoxifen therapy and endometrial pathologies. We investigated the usefulness of diagnostic hysteroscopy and transvaginal ultrasonography (TVS) and estimated whether diagnostic hysteroscopy improves detection of endometrial pathologies in postmenopausal breast cancer patients on tamoxifen. Methods Ninety-seven postmenopausal breast cancer patients who had been taking tamoxifen 20 mg/d for ≥6 months went through TVS, diagnostic hysteroscopy, and endometrial biopsy examinations. The presence of endometrial histopathologic features with abnormal TVS and diagnostic hysteroscopic findings were correlated. Results No endometrial cancer was found in any of the 97 patients. Fifty-three patients (54.6%) developed endometrial polyps as diagnosed histopathologically. Fifty-nine patients (60.8%) tested positive in TVS exams, of whom 43 had polyps, four had hyperplasia, and 12 atrophy. Thirty-eight patients (39.2%) tested negative in TVS exams, of whom 10had polyps, three hyperplasia, and 25 atrophy. TVS exams presented 63.6% specificity, 81.8% sensitivity, 72.9%positive-predictive value, and 73.7% negative-predictive value, whereas the corresponding values of diagnostic hysteroscopy were 100%, 98.1%, 100%, and 97.8% respectively. The correct ratio of hysteroscopy was significantly higher than that of TVS (P=0.000). Conclusions In postmenopausal breast cancer patients treated with tamoxifen, TVS alone is not sufficient for the detection of endometrial pathologies. Additional use of diagnostic hysteroscopy considerably improves the detection of polyps, thus significantly reducing the rate of false-negative findings of endometrial pathologies.

  12. Tamoxifen ecotoxicity and resulting risks for aquatic ecosystems.

    Science.gov (United States)

    Orias, Frédéric; Bony, Sylvie; Devaux, Alain; Durrieu, Claude; Aubrat, Marion; Hombert, Thibault; Wigh, Adriana; Perrodin, Yves

    2015-06-01

    Tamoxifen, a drug used to treat cancer, is regularly found in hydrosystems at concentrations of several hundred ng L(-1). To characterize its ecotoxicity, we implemented a battery of bioassays on organisms belonging to 3 different trophic levels: Pseudokirchneriella subcapitata, Chlorella vulgaris and Chlamydomonas reinhardtii, for primary producers, Daphnia magna (immobilization, grazing and reproduction) for primary consumers, and Danio rerio for secondary consumers (embryotoxicity test). In view of the results obtained and the ecotoxicity values of tamoxifen available in the literature, we established a PNEC (Predictive No Effect Concentration) equal to 81 ng L(-1) for continental water. This PNEC allowed us to calculate Risk Quotients (RQ) for 4 continental hydrosystems in 4 different countries in which measures of tamoxifen had already been performed on surface waters. In two of the situations studied, RQs were higher than 1, reaching a maximum of 2.6. These results show the need to deepen the characterization of ecotoxicological risks linked to the discharge of tamoxifen in surface waters. In addition, we propose applying this approach to other drug residues detected in the environment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. The role of BCAR4 in tamoxifen resistant breast cancer

    NARCIS (Netherlands)

    M.F. Godinho (Marcia)

    2012-01-01

    textabstractBreast cancer is one of the most common cancers in women, and it is the second leading cause of cancer-related deaths, just behind lung cancer. The antiestrogen tamoxifen has been successfully used for over three decades to treat patients with estrogen receptor alpha-positive breast canc

  14. Study Confirms Letrozole Prevents More Breast Cancer Recurrences than Tamoxifen

    Science.gov (United States)

    After a median of 8 years of follow-up, women with estrogen-receptor positive breast cancer who received 5 years of letrozole were less likely to have their cancer recur or to die during follow-up than women who received 5 years of tamoxifen.

  15. Risk of endometrial cancer after tamoxifen treatment of breast cancer

    NARCIS (Netherlands)

    F.E. van Leeuwen (Flora); J. Benraadt (J.); J.W.W. Coebergh (Jan Willem); L.A.L.M. Kiemeney (Bart); C.H.F. Gimbrère (Charles); R. Otter (Renée); L.J. Scheuten (Leo); R.A. Damhuis (Ronald); M. Bontenbal (Marijke); A.I. Diepenhorst; A.W. van den Belt-Dusebout (Alexandra); H. van Tinteren (Harm)

    1994-01-01

    textabstractSince large trials have been set up to assess whether tamoxifen decreases the risk of breast cancer in healthy women, it has become important to investigate the drug's potential adverse effects, including occurrence of endometrial cancer. We undertook a case-control study in the

  16. Tamoxifen treatment and gynecologic side effects : A review

    NARCIS (Netherlands)

    Mourits, MJE; De Vries, EGE; Willemse, PHB; Ten Hoor, KA; Hollema, H; Van der Zee, AGJ

    2001-01-01

    Objective: To review the literature on tamoxifen side effects on the female genital tract and psychosexual function in premenopausal and postmenopausal women. Data Sources: We used the English-language literature in MEDLINE and reference lists from selected articles. Search terms included: "tamoxife

  17. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial.

    Science.gov (United States)

    Dowsett, Mitch; Allred, Craig; Knox, Jill; Quinn, Emma; Salter, Janine; Wale, Chris; Cuzick, Jack; Houghton, Joan; Williams, Norman; Mallon, Elizabeth; Bishop, Hugh; Ellis, Ian; Larsimont, Denis; Sasano, Hironobu; Carder, Pauline; Cussac, Antonio Llombart; Knox, Fiona; Speirs, Valerie; Forbes, John; Buzdar, Aman

    2008-03-01

    To determine the relationship between quantitative estrogen-receptor (ER) and progesterone-receptor (PgR) expression and human epidermal growth factor 2 (HER-2) status with time to recurrence (TTR) in postmenopausal women with hormone receptor-positive primary breast cancer treated with anastrozole or tamoxifen as adjuvant therapy. Formalin-fixed, paraffin-embedded tumor blocks were retrospectively collected from patients in the monotherapy arms of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial and centrally tested for ER, PgR and HER-2. ER and PgR were scored using continuous scales and HER-2 was scored as 0 to 3+ with 2+ cases being analyzed by fluorescence in situ hybridization. Blocks were collected from 2,006 of 5,880 eligible patients. Tissue was assessable and ER and/or PgR positivity confirmed centrally in 1,782 cases. In these, TTR was longer for anastrozole than for tamoxifen by a similar extent to that in the overall trial. None of the three biomarkers identified a set of patients with differential benefit from anastrozole over tamoxifen. Patients with low ER, low PgR, and high HER-2 expression had a poorer prognosis with either drug. Only 2.6% of patients in the highest quartile of PgR experienced recurrence after 5 years, compared with 13.2% in the lowest quartile. Quantitative expression of ER and PgR and HER-2 status did not identify patients with differential relative benefit from anastrozole over tamoxifen: TTR was longer for anastrozole than for tamoxifen in all molecular subgroups. Low ER or PgR or high HER-2 expression are associated with a high risk of recurrence with either anastrozole or tamoxifen.

  18. MUC1-C ONCOPROTEIN INDUCES TAMOXIFEN RESISTANCE IN HUMAN BREAST CANCER CELLS

    Science.gov (United States)

    Kharbanda, Akriti; Rajabi, Hasan; Jin, Caining; Raina, Deepak; Kufe, Donald

    2013-01-01

    Resistance of estrogen receptor positive (ER+) breast cancer cells to tamoxifen has been linked in part to activation of (i) certain receptor tyrosine kinases, such as HER2, and (ii) the PI3K→AKT pathway. Mucin 1 (MUC1) is aberrantly overexpressed in about 90% of human breast cancers and the oncogenic MUC1-C subunit associates with ERα. The present studies using HER2 overexpressing BT-474 breast cancer cells, which are constitutively resistant to tamoxifen, demonstrate that silencing MUC1-C is associated with (i) downregulation of p-HER2 levels, and (ii) sensitivity to tamoxifen-induced growth inhibition and loss of clonogenic survival. The results also demonstate that overexpression of MUC1-C in tamoxifen-sensitive MCF-7 breast cancer cells results in upregulation of p-AKT and tamoxifen resistance. We show that MUC1-C forms complexes with ERα on the estrogen-responsive promoter of the Rab31 gene and that MUC1-C blocks tamoxifen-induced decreases in ERα occupancy. MUC1-C also attenuated tamoxifen-induced decreases in (i) recruitment of the coactivator CREB binding protein, (ii) Rab31 promoter activation, and (ii) Rab31 mRNA and protein levels. The importance of MUC1-C is further supported by the demonstration that targeting MUC1-C with the cell-penetrating peptide inhibitor, GO-203, sensitizes tamoxifen-resistant cells to tamoxifen treatment. Moreover, we show that targeting MUC1-C in combination with tamoxifen is highly synergistic in the treatment of tamoxifen-resistant breast cancer cells. These findings indicate that MUC1-C contributes to tamoxifen resistance and provide support for the investigation of MUC1-C inhibitors in the setting of tamoxifen refractory disease. PMID:23538857

  19. Annexin-A1 and caldesmon are associated with resistance to tamoxifen in estrogen receptor positive recurrent breast cancer.

    Science.gov (United States)

    De Marchi, Tommaso; Timmermans, Anne M; Smid, Marcel; Look, Maxime P; Stingl, Christoph; Opdam, Mark; Linn, Sabine C; Sweep, Fred C G J; Span, Paul N; Kliffen, Mike; van Deurzen, Carolien H M; Luider, Theo M; Foekens, John A; Martens, John W; Umar, Arzu

    2016-01-19

    Tamoxifen therapy resistance constitutes a major cause of death in patients with recurrent estrogen receptor (ER) positive breast cancer. Through high resolution mass spectrometry (MS), we previously generated a 4-protein predictive signature for tamoxifen therapy outcome in recurrent breast cancer. ANXA1 and CALD1, which were not included in the classifier, were however the most differentially expressed proteins. We first evaluated the clinical relevance of these markers in our MS cohort, followed by immunohistochemical (IHC) staining on an independent set of tumors incorporated in a tissue microarray (TMA) and regression analysis in relation to time to progression (TTP), clinical benefit and objective response. In order to assess which mechanisms ANXA1 and CALD1 might been involved in, we performed Ingenuity pathway analysis (IPA) on ANXA1 and CALD1 correlated proteins in our MS cohort. ANXA1 (Hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.22-2.75; P = 0.003) and CALD1 (HR = 1.57; 95% CI: 1.04-2.36; P = 0.039) based patient stratification showed significant association to TTP, while IHC staining on TMA showed that both ANXA1 (HR = 1.82; 95% CI: 1.12-3.00; P = 0.016) and CALD1 (HR = 2.29; 95% CI: 1.40-3.75; P = 0.001) expression was associated with shorter TTP independently of traditional predictive factors. Pearson correlation analysis showed that the majority of proteins correlated to ANXA1 also correlated with CALD1. IPA indicated that ANXA1 and CALD1 were associated with ER-downregulation and NFκB signaling. We hereby report that ANXA1 and CALD1 proteins are independent markers for tamoxifen therapy outcome and are associated to fast tumor progression.

  20. ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2.

    Science.gov (United States)

    Pancholi, Sunil; Lykkesfeldt, Anne E; Hilmi, Caroline; Banerjee, Susana; Leary, Alexandra; Drury, Suzanne; Johnston, Stephen; Dowsett, Mitch; Martin, Lesley-Ann

    2008-12-01

    Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumors. We used an MCF-7 breast tumor cell line (Tam(R)-1) resistant to tamoxifen to investigate this mechanism. We demonstrate that Tam(R)-1 express elevated levels of phosphorylated AKT and MAPK3/1-activated RPS6KA2 compared with the parental MCF-7 cell line (MCF-7). There was no change in the level of total ESR between the two cell lines; however, the Tam(R)-1 cells had increased phosphorylation of ESR1 ser(167). SiRNA blockade of AKT or MAPK3/1 had little effect on ESR1 ser(167) phosphorylation, but a combination of the two siRNAs abrogated this. Co-localization studies revealed an association between ERBB2 and ESR1 in the Tam(R)-1 but not MCF-7 cells. ESR1 was redistributed to extranuclear sites in Tam(R)-1 and was less transcriptionally competent compared with MCF-7 suggesting that nuclear ESR1 activity was suppressed in Tam(R)-1. Tamoxifen resistance in the Tam(R)-1 cells could be partially overcome by the ERBB2 inhibitor AG825 in combination with tamoxifen, and this was associated with re-localization of ESR1 to the nucleus. These data demonstrate that tamoxifen-resistant cells have the ability to switch between ERBB2 or ESR1 pathways promoting cell growth and that pharmacological inhibition of ERBB2 may be a therapeutic strategy for overcoming tamoxifen resistance.

  1. Skeletal events of Anastrozole versus Tamoxifen on bone mineral density and bone biomarker osteocalcin in postmenopausal women with early breast cancer

    Institute of Scientific and Technical Information of China (English)

    Lobna R Ezz Elarab; Menha Swellam; Manal M Abdel Wahab; Karima M Maher

    2010-01-01

    Objective:Postmenopausal women with breast cancer are at increased risk of bone loss because of age related estrogen deficiency face which accelerated with the use of aromatase inbibitors (AIs).We aimed to study the effect on bone mineral density (BMD) and bone formation biomarker osteocalcin level in postmenopausal breast cancer patients,for the first three years of adjuvant hormonal treatment of both groups Tamoxifen versus Anastrozol.Methods:One-hundered postmenopausal breast cancers were prospectively randomized to receive either Tamoxifen 20 rag/day (n=50) or Anastrozole 10 mg (n=50).Both BMD and osteocalcin were assessed initially before treatment and then at regular intervals for both groups.Results:Use of Tamoxifen was associated with significant annual decrease in osteocalcin (P=0.001),whereas Anastrozole group had gradual increase of the annual levels (P<0.01).BMD decreased significantly in Anastrozole versus Tamoxifen groups (2.6% vs.0.4%,P<0.001).Osteoporosis T<-2.5 was reported significantly higher in Anastrozole group (P<0.01).Women with initial osteopenia in Anastrozole group showed significant decrease in BMD (P<0.05).The addition of bisphosphonate for patients with early osteoporosis markedly improved both osteocalcin level and BMD.Conclusion:Tamoxifen preserves BMD in postmenopausal breast cancer patients,whereas Anastrozole accelerates age associated fall in BMD especially in the first year of therapy,moreover,the addition of bisphosphonate can help to decrease the skeletal related events associated with treatment to ensure better quality of life with treatment.

  2. Localization of tamoxifen in human breast cancer tumors by MALDI mass spectrometry imaging.

    Science.gov (United States)

    Végvári, Ákos; Shavkunov, Alexander S; Fehniger, Thomas E; Grabau, Dorthe; Niméus, Emma; Marko-Varga, György

    2016-03-01

    Tamoxifen is used in endocrine treatment of breast cancer to inhibit estrogen signaling. A set of stratified ER-positive and ER-negative tumor sections was subjected to manual deposition of tamoxifen solution in order to investigate its spatial distribution upon exposure to interaction within thin tissue sections. The localization of tamoxifen in tumor sections was assessed by matrix assisted laser deposition/ionization mass spectrometry imaging. The images of extracted ion maps were analyzed for comparison of signal intensity distributions. The precursor ion of tamoxifen (m/z 372.233) displayed heterogeneous signal intensity distributions in histological compartments of tumor tissue sections. The levels of tamoxifen in tumor cells compared with stroma were higher in ER-positive tissues, whereas ER-negative tissue sections showed lower signal intensities in tumor cells. The experimental model was successfully applied on frozen tumor samples allowing for differentiation between ER groups based on distribution of tamoxifen.

  3. A misdiagnosed Riedel's thyroiditis successfully treated by thyroidectomy and tamoxifen.

    Science.gov (United States)

    Wang, Chih-Jung; Wu, Ta-Jen; Lee, Chung-Ta; Huang, Shih-Ming

    2012-12-01

    Riedel's thyroiditis, known as invasive fibrous thyroiditis, is a very rare form of chronic thyroiditis. It is hard to make the diagnosis without surgical biopsy. We present a case of Riedel's thyroiditis in a 52-year-old female with past history of Hashimoto's thyroiditis. She suffered from bilateral neck pain, which radiated to both lower jaws. The erythrocyte sedimentation rate was 125 mm/hour. Subacute thyroiditis superimposed on Hashimoto's thyroiditis was diagnosed and treated with steroid. However the response was poor and she had a history of severe peptic ulcer. To avoid inducing the peptic ulcer by steroid, she received bilateral subtotal thyroidectomy. During surgery, the thyroid had severe adhesion to surrounding soft tissue and the pathology showed Riedel's thyroiditis. The neck pain improved after thyroidectomy. Tamoxifen has been given for 8 months and the size of remnant thyroid decreased to 8 mm. We concluded that combined thyroidectomy and tamoxifen successfully cured a patient with Riedel's thyroiditis.

  4. Tamoxifen in the Mouse Brain: Implications for Fate-Mapping Studies Using the Tamoxifen-Inducible Cre-loxP System.

    Science.gov (United States)

    Valny, Martin; Honsa, Pavel; Kirdajova, Denisa; Kamenik, Zdenek; Anderova, Miroslava

    2016-01-01

    The tamoxifen-inducible Cre-loxP system is widely used to overcome gene targeting pre-adult lethality, to modify a specific cell population at desired time-points, and to visualize and trace cells in fate-mapping studies. In this study we focused on tamoxifen degradation kinetics, because for all genetic fate-mapping studies, the period during which tamoxifen or its metabolites remain active in the CNS, is essential. Additionally, we aimed to define the tamoxifen administration scheme, enabling the maximal recombination rate together with minimal animal mortality. The time window between tamoxifen injection and the beginning of experiments should be large enough to allow complete degradation of tamoxifen and its metabolites. Otherwise, these substances could promote an undesired recombination, leading to data misinterpretation. We defined the optimal time window, allowing the complete degradation of tamoxifen and its metabolites, such as 4-hydroxytamoxifen, N-desmethyltamoxifen, endoxifen and norendoxifen, in the mouse brain after intraperitoneal tamoxifen injection. We determined the biological activity of these substances in vitro, as well as a minimal effective concentration of the most potent metabolite 4-hydroxytamoxifen causing recombination in vivo. For this purpose, we analyzed the recombination rate in double transgenic Cspg4-cre/Esr1/ROSA26Sortm14(CAG-tdTomato) mice, in which tamoxifen administration triggers the expression of red fluorescent protein in NG2-expressing cells, and employed a liquid chromatography, coupled with mass spectrometry, to determine the concentration of studied substances in the brain. We determined the degradation kinetics of these substances, and revealed that this process is influenced by mouse strains, age of animals, and dosage. Our results revealed that tamoxifen and its metabolites were completely degraded within 8 days in young adult C57BL/6J mice, while the age-matched FVB/NJ male mice displayed more effective degradation

  5. Tamoxifen in the mouse brain: Implications for fate-mapping studies using the tamoxifen-inducible Cre-loxP system

    Directory of Open Access Journals (Sweden)

    Martin Valny

    2016-10-01

    Full Text Available The tamoxifen-inducible Cre-loxP system is widely used to overcome gene targeting pre-adult lethality, to modify a specific cell population at desired time-points, and to visualize and trace cells in fate-mapping studies. In this study we focused on tamoxifen degradation kinetics, because for all genetic fate-mapping studies, the period during which tamoxifen or its metabolites remain active in the CNS, is essential. Additionally, we aimed to define the tamoxifen administration scheme, enabling the maximal recombination rate together with minimal animal mortality. The time window between tamoxifen injection and the beginning of experiments should be large enough to allow complete degradation of tamoxifen and its metabolites. Otherwise, these substances could promote an undesired recombination, leading to data misinterpretation. We defined the optimal time window, allowing the complete degradation of tamoxifen and its metabolites, such as 4-hydroxytamoxifen, N-desmethyltamoxifen, endoxifen and norendoxifen, in the mouse brain after intraperitoneal tamoxifen injection. We determined the biological activity of these substances in vitro, as well as a minimal effective concentration of the most potent metabolite 4-hydroxytamoxifen causing recombination in vivo. For this purpose, we analyzed the recombination rate in double transgenic Cspg4-cre/Esr1/ROSA26Sortm14(CAG-tdTomato mice, in which tamoxifen administration triggers the expression of red fluorescent protein in NG2-expressing cells, and employed a liquid chromatography, coupled with mass spectrometry, to determine the concentration of studied substances in the brain. We determined the degradation kinetics of these substances, and revealed that this process is influenced by mouse strains, age of animals, dosage, and disruption of the blood-brain barrier. Our results revealed that tamoxifen and its metabolites were completely degraded within 8 days in young adult C57BL/6J mice, while the age

  6. Inhibition of MAP kinase promotes the recruitment of corepressor SMRT by tamoxifen-bound estrogen receptor alpha and potentiates tamoxifen action in MCF-7 cells

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Wei, E-mail: hongwei@tijmu.edu.cn [Department of Immunology, Tianjin Medical University, 300070 Tianjin (China); Department of Laboratory Medicine, Tianjin Medical University, 300070 Tianjin (China); Chen, Linfeng [Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, 02115 MA (United States); Li, Juan [Department of Laboratory Medicine, Tianjin Medical University, 300070 Tianjin (China); Yao, Zhi [Department of Immunology, Tianjin Medical University, 300070 Tianjin (China)

    2010-05-28

    Estrogen receptor alpha (ER{alpha}), a ligand controlled transcription factor, plays an important role in breast cancer growth and endocrine therapy. Tamoxifen (TAM) antagonizes ER{alpha} activity and has been applied in breast cancer treatment. TAM-bound ER{alpha} associates with nuclear receptor-corepressors. Mitogen-activated protein kinase (MAPK) has been elucidated to result in cross-talk between growth factor and ER{alpha} mediated signaling. We show that activated MAPK represses interaction of TAM-bound ER{alpha} with silencing mediator for retinoid and thyroid hormone receptors (SMRT) and inhibits the recruitment of SMRT by ER{alpha} to certain estrogen target genes. Blockade of MAPK signaling cascade with MEK inhibitor U0126 promotes the interaction and subsequently inhibits ER{alpha} activity via enhanced recruitment of SMRT, leading to reduced expression of ER{alpha} target genes. The growth rate of MCF-7 cells was decelerated when treated with both TAM and U0126. Moreover, the growth of MCF-7 cells stably expressing SMRT showed a robust repression in the presence of TAM and U0126. These results suggest that activated MAPK signaling cascade attenuates antagonist-induced recruitment of SMRT to ER{alpha}, suggesting corepressor mediates inhibition of ER{alpha} transactivation and breast cancer cell growth by antagonist. Taken together, our finding indicates combination of antagonist and MAPK inhibitor could be a helpful approach for breast cancer therapy.

  7. Vascular Actions of Tamoxifen and Raloxifene

    Institute of Scientific and Technical Information of China (English)

    YuHUANG

    2005-01-01

    Cardiovascular disease is among the leadingcauses of mortality worldwide. A sexrelated difference exists in the incidence of cardiovascular diseases with increased risks of cardiovascular disease such as stroke after menopause. Previous observational studies show significant reductions in the risk of coronary heart disease among users of hormone replacement therapy (HRT) for the primary and secondary prevention of cardiovascular disease.

  8. Effects of the dexamethasone and tamoxifen on the {sup 99m}Tc-lipiodol tumor penetration tested on a model of rat hepato carcinoma; Effets de la dexamethasone et du tamoxifene sur la penetration tumorale du {sup 99m}Tc-lipiodol testes sur un modele d'hepatocarcinome de rat

    Energy Technology Data Exchange (ETDEWEB)

    Becker, S.; Ardisson, V.; Lepareur, N.; Garin, E. [Service de medecine nucleaire, centre Eugene-Marquis, Rennes, (France); Sergent, O. [SeRAIC U3891, Rennes, (France); Gaboriau, F. [Inserm U522, Rennes, (France); Noiret, N. [UMR CNRS 6226, ENSCR, Rennes, (France)

    2009-05-15

    Different chemical agents, as the dexamethasone and the tamoxifen have been described as modifying the membranes fluidity. however, no study has evaluated the impact of fluidity on the cell incorporation of the lipiodol in the frame of hepato carcinoma. We have emitted the hypothesis that an increasing of the membrane fluidity by an external agent would allow to increase the cell permeability to the lipiodol. A such effect would have for interest to increase the tumor dosimetry and consequently the therapy efficiency. The conclusions are that the dexamethasone and the tamoxifen fluidify the cell membrane leading to an increase of the tumor incorporation of the lipiodol of 32% and 120% respectively. This way of action could be interesting to optimize the therapy efficiency of the labelled lipiodol. (N.C.)

  9. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen.

    Science.gov (United States)

    Bergman, L; Beelen, M L; Gallee, M P; Hollema, H; Benraadt, J; van Leeuwen, F E

    2000-09-09

    Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53. Tamoxifen had been used by 108 (36.1%) of 299 cases and 245 (28.5%) controls (relative risk 1.5 [95% CI 1.1-2.0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p or = 2 years) than in non-users (17.4% vs 5.4%, p=0.006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15.4% vs 2.9%, p or = 5 years, 85% for 2-5 years vs 94% for non-users, p=0.02). Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.

  10. Impact of tamoxifen on adipocyte lineage tracing: Inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase

    Directory of Open Access Journals (Sweden)

    Risheng Ye

    2015-11-01

    Conclusions: These findings highlight the potential for tamoxifen-induced adipogenesis, and the associated drawbacks of the use of tamoxifen in lineage tracing studies, explaining the discrepancy in lineage tracing results from different systems with temporal control of gene targeting.

  11. BreastDefend enhances effect of tamoxifen in estrogen receptor-positive human breast cancer in vitro and in vivo.

    Science.gov (United States)

    Cheng, Shujie; Castillo, Victor; Welty, Matt; Alvarado, Mark; Eliaz, Isaac; Temm, Constance J; Sandusky, George E; Sliva, Daniel

    2017-02-16

    Tamoxifen (TAM) has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer and its combination with other therapies is being actively investigated as a way to increase efficacy and decrease side effects. Here, we evaluate the therapeutic potential of co-treatment with TAM and BreastDefend (BD), a dietary supplement formula, in ER-positive human breast cancer. Cell proliferation and apoptosis were determined in ER-positive human breast cancer cells MCF-7 by MTT assay, quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP, respectively. The molecular mechanism was identified using RNA microarray analysis and western blotting. Tumor tissues from xenograft mouse model were analyzed by immunohistochemistry. Our data clearly demonstrate that a combination of 4-hydroxytamoxifen (4-OHT) with BD lead to profound inhibition of cell proliferation and induction of apoptosis in MCF-7 cells. This effect is consistent with the regulation of apoptotic and TAM resistant genes at the transcription and translation levels. Importantly, TAM and BD co-treatment significantly enhanced apoptosis, suppressed tumor growth and reduced tumor weight in a xenograft model of human ER-positive breast cancer. BD sensitized ER-positive human breast cancer cells to 4-OHT/TAM treatment in vitro and in vivo. BreastDefend can be used in an adjuvant therapy to increase the therapeutic effect of tamoxifen in patients with ER-positive breast cancer.

  12. Application of Mice Humanized for CYP2D6 to the Study of Tamoxifen Metabolism and Drug–Drug Interaction with Antidepressants

    Science.gov (United States)

    MacLeod, A. Kenneth; McLaughlin, Lesley A.; Henderson, Colin J.

    2017-01-01

    Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug–drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug–drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy. PMID:27756789

  13. CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH-Tamoxifen

    Energy Technology Data Exchange (ETDEWEB)

    Prather, Paul L. [Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205 (United States); FrancisDevaraj, FeAna; Dates, Centdrika R.; Greer, Aleksandra K.; Bratton, Stacie M. [Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205 (United States); Ford, Benjamin M.; Franks, Lirit N. [Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205 (United States); Radominska-Pandya, Anna, E-mail: RadominskaAnna@uams.edu [Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205 (United States)

    2013-11-15

    Highlights: •Tamoxifen produces cytotoxicity via estrogen-receptor (ER) independent mechanisms. •Tamoxifen binds to CB1 and CB2 cannabinoid receptors and acts as an inverse agonist. •CB1 and CB2 receptors are novel molecular targets for Tamoxifen. •ER-independent effects for Tamoxifen may be mediated via CB1 and/or CB2 receptors. -- Abstract: Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam can produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9–3 μM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel

  14. Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

    DEFF Research Database (Denmark)

    Joshi, Tejal; Elias, Daniel; Stenvang, Jan

    2016-01-01

    Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated ...

  15. Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment

    NARCIS (Netherlands)

    Graan, A.J. de; Teunissen, S.F.; Vos, F.Y. de; Loos, W.J.; Schaik, R.H. van; Jongh, F.E. de; Vos, A.I. de; Alphen, R.J. van; Holt, B. van der; Verweij, J.; Seynaeve, C.; Beijnen, J.H.; Mathijssen, R.H.

    2011-01-01

    PURPOSE: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the val

  16. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

    NARCIS (Netherlands)

    Bergman, L; Beelen, MLR; Gallee, MPW; Hollema, H; Benraadt, J; van Leeuwen, FE

    2000-01-01

    Background Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. Methods We did a nationwide case-control study on the risk an

  17. Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment

    NARCIS (Netherlands)

    Graan, A.J. de; Teunissen, S.F.; Vos, F.Y. de; Loos, W.J.; Schaik, R.H. van; Jongh, F.E. de; Vos, A.I. de; Alphen, R.J. van; Holt, B. van der; Verweij, J.; Seynaeve, C.; Beijnen, J.H.; Mathijssen, R.H.

    2011-01-01

    PURPOSE: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the val

  18. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

    NARCIS (Netherlands)

    Bergman, L; Beelen, MLR; Gallee, MPW; Hollema, H; Benraadt, J; van Leeuwen, FE

    2000-01-01

    Background Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. Methods We did a nationwide case-control study on the risk an

  19. Approaches for predicting effects of unintended environmental exposure to an endocrine active pharmaceutical, tamoxifen

    Science.gov (United States)

    Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen is a ubiquitous pharmaceutical and interacts with estrogen receptors, a case study was conducted with this compound to (1) determine effects on reproductive endpoints in a nontarget s...

  20. Approaches for predicting effects of unintended environmental exposure to an endocrine active pharmaceutical, tamoxifen

    Science.gov (United States)

    Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen is a ubiquitous pharmaceutical and interacts with estrogen receptors, a case study was conducted with this compound to (1) determine effects on reproductive endpoints in a nontarget s...

  1. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Phillips, Kelly-Anne; Milne, Roger L; Rookus, Matti A;

    2013-01-01

    To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.......To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers....

  2. Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas

    Science.gov (United States)

    Bon, Giulia; Di Carlo, Selene E.; Fabi, Alessandra; Nisticò, Cecilia; Vici, Patrizia; Melucci, Elisa; Buglioni, Simonetta; Perracchio, Letizia; Sperduti, Isabella; Rosanò, Laura; Sacchi, Ada; Mottolese, Marcella; Falcioni, Rita

    2008-01-01

    Background Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between α6β4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance. Methods and Findings Using human breast cancer cell lines displaying different levels of α6β4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the α6β4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between α6β4 and ErbB-3 in P-Akt-positive and ERβ1-negative breast cancers derived from patients with lower disease free survival. Conclusions We provided evidence that a strong relationship occurs between α6β4 and ErbB-3 positivity in ERβ1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERβ1-negative breast cancer derived from patients

  3. Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.

    Directory of Open Access Journals (Sweden)

    Valentina Folgiero

    Full Text Available BACKGROUND: Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between alpha6beta4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance. METHODS AND FINDINGS: Using human breast cancer cell lines displaying different levels of alpha6beta4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the alpha6beta4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between alpha6beta4 and ErbB-3 in P-Akt-positive and ERbeta1-negative breast cancers derived from patients with lower disease free survival. CONCLUSIONS: We provided evidence that a strong relationship occurs between alpha6beta4 and ErbB-3 positivity in ERbeta1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in

  4. Granulosa cell tumor of the ovary and antecedent of adjuvant tamoxifen use for breast cancer

    Directory of Open Access Journals (Sweden)

    Abahssain Halima

    2010-08-01

    Full Text Available Abstract Background Adult granulosa cell tumor associated with antecedent use of tamoxifen as adjuvant hormonotherapy for breast cancer is rare. The pathogenesis of this occurrence remains difficult to explain. The estrogenic effect of tamoxifen can be one such explanation. Case presentation A 47 year-old women was treated with surgery, chemotherapy, radiotherapy and tamoxifen for stage III estrogen receptor positive breast carcinoma. Ten months after stopping tamoxifen, we diagnosed a stage Ic granulosa cell tumor of the ovary. Conclusions Use of tamoxifen has been found to be associated with gynecological tumors like endometrial carcinoma. Its association with granulosa cell tumor of the ovary is uncommon. Only two previous cases have been reported in literature.

  5. Poly(amidoamine-Cholesterol Conjugate Nanoparticles Obtained by Electrospraying as Novel Tamoxifen Delivery System

    Directory of Open Access Journals (Sweden)

    R. Cavalli

    2011-01-01

    Full Text Available A new poly(amidoamine-cholesterol (PAA-cholesterol conjugate was synthesized, characterized and used to produce nanoparticles by the electrospraying technique. The electrospraying is a method of liquid atomization that consists in the dispersion of a solution into small charged droplets by an electric field. Tuning the electrospraying process parameters spherical PAA-chol nanoparticles formed. The PAA-cholesterol nanoparticles showed sizes lower than 500 nm and spherical shape. The drug incorporation capacity was investigated using tamoxifen, a lipophilic anticancer drug, as model drug. The incorporation of the tamoxifen did not affect the shape and sizes of nanoparticles showing a drug loading of 40%. Tamoxifen-loaded nanoparticles exhibited a higher dose-dependent cytotoxicity than free tamoxifen, while blank nanoparticles did not show any cytotoxic effect at the same concentrations. The electrospray technique might be proposed to produce tamoxifen-loaded PAA-chol nanoparticle in powder form without any excipient in a single step.

  6. Tamoxifen and its active metabolites inhibit dopamine transporter function independently of the estrogen receptors.

    Science.gov (United States)

    Mikelman, Sarah R; Guptaroy, Bipasha; Gnegy, Margaret E

    2017-04-01

    As one of the primary mechanisms by which dopamine signaling is regulated, the dopamine transporter (DAT) is an attractive pharmacological target for the treatment of diseases based in dopaminergic dysfunction. In this work we demonstrate for the first time that the commonly prescribed breast cancer therapeutic tamoxifen and its major metabolites, 4-hydroxytamoxifen and endoxifen, inhibit DAT function. Tamoxifen inhibits [(3) H]dopamine uptake into human DAT (hDAT)-N2A cells via an uncompetitive or mixed mechanism. Endoxifen, an active metabolite of tamoxifen, asymmetrically inhibits DAT function in hDAT-N2A cells, showing a preference for the inhibition of amphetamine-stimulated dopamine efflux as compared to dopamine uptake. Importantly, we demonstrate that the effects of tamoxifen and its metabolites on the DAT occur independently of its activity as selective estrogen receptor modulators. This work suggests that tamoxifen is inhibiting DAT function through a previously unidentified mechanism. © 2017 International Society for Neurochemistry.

  7. Risk of skin cancer following tamoxifen treatment in more than 16,000 breast cancer patients

    DEFF Research Database (Denmark)

    Præstegaard, Camilla; Kjaer, Susanne K.; Andersson, Michael

    2016-01-01

    Background: Women with breast cancer are at increased risk of developing skin cancer. Little is known about how tamoxifen affects this risk. We aimed to investigate whether tamoxifen treatment following breast cancer is associated with skin cancer. Methods: A cohort consisting of 44,589 women...... diagnosed with breast cancer during 1977–2007 from the nationwide clinical database of the Danish Breast Cancer Cooperative Group, was followed for a primary skin cancer [basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or melanoma] in the Danish Cancer Registry supplemented by data on BCC and SCC...... from the Danish Pathology Register. We investigated incidence of skin cancer among 16,214 women treated with tamoxifen compared to 28,375 women not treated with tamoxifen by calculating incidence rate ratios (IRRs) in Cox regression models. Results: Tamoxifen users were followed for a median of 2...

  8. Inositol hexaphosphate (IP6) enhances the anti-proliferative effects of adriamycin and tamoxifen in breast cancer.

    Science.gov (United States)

    Tantivejkul, Kwanchanit; Vucenik, Ivana; Eiseman, Julie; Shamsuddin, AbulKalam M

    2003-06-01

    The current treatment of breast carcinomas recognizes the importance of combination therapy in order to increase efficacy and decrease side effects of conventional chemotherapy. Inositol hexaphosphate (IP6), a naturally occurring polyphosphorylated carbohydrate, has shown a significant anti-cancer effect in various in vivo and in vitro models, including breast cancer. In this study, we investigated the in vitro growth inhibitory activity of IP6 in combination with adriamycin or tamoxifen, against three human breast cancer cell lines: estrogen receptor (ER) alpha-positive MCF-7, ER alpha-negative MDA-MB 231 and adriamycin-resistant MCF-7 (MCF-7/Adr) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Much lower concentrations of IP6 were required after 96 h of treatment to inhibit the growth of MCF-7/Adr cells than MCF-7 cells; the IC50 for MCF-7/Adr cells was 1.26 mM compared to 4.18 mM for MCF-7 cells. The ER-negative MDA-MB 231 cells were also highly sensitive to IP6 with IC50 being 1.32 mM. To determine the effects of IP6 in combination with either adriamycin or tamoxifen, the median effect principle and Webb's fraction method were used to determine the combination index (CI) and the statistical differences. Growth suppression was markedly increased when IP6 was administered prior to the addition of adriamycin, especially against MCF-7 cells (CI = 0.175 and p IP6 was administered after tamoxifen in all three cell lines studied (CI = 0.343, 0.701 and 0.819; p IP6 with LC50 values ranging from 0.91 to 5.75 mM (n = 10). Our data not only confirm that IP6 alone inhibits the growth of breast cancer cells; but it also acts synergistically with adriamycin or tamoxifen, being particularly effective against ER alpha-negative cells and adriamycin-resistant cell lines.

  9. Tamoxifen inhibits mitochondrial membrane damage caused by disulfiram.

    Science.gov (United States)

    Pavón, Natalia; Buelna-Chontal, Mabel; Correa, Francisco; Yoval-Sánchez, Belem; Belmont, Javier; Hernández-Esquivel, Luz; Rodríguez-Zavala, José S; Chávez, Edmundo

    2017-10-01

    In this work, we studied the protective effects of tamoxifen (TAM) on disulfiram (Dis)-induced mitochondrial membrane insult. The results indicate that TAM circumvents the inner membrane leakiness manifested as Ca(2+) release, mitochondrial swelling, and collapse of the transmembrane electric gradient. Furthermore, it was found that TAM prevents inactivation of the mitochondrial enzyme aconitase and detachment of cytochrome c from the inner membrane. Interestingly, TAM also inhibited Dis-promoted generation of hydrogen peroxide. Given that TAM is an antioxidant molecule, it is plausible that its protection may be due to the inhibition of Dis-induced oxidative stress.

  10. MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer.

    Science.gov (United States)

    Zhao, Jian-Jun; Lin, Jianhong; Yang, Hua; Kong, William; He, Lili; Ma, Xu; Coppola, Domenico; Cheng, Jin Q

    2008-11-07

    A search for regulators of estrogen receptor alpha (ERalpha) expression has yielded a set of microRNAs (miRNAs) for which expression is specifically elevated in ERalpha-negative breast cancer. Here we show distinct expression of a panel of miRNAs between ERalpha-positive and ERalpha-negative breast cancer cell lines and primary tumors. Of the elevated miRNAs in ERalpha-negative cells, miR-221 and miR-222 directly interact with the 3'-untranslated region of ERalpha. Ectopic expression of miR-221 and miR-222 in MCF-7 and T47D cells resulted in a decrease in expression of ERalpha protein but not mRNA, whereas knockdown of miR-221 and miR-222 partially restored ERalpha in ERalpha protein-negative/mRNA-positive cells. Notably, miR-221- and/or miR-222-transfected MCF-7 and T47D cells became resistant to tamoxifen compared with vector-treated cells. Furthermore, knockdown of miR-221 and/or miR-222 sensitized MDA-MB-468 cells to tamoxifen-induced cell growth arrest and apoptosis. These findings indicate that miR-221 and miR-222 play a significant role in the regulation of ERalpha expression at the protein level and could be potential targets for restoring ERalpha expression and responding to antiestrogen therapy in a subset of breast cancers.

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

    Directory of Open Access Journals (Sweden)

    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. Identification of cyclohexanone derivatives that act as catalytic inhibitors of topoisomerase I: effects on tamoxifen-resistant MCF-7 cancer cells.

    Science.gov (United States)

    Leung, Euphemia; Rewcastle, Gordon W; Joseph, Wayne R; Rosengren, Rhonda J; Larsen, Lesley; Baguley, Bruce C

    2012-12-01

    Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that they arose from expansion of pre-existing minor populations. We have searched for therapeutic agents that exhibit selective growth inhibition of the resistant lines and here investigate 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91). We found that two of the tamoxifen-resistant sub-lines (TamR3 and TamC3) unexpectedly showed increased sensitivity to RL90 and RL91. We utilized growth inhibition assays, flow cytometry and immunoblotting to establish a mechanistic basis for their action. Treated sensitive cells showed S-phase selective DNA damage, as detected by histone H2AX phosphorylation. Cellular responses were similar to those induced by the topoisomerase I poison camptothecin. Although IC(50) values of camptothecin, RL90, RL91 were correlated, studies with purified mammalian topoisomerase I suggested that RL90 and RL91 differed from camptothecin by acting as catalytic topoisomerase I inhibitors. These drugs provide a platform for the further development of DNA damaging drugs that have selective effects on tamoxifen resistant breast cancer cells. The results also raise the question of whether clinical topoisomerase I poisons such as irinotecan and topotecan might be active in the treatment of some types of tamoxifen-resistant cancer.

  13. Crosstalk events in the estrogen signaling pathway may affect tamoxifen efficacy in breast cancer molecular subtypes.

    Science.gov (United States)

    de Anda-Jáuregui, Guillermo; Mejía-Pedroza, Raúl A; Espinal-Enríquez, Jesús; Hernández-Lemus, Enrique

    2015-12-01

    Steroid hormones are involved on cell growth, development and differentiation. Such effects are often mediated by steroid receptors. One paradigmatic example of this coupling is the estrogen signaling pathway. Its dysregulation is involved in most tumors of the mammary gland. It is thus an important pharmacological target in breast cancer. This pathway, however, crosstalks with several other molecular pathways, a fact that may have consequences for the effectiveness of hormone modulating drug therapies, such as tamoxifen. For this work, we performed a systematic analysis of the major routes involved in crosstalk phenomena with the estrogen pathway - based on gene expression experiments (819 samples) and pathway analysis (493 samples) - for biopsy-captured tissue and contrasted in two independent datasets with in vivo and in vitro pharmacological stimulation. Our results confirm the presence of a number of crosstalk events across the estrogen signaling pathway with others that are dysregulated in different molecular subtypes of breast cancer. These may be involved in proliferation, invasiveness and apoptosis-evasion in patients. The results presented may open the way to new designs of adjuvant and neoadjuvant therapies for breast cancer treatment.

  14. Novel use of rituximab in a case of Riedel's thyroiditis refractory to glucocorticoids and tamoxifen.

    Science.gov (United States)

    Soh, Shui-Boon; Pham, Alan; O'Hehir, Robyn E; Cherk, Martin; Topliss, Duncan J

    2013-09-01

    A 42-year-old woman presented with a rapidly enlarging right-sided thyroid mass and underwent hemithyroidectomy. Riedel's thyroiditis was only diagnosed upon surgical decompression of the right carotid artery 2 years later. She became more symptomatic as Riedel's thyroiditis progressed, and mediastinal fibrosclerosis developed over the next 12 months. Oral prednisolone failed to improve her condition, and she was commenced on tamoxifen. Despite initial improvement, her symptoms recurred 2 years later, mainly arising from compression of the trachea and esophagus at the thoracic inlet. Fluorodeoxyglucose positron emission tomographic scan showed locally advanced active invasive fibrosclerosis in the neck and mediastinum. An elevated activin-A level of 218 pg/mL was consistent with active inflammation. IgG subtypes (including IgG4) were normal. Two courses of iv methylprednisolone were given but only produced transient improvement. Subsequently, the patient received 3 doses of i.v. rituximab at monthly intervals and had prompt sustained symptomatic improvement. Activin-A level decreased to 122 pg/mL 10 months after rituximab therapy. Fluorodeoxyglucose positron emission tomographic scan 6 weeks after therapy showed reduction in inflammation. A further scan at 10 months demonstrated ongoing response to rituximab. This is a case of refractory Riedel's thyroiditis with symptomatic, biochemical, and radiological improvement that has persisted 14 months after rituximab. The likelihood and duration of response to rituximab in Riedel's thyroiditis requires further study.

  15. The Exposure of Breast Cancer Cells to Fulvestrant and Tamoxifen Modulates Cell Migration Differently

    Directory of Open Access Journals (Sweden)

    Dionysia Lymperatou

    2013-01-01

    Full Text Available There is no doubt that there are increased benefits of hormonal therapy to breast cancer patients; however, current evidence suggests that estrogen receptor (ER blockage using antiestrogens is associated with a small induction of invasiveness in vitro. The mechanism by which epithelial tumor cells escape from the primary tumor and colonize to a distant site is not entirely understood. This study investigates the effect of two selective antagonists of the ER, Fulvestrant (Fulv and Tamoxifen (Tam, on the invasive ability of breast cancer cells. We found that 17β-estradiol (E2 demonstrated a protective role regarding cell migration and invasion. Fulv did not alter this effect while Tam stimulated active cell migration according to an increase in Snail and a decrease in E-cadherin protein expression. Furthermore, both tested agents increased expression of matrix metalloproteinases (MMPs and enhanced invasive potential of breast cancer cells. These changes were in line with focal adhesion kinase (FAK rearrangement. Our data indicate that the anti-estrogens counteracted the protective role of E2 concerning migration and invasion since their effect was not limited to antiproliferative events. Although Fulv caused a less aggressive result compared to Tam, the benefits of hormonal therapy concerning invasion and metastasis yet remain to be investigated.

  16. Bioanalytical methods for determination of tamoxifen and its phase I metabolites: A review

    Energy Technology Data Exchange (ETDEWEB)

    Teunissen, S.F., E-mail: Bas.Teunissen@slz.nl [Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam (Netherlands); Rosing, H. [Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam (Netherlands); Schinkel, A.H. [Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam (Netherlands); Schellens, J.H.M. [Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam (Netherlands); Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht (Netherlands); Beijnen, J.H. [Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam (Netherlands); Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht (Netherlands)

    2010-12-17

    The selective estrogen receptor modulator tamoxifen is used in the treatment of early and advanced breast cancer and in selected cases for breast cancer prevention in high-risk subjects. The cytochrome P450 enzyme system and flavin-containing monooxygenase are responsible for the extensive metabolism of tamoxifen into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta. An extensive overview of publications on the determination of tamoxifen and its phase I metabolites in biological samples is presented. In these publications techniques were used such as capillary electrophoresis, liquid, gas and thin layer chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection, liquid scintillation counting and nuclear magnetic resonance spectroscopy). A trend is seen towards the use of liquid chromatography coupled to mass spectrometry (LC-MS). State-of-the-art LC-MS equipment allowed for identification of unknown metabolites and quantification of known metabolites reaching lower limit of quantification levels in the sub pg mL{sup -1} range. Although tamoxifen is also metabolized into phase II metabolites, the number of publications reporting on phase II metabolism of tamoxifen is scarce. Therefore the focus of this review is on phase I metabolites of tamoxifen. We conclude that in the past decades tamoxifen metabolism has been studied extensively and numerous metabolites have been identified. Assays have been developed for both the identification and quantification of tamoxifen and its metabolites in an array of biological samples. This review can be used as a resource for method transfer and development of analytical methods used to support pharmacokinetic and pharmacodynamic studies of tamoxifen and its phase I metabolites.

  17. Tamoxifen enhances the control of acromegaly treated with somatostatin analog lanreotide.

    Science.gov (United States)

    Maiza, Jean-Christophe; Castillo-Ros, Stéphane; Matta, Maria; Bennet, Antoine; Caron, Philippe

    2012-12-01

    We present the case of a 51-year old female patient with acromegaly that was resistant to somatostatin analogs and dopamine agonists. The patient was diagnosed with breast cancer requiring treatment with the anti-estrogen tamoxifen. Prior to initiating the treatment with tamoxifen, the IGF-I level was very high at 415% of the upper limit of normal for the patient's age and sex. During the tamoxifen treatment, the level of IGF-I dropped spectacularly down to normal levels. This observation highlights the effect of an anti-estrogen treatment in certain female patients with acromegaly.

  18. Exposure to Non-Therapeutic INR in a High Risk Cardiovascular Patient: Potential Hazard Reduction with Genotype-guided Warfarin (Coumadin®) Dosing

    Science.gov (United States)

    Rodríguez-Vélez, Rosángela; Ortiz-Rivera, Oscar J.; Bower, Bruce; Gorowski, Krystyna; Windemuth, Andreas; Villagra, David; Kocherla, Mohan; Seip, Richard L; D'Agostino, Darrin; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

    2013-01-01

    A case to illustrate the utility of genetic screening in warfarin (Coumadin®) management is reported. A 45 year-old woman of Puerto Rican ancestry was admitted to the emergency room twice within one month with chest pain. She was diagnosed with congestive heart failure, which was stabilized both times. At her second release, warfarin therapy was initiated at 5 mg/day to prevent thrombus formation and was lowered to 3.75 mg/day at day 7 by her primary physician. International Normalized Ratio (INR) test results in the follow-up period at days 1, 7, and 10 of warfarin therapy were 4.5, 6.5, and 7.3, respectively—far in excess of the therapeutic range, despite the lower dosage in effect from day 7 onward. the patient achieved target INR over the next 43 days after downward adjustment of the dose to a dose of 1.5 mg/day by trial and error. DNA-typing specific for the CYP2C9*2, *3, *4, *5, *6 alleles and seven variants in the VKORC1 gene, including the VKORC1-1639 G>A polymorphism, revealed the presence of combinatorial CYP2C9*2/*3 and VKORC1-1639 G/A genotypes in this patient. Entering the patient's demographic and genotype status data into independent algorithms available in the public domain to predict effective warfarin dose yielded predicted doses which ranged from 1.5 to 1.8 mg/day. Notably, the prediction of 1.5 mg/day, which was generated by the online resource www.warfarindosing.org, coincided with the patient's actual effective warfarin dose. We conclude that the rapid rise in INR observed upon the initiation of warfarin therapy and the final effective warfarin dose of 1.5 mg/day, are attributable in some part to the presence of two minor alleles in CYP2C9, which together significantly reduce warfarin metabolism. Warfarin genotyping can therefore inform the clinician of the predicted effective warfarin dose. the results highlight the potential for warfarin genetic testing to improve patient care. PMID:21261182

  19. Tool Weighs Benefits, Risks of Raloxifene or Tamoxifen to Prevent Breast Cancer

    Science.gov (United States)

    Researchers have developed a benefit-risk index to help guide decisions on whether postmenopausal women at increased risk of developing breast cancer should take raloxifene or tamoxifen to reduce that risk.

  20. A novel histone deacetylase inhibitor augments tamoxifen-mediated attenuation of breast carcinoma growth.

    Science.gov (United States)

    Restall, Christina; Doherty, Judy; Liu, Hong Bin; Genovese, Rosemary; Paiman, Lisa; Byron, Keith A; Anderson, Robin L; Dear, Anthony E

    2009-07-15

    Earlier we generated novel derivatives of the hydroxamate-based histone deacetylase inhibitor (HDACi), Oxamflatin (Ox), which demonstrate considerable HDACi activity. Here the effects of one such derivative, Metacept-1 (MCT-1), alone or in combination with tamoxifen on mammary tumour growth have been assessed in a syngeneic orthotopic model. MCT-1 alone resulted in a trend towards inhibition of growth of 4T1.2 mammary tumours. Since the combination of MCT-1 and tamoxifen up-regulates estrogen receptor expression in 4T1.2 cells in vitro, we tested this combination and found a significant reduction in primary tumour growth over tamoxifen treatment alone. Taken together, these observations suggest that the novel HDACi MCT-1 may warrant further exploration in the treatment of estrogen receptor positive breast carcinoma, particularly when used in combination with conventional agents such as tamoxifen.

  1. In Vitro Metabolism of Tamoxifen in Human, Rat, and Fish Microsomes

    Science.gov (United States)

    Results from an in vivo study comparing biologically-active metabolites in the plasma of Wistar rats and cunner fish (Tautogolabrus adspersus) treated with tamoxifen indicate notable differences in circulating metabolite concentrations between these two species. After a single or...

  2. Evaluation of trichodynia (hair pain) during chemotherapy or tamoxifen treatment in breast cancer patients.

    Science.gov (United States)

    Kanti, V; Nuwayhid, R; Lindner, J; Hillmann, K; Bangemann, N; Kleine-Tebbe, A; Blume-Peytavi, U; Garcia Bartels, N

    2016-01-01

    In women receiving antineoplastic therapy, hair loss is often accompanied by distressing hair or scalp sensations, such as hair pain (trichodynia) and pruritus. A scientific approach to objectively evaluate the course and characteristics of these unpleasant sensations is of great importance for the establishment of treatment strategies. An observational cohort study was conducted in 34 female breast cancer patients, postoperatively undergoing chemotherapy (group C, n = 17) or endocrine therapy with tamoxifen (group T, n = 17). For 28 weeks after therapy initiation, patients experiencing hair pain and/or scalp pruritus were required to complete a specially developed diary, based on a modification of pain questionnaires. Sensations were journalized in terms of time of onset, duration, intensity on a numeric rating scale, dependence on touching the scalp or hair and character of the sensation, chosen from given descriptors or using own words. In group C, all patients who completed the questionnaire experienced hair and scalp sensations: 87% both trichodynia and pruritus, 13% trichodynia only. Reported intensities ranged between 1 and 10. In group T, 31% of participants reported hair and scalp sensations: 12% both trichodynia and pruritus, 12% pruritus only, 7% trichodynia only. Intensities were rated between 1 and 5. No sensations were reported after week 11 in either group. Hair and scalp sensations in group C were significantly more common, lasted longer, and were of greater intensity and more differentiated qualities than in group T. The occurrence of trichodynia in chemotherapy patients corresponded with the onset and duration of hair loss, thus suggesting a possible correlation. © 2015 European Academy of Dermatology and Venereology.

  3. Tamoxifen-DNA adduct formation in monkey and human reproductive organs.

    Science.gov (United States)

    Hernandez-Ramon, Elena E; Sandoval, Nicole A; John, Kaarthik; Cline, J Mark; Wood, Charles E; Woodward, Ruth A; Poirier, Miriam C

    2014-05-01

    The estrogen analog tamoxifen (TAM), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. Proliferation stimulus of the uterine endometrium is likely involved in tumor induction, but genotoxicity may also play a role. Formation of TAM-DNA adducts in human tissues has been reported but remains controversial. To address this issue, we examined TAM-DNA adducts in uteri from two species of monkeys, Erythrocebus patas (patas) and Macaca fascicularis (macaque), and in human endometrium and myometrium. Monkeys were given 3-4 months of chronic TAM dosing scaled to be equivalent to the daily human dose. In the uteri, livers and brains from the patas (n = 3), and endometrium from the macaques (n = 4), TAM-DNA adducts were measurable by TAM-DNA chemiluminescence immunoassay. Average TAM-DNA adduct values for the patas uteri (23 adducts/10(8) nucleotides) were similar to those found in endometrium of the macaques (19 adducts/10(8) nucleotides). Endometrium of macaques exposed to both TAM and low-dose estradiol (n = 5) averaged 34 adducts/10(8) nucleotides. To examine TAM-DNA persistence in the patas, females (n = 3) were exposed to TAM for 3 months and to no drug for an additional month, resulting in low or non-detectable TAM-DNA in livers and uteri. Human endometrial and myometrial samples from women receiving (n = 8) and not receiving (n = 8) TAM therapy were also evaluated. Women receiving TAM therapy averaged 10.3 TAM-DNA adducts/10(8) nucleotides, whereas unexposed women showed no detectable TAM-DNA. The data indicate that genotoxicity, in addition to estrogen agonist effects, may contribute to TAM-induced human endometrial cancer.

  4. Development, Characterization, and In Vitro Evaluation of Tamoxifen Microemulsions

    Directory of Open Access Journals (Sweden)

    E. Monteagudo

    2012-01-01

    Full Text Available Microemulsions (MEs were designed by an innovative rational development, characterized, and used to load up to 20 mM of Tamoxifen citrate (TMX. They were made with acceptable and well-characterized excipients for all the routes of administration. Some of their properties, such as nanometric mean size and long stability shelf life, make them interesting drug delivery systems. The results obtained after the in vitro inhibition of estradiol-induced proliferation in MCF-7 breast cancer cells demonstrated a significant effect in cell growth. A decreasing of at least 90% in viable cells was shown after the incubation with MEs containing 20 mM of TMX. Besides, two compositions which loaded 10 mM of drug showed a cytotoxic effect higher than 70%. These results encourage the evaluation of alternative protocols for this drug administration, not only for estrogen receptor (ER positive tumors, but also for ER negative.

  5. Tamoxifen Treatment of Breast Cancer Cells: Impact on Hedgehog/GLI1 Signaling.

    Science.gov (United States)

    Villegas, Victoria E; Rondón-Lagos, Milena; Annaratone, Laura; Castellano, Isabella; Grismaldo, Adriana; Sapino, Anna; Zaphiropoulos, Peter G

    2016-02-27

    The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, the identification of possible mechanisms involved in TAM-resistance should help the development of new therapeutic targets. In this study, we present in vitro data using a panel of different breast cancer cell lines and demonstrate the modulatory effect of TAM on cellular proliferation and expression of Hedgehog signaling components, including the terminal effector of the pathway, the transcription factor GLI1. A variable pattern of expression following TAM administration was observed, reflecting the distinctive properties of the ER+ and ER- cell lines analyzed. Remarkably, the TAM-induced increase in the proliferation of the ER+ ZR-75-1 and BT474 cells parallels a sustained upregulation of GLI1 expression and its translocation to the nucleus. These findings, implicating a TAM-GLI1 signaling cross-talk, could ultimately be exploited not only as a means for novel prognostication markers but also in efforts to effectively target breast cancer subtypes.

  6. In vitro and in vivo effects of tamoxifen against larval stage Echinococcus granulosus.

    Science.gov (United States)

    Nicolao, María Celeste; Elissondo, María Celina; Denegri, Guillermo M; Goya, Alejandra B; Cumino, Andrea C

    2014-09-01

    Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestode Echinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore the in vitro and in vivo effects of tamoxifen (TAM) against E. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival of E. granulosus protoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment.

  7. In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

    Science.gov (United States)

    Nicolao, María Celeste; Elissondo, María Celina; Denegri, Guillermo M.; Goya, Alejandra B.

    2014-01-01

    Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestode Echinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore the in vitro and in vivo effects of tamoxifen (TAM) against E. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival of E. granulosus protoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment. PMID:24936598

  8. Genital tuberculosis in a tamoxifen-treated postmenopausal woman with breast cancer and bloody vaginal discharge

    Directory of Open Access Journals (Sweden)

    Maraki Sofia

    2006-09-01

    Full Text Available Abstract Background Female genital tuberculosis is an uncommon disease that is rarely diagnosed in developed countries. Case presentation A 61-year-old postmenopausal woman who had undergone surgery and treated with adjuvant chemotherapy for infiltrating ductal carcinoma of the breast five years ago, presented with bloody vaginal discharge, fatigue, weight loss, and low grade fevers at night for two months. Histological examination of the endometrium, done based on the suspicion of a second primary cancer due to the tamoxifen therapy, revealed a granulomatous reaction. Liquid and solid mycobacterial cultures of the tissues were performed. Although the acid fast staining was negative, the liquid culture was positive for Mycobacterium tuberculosis. Involvement of other systems was not detected. The patient was treated with a three-drug antituberculosis regimen for 9 months and recovered fully. Conclusion Female genital tuberculosis is a rare but curable disease that should be included in the differential diagnosis of women with menstrual problems. Early diagnosis is important and may prevent unnecessary invasive procedures for the patient.

  9. Modulation of Tamoxifen Cytotoxicity by Caffeic Acid Phenethyl Ester in MCF-7 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Tarek K. Motawi

    2016-01-01

    Full Text Available Although Tamoxifen (TAM is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination.

  10. The prescription pattern of Chinese herbal products that contain dang-qui and risk of endometrial cancer among tamoxifen-treated female breast cancer survivors in Taiwan: a population-based study.

    Directory of Open Access Journals (Sweden)

    Chien-Tung Wu

    Full Text Available PURPOSE: The increased practice of traditional Chinese medicine worldwide has raised concerns regarding herb-drug interactions. We analyzed the usage of Chinese herbal products containing dang-qui and investigated whether dang-qui therapy increases endometrial cancer risk among tamoxifen-treated breast cancer survivors in Taiwan. METHODS: All patients newly diagnosed with invasive breast cancer who received tamoxifen treatment from January 1, 1998, to December 31, 2008 were selected from the National Health Insurance Research Database. The usage, frequency of service and type of Chinese herbal products containing dang-qui prescribed across the 31,970 survivors were evaluated. Logistic regression method was employed to estimate the odds ratios for utilization of Chinese herbal products containing dang-qui. Cox proportional hazard regression was performed to calculate the hazard ratio of endometrial cancer associated with dang-qui use within the cohort. RESULTS: Almost one in two study subjects had used dang-qui. Among 31,938 tamoxifen-treated breast cancer survivors, 157 cases of subsequent endometrial cancer were identified. The hazard ratio for development of endometrial cancer among breast cancer survivors aged 20-79 years who had taken dang-qui after tamoxifen treatment was decreased compared to survivors who had never used dang-qui (HR: 0.61, 95%CI: 0.44-0.84. To minimise potential confounding factors, women with breast cancer in the reproductive age were excluded from further analysis, and the negative relationship between dang-qui consumption and subsequent endometrial cancer among breast cancer survivors aged 55-79 years was still observed, although not significantly (HR: 0.74, 95%CI: 0.46-1.17. CONCLUSIONS: Dang-qui consumption is common among breast cancer survivors aged 20-79 years and seems decrease the risk of subsequent endometrial cancer after less than a cumulative dose of 7,500 mg of tamoxifen treatment.

  11. Interaction of tamoxifen and noise-induced damage to the cochlea.

    Science.gov (United States)

    Pillai, Jagan A; Siegel, Jonathan H

    2011-12-01

    Tamoxifen has been used extensively in the treatment of breast cancer and other neoplasms. In addition to its well-known action on estrogen receptors it is also known to acutely block chloride channels that participate in cell volume regulation. Tamoxifen's role in preventing cochlear outer hair cell (OHC) swelling in vitro suggested that OHC swelling noted following noise exposure could potentially be a therapeutic target for tamoxifen in its role as a chloride channel blocker to help prevent noise-induced hearing loss. To investigate this possibility, the effects of exposure to tamoxifen on physiologic measures of cochlear function in the presence and absence of subsequent noise exposure were studied. Male Mongolian gerbils (2-4 months old) were randomly assigned to different groups. Tamoxifen at ∼10 mg/kg was administered to one of the groups. Five hours later they were exposed to a one-third octave band of noise centered at 8 kHz in a sound-isolation chamber for 30 min at 108 dB SPL. Compound action potential (CAP) thresholds and distortion product otoacoustic emission (DPOAE) levels were measured 30-35 days following noise exposure. Tamoxifen administration did not produce any changes in CAP thresholds and DPOAE levels when administered by itself in the absence of noise. Tamoxifen causes a significant increase in CAP thresholds from 8 to 15 kHz following noise exposure compared to CAP thresholds in animals exposed to noise alone. No significant differences were seen in the DPOAE levels in the f(2) = 8-15 kHz frequency range where maximum noise-induced increases in CAP thresholds were seen. Contrary to our original expectation, it is concluded that tamoxifen potentiates the degree of damage to the cochlea resulting from noise exposure.

  12. Tamoxifen inhibits malignant peripheral nerve sheath tumor growth in an estrogen receptor–independent manner

    OpenAIRE

    Byer, Stephanie J.; Eckert, Jenell M.; Brossier, Nicole M.; CLODFELDER-MILLER, BUFFIE J.; Turk, Amy N.; Carroll, Andrew J.; John C Kappes; Zinn, Kurt R; Prasain, Jeevan K.; CARROLL, STEVEN L.

    2010-01-01

    Few therapeutic options are available for malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with neurofibromatosis type 1 (NF1). Guided by clinical observations suggesting that some NF1-associated nerve sheath tumors are hormonally responsive, we hypothesized that the selective estrogen receptor (ER) modulator tamoxifen would inhibit MPNST tumorigenesis in vitro and in vivo. To test this hypothesis, we examined tamoxifen effects on MPNST cell proliferati...

  13. Effect of exemestane on tamoxifen pharmacokinetics in postmenopausal women treated for breast cancer.

    Science.gov (United States)

    Hutson, Paul R; Love, Richard R; Havighurst, Thomas C; Rogers, Eric; Cleary, James F

    2005-12-15

    Rodent models of human breast cancer suggest that the combination of the steroidal aromatase inhibitor exemestane with tamoxifen may have additive activity. Clinical trials combining tamoxifen with letrozole or anastrazole have shown minor pharmacokinetic drug interactions. We did an open-label crossover clinical trial of the effect of exemestane on tamoxifen pharmacokinetics. Thirty-two postmenopausal women who were clinically disease-free following primary treatments for breast cancer receiving tamoxifen for at least 3 months were studied. Blood was collected for pharmacokinetic analysis after at least 4 months of receiving 20 mg tamoxifen daily. Subjects then began 8 weeks of oral exemestane (25 mg daily), followed by another set of blood samples. There were no serious toxicities noted when the two drugs were combined. There was no significant effect of exemestane on the area under the plasma concentration versus time curve (AUC) of tamoxifen at steady state before [3.04 mg h/L; 90% confidence interval (90% CI), 2.71-3.44] and during exemestane treatment (3.05 mg h/L; 90% CI, 2.72-3.41). There were no significant changes in the formation of primary tamoxifen metabolites. Oral clearance of exemestane averaged 602 L/h based on an average plasma exemestane AUC of 41.5 microg h/L (90% CI, 36.7-62.6). Plasma concentrations of estradiol, estrone, and estrone sulfate decreased when exemestane was begun; estradiol concentrations consistently decreased below the limit of quantitation. There is no pharmacokinetic interaction between tamoxifen and exemestane. No modification in the standard regimen of either drug seems to be indicated if they are used in combination. The combination of the two drugs was well tolerated during the 8-week evaluation period.

  14. Induction of apoptosis and inhibition of proliferation of C6 glioma cells in vitro by tamoxifen

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To investigate the anti-tumor effect and mechanism of tamoxifen on rat C6 glioma cells. Methods C6 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with 3% fetal calf serum (FCS), and treated with tamoxifen of different concentrations, i.e. group A (1.25μmol/L), group B (2.50 μmol/L), group C (5.00 μmol/L), group D (10.00 μmol/L), group E (20.00 μmol/L) and control group (0.00 μmol/L). Morphological changes, MTT assay and 5-bromo-2'-deoxyuriding labeling ratio were assessed. Apoptosis was observed by flow cytometry. Results C6 cells treated with different doses of tamoxifen for 24, 48, and 72 hours became irregular in shape, while cells treated with vehicle grew normally. MTT assay showed that tamoxifen did not suppress C6 cell growth until 72 hours after treatment. Seventy-two hours after treatment, there were significant differences in cell viable rate between group A versus groups C, D and E; so did group B versus group D as well as group E (P<0.05). BrdU incorporation assay indicated significant difference of BrdU labbled index (BrdU LI) among groups A, C, E and control group 48 hours after treatment (P<0.05). And the BrdU LI decreased with the increased concentration of tamoxifen. Flow cytometry (FCM) showed significant difference between treated group and control group at 24, 48, and 72 hours after treatment (P<0.05). Conclusion Tamoxifen significantly suppresses the growth of C6 glioma cells in a time- and dose-dependent manner. The mechanism of tamoxifen suppressing C6 glioma cells may be inhibiting proliferation and inducing apoptosis. Therefore, tamoxifen can be a candidate as a chemotherapy agent for glioma.

  15. Tamoxifen and fatty fiver disease%三苯氧胺与脂肪性肝病

    Institute of Scientific and Technical Information of China (English)

    沈婕; 何胜利

    2011-01-01

    Tamoxifen has shown definitive effect when used as the adjuvant hormonal treatment in women with estrogen-receptor-positive breast cancer. However, long-term use of Tamoxifen can induce fatty liver disease. It has been proposed that tamoxifen may act throught mechanisms such as inducing triacylglycerol accumulation in mitochondria, abnormal fatty acid oxidation, and antagonizing actions of estrogen on hepatic lipid metabolism. Therefore, it is necessary to monitor lipid profile and liver function, conduct regular ultrasonography and CT examination in patients receiving tamoxifen treatment. Replacing tamoxifen with toremifene oraromatase inhibitors, or using lipid-lowering medicines may help prevent tamoxifen-induced fatty liver disease.%三苯氧胺用于雌激素受体阳性乳腺癌患者的内分泌治疗效果肯定,但长期应用可诱发脂肪性肝病.其机制包括药物聚集于肝细胞线粒体、脂肪酸氧化异常、雌激素拮抗作用等.对服用三苯氧胺的乳腺癌患者需定期监测肝功能、血脂、超声及CT等.可选择托瑞米芬、芳香化酶抑制剂替代治疗及应用降脂药物等进行防治.

  16. Tamoxifen treatment in hamsters induces protection during taeniosis by Taenia solium.

    Science.gov (United States)

    Escobedo, Galileo; Palacios-Arreola, M Isabel; Olivos, Alfonso; López-Griego, Lorena; Morales-Montor, Jorge

    2013-01-01

    Human neurocysticercosis by Taenia solium is considered an emergent severe brain disorder in developing and developed countries. Discovery of new antiparasitic drugs has been recently aimed to restrain differentiation and establishment of the T. solium adult tapeworm, for being considered a central node in the disease propagation to both pigs and humans. Tamoxifen is an antiestrogenic drug with cysticidal action on Taenia crassiceps, a close relative of T. solium. Thus, we evaluated the effect of tamoxifen on the in vitro evagination and the in vivo establishment of T. solium. In vitro, tamoxifen inhibited evagination of T. solium cysticerci in a dose-time dependent manner. In vivo, administration of tamoxifen to hamsters decreased the intestinal establishment of the parasite by 70%, while recovered tapeworms showed an 80% reduction in length, appearing as scolices without strobilar development. Since tamoxifen did not show any significant effect on the proliferation of antigen-specific immune cells, intestinal inflammation, and expression of Th1/Th2 cytokines in spleen and duodenum, this drug could exert its antiparasite actions by having direct detrimental effects upon the adult tapeworm. These results demonstrate that tamoxifen exhibits a strong cysticidal and antitaeniasic effect on T. solium that should be further explored in humans and livestock.

  17. Thoughts on tamoxifen resistant breast cancer. Are coregulators the answer or just a red herring?

    Science.gov (United States)

    Graham, J D; Bain, D L; Richer, J K; Jackson, T A; Tung, L; Horwitz, K B

    2000-11-30

    The antiestrogen tamoxifen is an effective treatment for estrogen receptor positive breast cancers, slowing tumor growth and preventing disease recurrence, with relatively few side effects. However, many patients who initially respond to treatment, later become resistant to treatment. Tamoxifen has both agonist and antagonist activities, which are manifested in a tissue-specific pattern. Development of tamoxifen resistance can be characterized by an increase in the partial agonist properties of the antiestrogen in the breast, resulting in loss of growth inhibition and even inappropriate tumor stimulation. Nuclear receptor function is modulated by transcriptional coregulators, which either enhance or repress receptor activity. Using a mixed antagonist-biased two-hybrid screening strategy, we identified two such proteins: the human homolog of the nuclear receptor corepressor, N-CoR, and a novel coactivator, L7/SPA (Switch Protein for Antagonists). In transcriptional studies N-CoR suppressed the agonist properties of tamoxifen and RU486, while L7/SPA increased agonist effects. We speculated that the relative level of these coactivators and corepressors might determine the balance of agonist and antagonist properties of mixed antagonists such as tamoxifen. Using quantitative RT-PCR we therefore measured the levels of transcripts encoding these coregulators, as well as the corepressor SMRT, and the coactivator SRC-1, in a small cohort of tamoxifen resistant and sensitive breast tumors. The results suggest that tumor sensitivity to mixed antagonists may be governed by a complex set of transcription factors, which we are only now beginning to understand.

  18. Integrated quantitative analysis of the phosphoproteome and transcriptome in tamoxifen-resistant breast cancer.

    Science.gov (United States)

    Oyama, Masaaki; Nagashima, Takeshi; Suzuki, Takashi; Kozuka-Hata, Hiroko; Yumoto, Noriko; Shiraishi, Yuichi; Ikeda, Kazuhiro; Kuroki, Yoko; Gotoh, Noriko; Ishida, Takanori; Inoue, Satoshi; Kitano, Hiroaki; Okada-Hatakeyama, Mariko

    2011-01-07

    Quantitative phosphoproteome and transcriptome analysis of ligand-stimulated MCF-7 human breast cancer cells was performed to understand the mechanisms of tamoxifen resistance at a system level. Phosphoproteome data revealed that WT cells were more enriched with phospho-proteins than tamoxifen-resistant cells after stimulation with ligands. Surprisingly, decreased phosphorylation after ligand perturbation was more common than increased phosphorylation. In particular, 17β-estradiol induced down-regulation in WT cells at a very high rate. 17β-Estradiol and the ErbB ligand heregulin induced almost equal numbers of up-regulated phospho-proteins in WT cells. Pathway and motif activity analyses using transcriptome data additionally suggested that deregulated activation of GSK3β (glycogen-synthase kinase 3β) and MAPK1/3 signaling might be associated with altered activation of cAMP-responsive element-binding protein and AP-1 transcription factors in tamoxifen-resistant cells, and this hypothesis was validated by reporter assays. An examination of clinical samples revealed that inhibitory phosphorylation of GSK3β at serine 9 was significantly lower in tamoxifen-treated breast cancer patients that eventually had relapses, implying that activation of GSK3β may be associated with the tamoxifen-resistant phenotype. Thus, the combined phosphoproteome and transcriptome data set analyses revealed distinct signal transcription programs in tumor cells and provided a novel molecular target to understand tamoxifen resistance.

  19. Tamoxifen Treatment in Hamsters Induces Protection during Taeniosis by Taenia solium

    Directory of Open Access Journals (Sweden)

    Galileo Escobedo

    2013-01-01

    Full Text Available Human neurocysticercosis by Taenia solium is considered an emergent severe brain disorder in developing and developed countries. Discovery of new antiparasitic drugs has been recently aimed to restrain differentiation and establishment of the T. solium adult tapeworm, for being considered a central node in the disease propagation to both pigs and humans. Tamoxifen is an antiestrogenic drug with cysticidal action on Taenia crassiceps, a close relative of T. solium. Thus, we evaluated the effect of tamoxifen on the in vitro evagination and the in vivo establishment of T. solium. In vitro, tamoxifen inhibited evagination of T. solium cysticerci in a dose-time dependent manner. In vivo, administration of tamoxifen to hamsters decreased the intestinal establishment of the parasite by 70%, while recovered tapeworms showed an 80% reduction in length, appearing as scolices without strobilar development. Since tamoxifen did not show any significant effect on the proliferation of antigen-specific immune cells, intestinal inflammation, and expression of Th1/Th2 cytokines in spleen and duodenum, this drug could exert its antiparasite actions by having direct detrimental effects upon the adult tapeworm. These results demonstrate that tamoxifen exhibits a strong cysticidal and antitaeniasic effect on T. solium that should be further explored in humans and livestock.

  20. Tamoxifen Treatment in Hamsters Induces Protection during Taeniosis by Taenia solium

    Science.gov (United States)

    Escobedo, Galileo; Palacios-Arreola, M. Isabel; Olivos, Alfonso; López-Griego, Lorena; Morales-Montor, Jorge

    2013-01-01

    Human neurocysticercosis by Taenia solium is considered an emergent severe brain disorder in developing and developed countries. Discovery of new antiparasitic drugs has been recently aimed to restrain differentiation and establishment of the T. solium adult tapeworm, for being considered a central node in the disease propagation to both pigs and humans. Tamoxifen is an antiestrogenic drug with cysticidal action on Taenia crassiceps, a close relative of T. solium. Thus, we evaluated the effect of tamoxifen on the in vitro evagination and the in vivo establishment of T. solium. In vitro, tamoxifen inhibited evagination of T. solium cysticerci in a dose-time dependent manner. In vivo, administration of tamoxifen to hamsters decreased the intestinal establishment of the parasite by 70%, while recovered tapeworms showed an 80% reduction in length, appearing as scolices without strobilar development. Since tamoxifen did not show any significant effect on the proliferation of antigen-specific immune cells, intestinal inflammation, and expression of Th1/Th2 cytokines in spleen and duodenum, this drug could exert its antiparasite actions by having direct detrimental effects upon the adult tapeworm. These results demonstrate that tamoxifen exhibits a strong cysticidal and antitaeniasic effect on T. solium that should be further explored in humans and livestock. PMID:23509701

  1. Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials

    Science.gov (United States)

    Yan, Shunchao; Li, Kai; Jiao, Xin; Zou, Huawei

    2015-01-01

    Background Ovarian function suppression (OFS) significantly downregulates the concentration of plasma estrogens. However, it is unclear whether it offers any survival benefits if combined with adjuvant tamoxifen treatment in premenopausal women. This meta-analysis was designed to assess data from previous studies involving adjuvant tamoxifen treatment plus OFS in premenopausal breast cancer. Methods Electronic literature databases (PubMed, Embase, the Web of Science, and the Cochrane Library) were searched for relevant randomized controlled trials published prior to February 1, 2015. Only randomized controlled trials that compared tamoxifen alone with tamoxifen plus OFS for premenopausal women with breast cancer were selected. The evaluated endpoints were disease-free survival and overall survival. Results Four randomized controlled trials comprising 6,279 patients (OFS combination, n=3,133; tamoxifen alone, n=3,146) were included in the meta-analysis. There was no significant improvement in disease-free survival or overall survival with addition of OFS in either the whole population or the hormone receptor-positive subgroup. The risk of distant recurrence was not reduced with the addition of OFS in the whole population. A subgroup analysis showed that addition of OFS significantly improved overall survival in patients who were administered chemotherapy. Conclusion Based on the available studies, concurrent administration of OFS and adjuvant tamoxifen treatment for premenopausal women with breast cancer has no effect on prolonging disease-free survival and overall survival, excluding patients who were administered chemotherapy. It should not be widely recommended, except perhaps for women who were hormone-receptor positive and who were also administered adjuvant chemotherapy. PMID:26109867

  2. Effects of low-dose tamoxifen on breast cancer biomarkers Ki-67, estrogen and progesterone receptors.

    Science.gov (United States)

    de Sousa, Juarez Antônio; Facina, Gil; da Silva, Benedito Borges; Gebrim, Luiz Henrique

    2006-09-14

    Breast carcinoma is the most common malignancy among women and it has a major impact on mortality. Studies of primary chemoprevention with tamoxifen have generated high expectations and considerable success rates. The efficacy of lower doses of tamoxifen is similar to that seen with a standard dose of the drug, and there has been a reduction in healthcare costs and side effects. The immune reaction to monoclonal antibody Ki-67 (MIB-1) and the expression of estrogen receptors (1D5) and progesterone receptors (PgR 636) in breast carcinoma were studied in patients treated with 10 mg of tamoxifen for a period of 14 days. A prospective randomized clinical trial was conducted with 38 patients divided into two groups: Group A: N = 20 (control group--without medication) and Group B: N = 18 (tamoxifen/10 mg/day for 14 days). All patients signed an informed consent term previously approved by both institutions. Patients underwent incisional biopsy before treatment and 14 days later a tumor tissue sample was obtained during surgical treatment. Positivity was quantitatively assessed, counting at least 1.000 cells per slide. For statistical data analysis, a Wilcoxon non-parametric test was used, and alpha was set at 5%. Both groups (A and B) were considered homogeneous regarding control variables. In Group A (control), there was no statistically significant reduction in Ki-67 (MIB-1) (p = 0.627), estrogen receptor (1D5) (p = 0.296) and progesterone receptor positivity (PgR 636) (p = 0.381). In Group B (tamoxifen 10 mg/day), the mean percentage of nuclei stained by Ki-67 (MIB-1) was 24.69% before and 10.43% after tamoxifen treatment. Mean percentage of nuclei stained by estrogen receptor (1D5) was 59.53% before and 25.99% after tamoxifen treatment. Mean percentage of nuclei stained by progesterone receptor (PgR 636), was 59.34 before and 29.59% after tamoxifen treatment. A statistically significant reduction was found with the three markers (p Tamoxifen significantly reduced

  3. Understanding tamoxifen adherence in women with breast cancer: A qualitative study.

    Science.gov (United States)

    Moon, Zoe; Moss-Morris, Rona; Hunter, Myra S; Hughes, Lyndsay D

    2017-08-29

    Non-adherence to tamoxifen is common in breast cancer survivors and is associated with poor clinical outcomes. This study aimed to understand womens' experiences of taking tamoxifen and to identify factors which may be associated with non-adherence. A qualitative study using semi-structured interviews. Thirty-two breast cancer survivors who had been prescribed tamoxifen took part in interviews conducted face to face or over the telephone. They were transcribed verbatim and analysed using inductive thematic analysis with elements of grounded theory. A key theme identified in the data was weighing up costs and benefits of treatment, which resulted in women falling into three groups; tamoxifen is keeping me alive, tamoxifen is not worth the reduced risk of recurrence, or conflicting beliefs about the harms and benefits of treatment. Additional themes were living with risk of recurrence and information & support. Women who believed that the necessity of tamoxifen outweighed its costs were more likely to be adherent, whereas women who thought that the benefits did not outweigh the side effects were more likely to have discontinued. A third more ambivalent group believed strongly in the importance of treatment, but were struggling with side effects and were often non-adherent. Patients sometimes felt unsupported and discussed a need for more comprehensive information. To increase adherence, future research needs to explore ways to increase beliefs around tamoxifen necessity and how to help women cope with side effects. Statement of contribution What is already known on this subject? Non-adherence to tamoxifen is associated with increased risk of recurrence and mortality. Up to 50% of patients are non-adherent to tamoxifen by the fifth year of treatment Few consistent predictors of tamoxifen non-adherence have been identified. What does this study add? Many women report not knowing how to manage their side effects. Non-adherence is related to how women weigh up their side

  4. The Chemopreventive Effect of Tamoxifen Combined with Celecoxib on DMBA chemically-Induced Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    Xiaoxu Liu; Huafeng Kang; Xijing Wang; Zhijun Dai; Fengjie Xue; Xinghuan Xue

    2007-01-01

    Objective: To investigate the chemopreventive effect of tamoxifen combined with a COX-2 selective inhibitor, celecoxib, on breast cancer in rats chemically induced by 7,12-dimethylben (a)anthracene (DMBA). Methods:DMBA was irrigated into the stomaches of SD female rats to build breast cancer model. A total of 120 rats were divided into four groups: control group, tamoxifen group, celecoxib group and combined group. The incidence rate, latent period, number and volume of breast cancer were detected and analyzed. Results:The tumor incidence rate of tamoxifen group (48.15%, 13/27) and celecoxib group (50.00%,14/28) were lower than that of control group (85.71%, 24/28), but higher than that of combined group (21.43%, 6/28). The tumor's latent period of tamoxifen group (97.54±1.85 d) and celecoxib group (96.79±2.89 d) were longer than that of control group (89.50±5.99 d), but shorter than that of combined group (103.67±3.39 d). The average tumor number of tamoxifen group (1.77±0.73) and celecoxib group (1.71±0.61) were less than that of control group (3.50±1.62), but more than that of combined group ( 1.17±0.42 ). The average tumor volume of tamoxifen group (1.78±0.71 cm3) and celecoxib group (2.05±1.04 cm3) were smaller than that of control group (6.42±3.96 cm3), but bigger than that of combined group (0.71±0.96 cm3) (P < 0.05 respectively).Conclusion:Celecoxib and tamoxifen are effective drugs in preventing the occurrence of rat breast cancer chemically induced by DMBA. Furthermore, combination of them has better chemopreventive effect.

  5. MEK activity controls IL-8 expression in tamoxifen-resistant MCF-7 breast cancer cells.

    Science.gov (United States)

    Kim, Sangmin; Jeon, Myeongjin; Lee, Jeong Eon; Nam, Seok Jin

    2016-04-01

    Although tamoxifen reduces disease progression, tamoxifen resistance occurs during the course of estrogen receptor-positive [ER+] breast cancer treatment. In the present study, we investigated the possibility that interleukin-8 (IL-8) is a prognostic marker for tamoxifen resistance and aimed to clarify the regulation of IL-8 expression in tamoxifen-resistant cells. Clinically, IL-8 expression is positively correlated with survival in luminal A type breast cancer patients, but not in luminal B type breast cancer patients. In addition, the levels of IL-8 mRNA and protein expression were significantly increased in tamoxifen-resistant (TamR) cells compared to tamoxifen-sensitive (TamS) cells. To determine the regulatory mechanism of IL-8 expression in TamR cells, we analyzed the activities of signaling molecules. Our results showed that the phosphorylation levels of MEK and Akt were markedly increased in TamR cells, but there was no change in the phosphorylation level of p38 MAPK. On the contrary, we observed that elevated IL-8 mRNA expression was suppressed by a specific MEK1/2 inhibitor, UO126, but not by the specific PI-3K inhibitor LY294002, in TamR cells, whereas, we found that overexpression of constitutively active-MEK (CA-MEK) significantly increased the levels of IL-8 mRNA expression in TamS cells. Finally, we investigated the effect of the specific CXCR1/2 inhibitor SB225002 on anchorage-independent growth of TamR cells, and found that the growth was completely suppressed by SB225002. Taken together, our results demonstrate that IL-8 expression is regulated through a MEK/ERK-dependent pathway in TamR cells, suggesting that IL-8 and its receptors may be promising therapeutic targets for overcoming tamoxifen resistance.

  6. Tamoxifen dosing for Cre-mediated recombination in experimental bronchopulmonary dysplasia.

    Science.gov (United States)

    Ruiz-Camp, Jordi; Rodríguez-Castillo, José Alberto; Herold, Susanne; Mayer, Konstantin; Vadász, István; Tallquist, Michelle D; Seeger, Werner; Ahlbrecht, Katrin; Morty, Rory E

    2017-02-01

    Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth characterized by blunted post-natal lung development. BPD can be modelled in mice by exposure of newborn mouse pups to elevated oxygen levels. Little is known about the mechanisms of perturbed lung development associated with BPD. The advent of transgenic mice, where genetic rearrangements can be induced in particular cell-types at particular time-points during organogenesis, have great potential to explore the pathogenic mechanisms at play during arrested lung development. Many inducible, conditional transgenic technologies available rely on the application of the estrogen-receptor modulator, tamoxifen. While tamoxifen is well-tolerated and has been widely employed in adult mice, or in healthy developing mice; tamoxifen is not well-tolerated in combination with hyperoxia, in the most widely-used mouse model of BPD. To address this, we set out to establish a safe and effective tamoxifen dosing regimen that can be used in newborn mouse pups subjected to injurious stimuli, such as exposure to elevated levels of environmental oxygen. Our data reveal that a single intraperitoneal dose of tamoxifen of 0.2 mg applied to newborn mouse pups in 10 μl Miglyol vehicle was adequate to successfully drive Cre recombinase-mediated genome rearrangements by the fifth day of life, in a murine model of BPD. The number of recombined cells was comparable to that observed in regular tamoxifen administration protocols. These findings will be useful to investigators where tamoxifen dosing is problematic in the background of injurious stimuli and mouse models of human and veterinary disease.

  7. Comparison of gene expression profiles predicting progression in breast cancer patients treated with tamoxifen.

    Science.gov (United States)

    Kok, Marleen; Linn, Sabine C; Van Laar, Ryan K; Jansen, Maurice P H M; van den Berg, Teun M; Delahaye, Leonie J M J; Glas, Annuska M; Peterse, Johannes L; Hauptmann, Michael; Foekens, John A; Klijn, Jan G M; Wessels, Lodewyk F A; Van't Veer, Laura J; Berns, Els M J J

    2009-01-01

    Molecular signatures that predict outcome in tamoxifen treated breast cancer patients have been identified. For the first time, we compared these response profiles in an independent cohort of (neo)adjuvant systemic treatment naïve breast cancer patients treated with first-line tamoxifen for metastatic disease. From a consecutive series of 246 estrogen receptor (ER) positive primary tumors, gene expression profiling was performed on available frozen tumors using 44K oligoarrays (n = 69). A 78-gene tamoxifen response profile (formerly consisting of 81 cDNA-clones), a 21-gene set (microarray-based Recurrence Score), as well as the HOXB13-IL17BR ratio (Two-Gene-Index, RT-PCR) were analyzed. Performance of signatures in relation to time to progression (TTP) was compared with standard immunohistochemical (IHC) markers: ER, progesterone receptor (PgR) and HER2. In univariate analyses, the 78-gene tamoxifen response profile, 21-gene set and HOXB13-IL17BR ratio were all significantly associated with TTP with hazard ratios of 2.2 (95% CI 1.3-3.7, P = 0.005), 2.3 (95% CI 1.3-4.0, P = 0.003) and 4.2 (95% CI 1.4-12.3, P = 0.009), respectively. The concordance among the three classifiers was relatively low, they classified only 45-61% of patients in the same category. In multivariate analyses, the association remained significant for the 78-gene profile and the 21-gene set after adjusting for ER and PgR. The 78-gene tamoxifen response profile, the 21-gene set and the HOXB13-IL17BR ratio were all significantly associated with TTP in an independent patient series treated with tamoxifen. The addition of multigene assays to ER (IHC) improves the prediction of outcome in tamoxifen treated patients and deserves incorporation in future clinical studies.

  8. Tamoxifen use and acute pancreatitis: A population-based cohort study.

    Science.gov (United States)

    Hsu, Fan-Gen; Hsieh, Yow-Wen; Sheu, Ming-Jyh; Lin, Che-Chen; Lin, Cheng-Li; Hsu, Chung Y; Lee, Chang-Yin; Chang, Mei-Yin; Chang, Kuang-Hsi

    2017-01-01

    Several case reports have indicated that tamoxifen induced acute pancreatitis (AP); but no pharmacoepidemiological data support the claim. Therefore, we investigated whether tamoxifen use is correlated with the risk of AP in patients with breast cancer. This population-based cohort study used the Taiwan National Health Insurance Research Database. A cohort of 22 005 patients aged ≥20 years with breast cancer from January 1, 2000 to December 31, 2009 was identified and the date of cancer diagnosis was set as the index date. The end point was developing AP during the follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated to determine the correlation between the risk of AP and tamoxifen use. Because the drug use varied over time, it was measured as a time-dependent covariate in the Cox proportional hazard model. The same approaches were applied in PS-matched cohorts. After adjustment for covariates and medication use including fluorouracil and doxorubicin, the risk of AP was not significant between tamoxifen users and tamoxifen nonusers (adjusted HR = 0.94, 95% CI = 0.74-1.19) in the non-matching cohorts. The results revealed no dose-response trend between tamoxifen use and the risk of AP (adjusted HR = 0.98, 95% CI = 0.96-1.00). The comorbidities DM and gallstones were associated with a significantly increased risk of AP. Similar trends were observed in PS-matched cohorts. No significant correlation was observed between tamoxifen use and the risk of AP in patients with breast cancer.

  9. ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen

    Directory of Open Access Journals (Sweden)

    Sensorn I

    2016-04-01

    Full Text Available Insee Sensorn,1,* Chonlaphat Sukasem,2,* Ekaphop Sirachainan,3 Montri Chamnanphon,2 Ekawat Pasomsub,4 Narumol Trachu,5 Porntip Supavilai,1 Darawan Pinthong,1 Sansanee Wongwaisayawan6 1Department of Pharmacology, Faculty of Science, Mahidol University, 2Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 3Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 4Division of Virology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 5Research Center, Faculty of Medicine, Ramathibodi Hospital, 6Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand *These authors contributed equally to this work Background: Genetic polymorphisms of drug-metabolizing enzymes and transporters have been extensively studied with regard to tamoxifen treatment outcomes. However, the results are inconclusive. Analysis of organ-specific metastasis may reveal the association of these pharmacogenetic factors. The aim of this study is to investigate the impact of CYP3A5, CYP2D6, ABCB1, and ABCC2 polymorphisms on the risk of all distant and organ-specific metastases in Thai patients who received tamoxifen adjuvant therapy. Methods: Genomic DNA was extracted from blood samples of 73 patients with breast cancer who received tamoxifen adjuvant therapy. CYP3A5 (6986A>G, CYP2D6 (100C>T, ABCB1 (3435C>T, and ABCC2 (-24C>T were genotyped using allelic discrimination real-time polymerase chain reaction assays. The impacts of prognostic clinical factors and genetic variants on disease-free survival were analyzed using the Kaplan–Meier method and Cox regression analysis. Results: In the univariate analysis, primary tumor size >5 cm was significantly associated with increased risk of distant metastasis (P=0

  10. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial

    DEFF Research Database (Denmark)

    Coombes, R C; Kilburn, L S; Snowdon, C F;

    2007-01-01

    BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects ...

  11. Effect of Concomitant CYP2D6 Inhibitor Use and Tamoxifen Adherence on Breast Cancer Recurrence in Early-Stage Breast Cancer

    National Research Council Canada - National Science Library

    Vincent O. Dezentjé; Nico J.C. van Blijderveen; Hans Gelderblom; Hein Putter; Myrthe P.P. van Herk-Sukel; Mariel K. Casparie; Antoine C.G. Egberts; Johan W.R. Nortier; Henk-Jan Guchelaar

    2010-01-01

    .... Concomitant use of CYP2D6 inhibitors, such as selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in patients with breast cancer...

  12. Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients

    Science.gov (United States)

    Fernández-Santander, Ana; Gaibar, María; Novillo, Apolonia; Romero-Lorca, Alicia; Rubio, Margarita; Chicharro, Luis Miguel; Tejerina, Armando; Bandrés, Fernando

    2013-01-01

    Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen. PMID:23922954

  13. Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

    Science.gov (United States)

    Fernández-Santander, Ana; Gaibar, María; Novillo, Apolonia; Romero-Lorca, Alicia; Rubio, Margarita; Chicharro, Luis Miguel; Tejerina, Armando; Bandrés, Fernando

    2013-01-01

    Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.

  14. Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

    Directory of Open Access Journals (Sweden)

    Ana Fernández-Santander

    Full Text Available Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001. No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively, as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.

  15. Beta-interferon, retinoids and tamoxifen in metastatic breast cancer: long-term follow-up of a phase II study.

    Science.gov (United States)

    Recchia, Francesco; Sica, Gigliola; Candeloro, Giampiero; Necozione, Stefano; Bisegna, Roberta; Bratta, Massimo; Rea, Silvio

    2009-04-01

    Based on a series of in vitro data, including the additive and/or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines, and on clinical reports, we designed a pilot phase II study to test the activity and toxicity of simultaneous administration of beta-interferon (beta-IFN), retinoids (R) and tamoxifen (TAM) as a salvage therapy in a group of patients with metastatic breast cancer (MBC). Herein we describe the outcome of this cohort of patients after a median follow-up of 150 months. Sixty-five stage IV breast cancer patients, 13 pre-treated with hormones, 38 with chemotherapy and 15 with both, received, as a salvage therapy, TAM, beta-IFN and R. Among 65 evaluable patients, 36 achieved a clinical response (55.5%) (95% c.i. 42-67.7%). Toxicity was moderate and mainly hepatic. Median progression-free and overall survival, which did not show any statistically significant difference in patients with different estrogen and progesterone receptor content, were 43 months and 47.9 months, respectively. In conclusion, the study shows that long-term treatment with TAM, beta-IFN and R in MBC is feasible, has moderate toxicity and seems to give a long-term benefit, irrespective of the receptorial status.

  16. Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia.

    Science.gov (United States)

    Morad, Samy A F; Ryan, Terence E; Neufer, P Darrell; Zeczycki, Tonya N; Davis, Traci S; MacDougall, Matthew R; Fox, Todd E; Tan, Su-Fern; Feith, David J; Loughran, Thomas P; Kester, Mark; Claxton, David F; Barth, Brian M; Deering, Tye G; Cabot, Myles C

    2016-07-01

    The objective of our study was to determine the mechanism of action of the short-chain ceramide analog, C6-ceramide, and the breast cancer drug, tamoxifen, which we show coactively depress viability and induce apoptosis in human acute myelogenous leukemia cells. Exposure to the C6-ceramide-tamoxifen combination elicited decreases in mitochondrial membrane potential and complex I respiration, increases in reactive oxygen species (ROS), and release of mitochondrial proapoptotic proteins. Decreases in ATP levels, reduced glycolytic capacity, and reduced expression of inhibitors of apoptosis proteins also resulted. Cytotoxicity of the drug combination was mitigated by exposure to antioxidant. Cells metabolized C6-ceramide by glycosylation and hydrolysis, the latter leading to increases in long-chain ceramides. Tamoxifen potently blocked glycosylation of C6-ceramide and long-chain ceramides. N-desmethyltamoxifen, a poor antiestrogen and the major tamoxifen metabolite in humans, was also effective with C6-ceramide, indicating that traditional antiestrogen pathways are not involved in cellular responses. We conclude that cell death is driven by mitochondrial targeting and ROS generation and that tamoxifen enhances the ceramide effect by blocking its metabolism. As depletion of ATP and targeting the "Warburg effect" represent dynamic metabolic insult, this ceramide-containing combination may be of utility in the treatment of leukemia and other cancers. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  17. Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia1

    Science.gov (United States)

    Morad, Samy A. F.; Ryan, Terence E.; Neufer, P. Darrell; Zeczycki, Tonya N.; Davis, Traci S.; MacDougall, Matthew R.; Fox, Todd E.; Tan, Su-Fern; Feith, David J.; Loughran, Thomas P.; Kester, Mark; Claxton, David F.; Barth, Brian M.; Deering, Tye G.; Cabot, Myles C.

    2016-01-01

    The objective of our study was to determine the mechanism of action of the short-chain ceramide analog, C6-ceramide, and the breast cancer drug, tamoxifen, which we show coactively depress viability and induce apoptosis in human acute myelogenous leukemia cells. Exposure to the C6-ceramide-tamoxifen combination elicited decreases in mitochondrial membrane potential and complex I respiration, increases in reactive oxygen species (ROS), and release of mitochondrial proapoptotic proteins. Decreases in ATP levels, reduced glycolytic capacity, and reduced expression of inhibitors of apoptosis proteins also resulted. Cytotoxicity of the drug combination was mitigated by exposure to antioxidant. Cells metabolized C6-ceramide by glycosylation and hydrolysis, the latter leading to increases in long-chain ceramides. Tamoxifen potently blocked glycosylation of C6-ceramide and long-chain ceramides. N-desmethyltamoxifen, a poor antiestrogen and the major tamoxifen metabolite in humans, was also effective with C6-ceramide, indicating that traditional antiestrogen pathways are not involved in cellular responses. We conclude that cell death is driven by mitochondrial targeting and ROS generation and that tamoxifen enhances the ceramide effect by blocking its metabolism. As depletion of ATP and targeting the “Warburg effect” represent dynamic metabolic insult, this ceramide-containing combination may be of utility in the treatment of leukemia and other cancers. PMID:27140664

  18. Tamoxifen:an FDA approved drug with neuroprotective effects for spinal cord injur y recover y

    Institute of Scientific and Technical Information of China (English)

    Jennifer M. Colón; Jorge D. Miranda

    2016-01-01

    Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inlfammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and syn-aptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneifcial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inlfammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the ifeld.

  19. Quantifiable mRNA transcripts for tamoxifen-metabolising enzymes in human endometrium.

    Science.gov (United States)

    Singh, Maneesh N; Stringfellow, Helen F; Walsh, Michael J; Ashton, Kate M; Paraskevaidis, Evangelos; Abdo, Khalil R; Martin-Hirsch, Pierre L; Phillips, David H; Martin, Francis L

    2008-07-10

    Tamoxifen has been used in the management of receptor-positive breast cancer for >20 years. Usage confers an elevated risk of developing endometrial carcinoma. Its mechanism of carcinogenicity remains unresolved with controversy as to whether or not this is mediated through a genotoxic mechanism. Usage is not only associated with an elevated occurrence of endometrioid endometrial carcinoma, but also type 2 and mixed epithelial-stromal tumours (MESTs) that have a poorer prognosis. Following hysterectomy, endometrial tissues (n=18) classified as benign (n=6), non-tamoxifen-associated carcinoma (n=6) and tamoxifen-associated carcinoma (n=6) were obtained; quantitative gene expression was performed. Employing real-time RT-PCR, the relative gene expressions of phase I/II metabolic enzymes CYP1A2, CYP1B1 and CYP3A4, cathechol-O-methyltransferase (COMT) and SULT2A1 were ascertained. Measurable mRNA transcripts, especially for those genes associated with tamoxifen bioactivation, were quantifiable in all the tissues examined. Whether this is evidence that generation of genotoxic tamoxifen metabolites may occur in human endometrial tissue remains to be ascertained.

  20. Effect of Tamoxifen on Seminiferous Tubules Structure during Pregnancy in Adult Mice

    Directory of Open Access Journals (Sweden)

    J Soleimani Rad

    2016-03-01

    Full Text Available Introduction: Tamoxifen is a nonsteroidal drug which mainly treats breast cancer. It is also applied for stimulation of ovulation and remedy of infertility. Regarding the tamoxifen binding to estrogen receptors and the possible role of estrogens in spermatogenesis, the present study aimed to histologically evaluate spermatogenesis in the seminiferous ducts of mice, whose mothers had received tamoxifen during pregnancy. Methods: In the present study, 30 female and 15 male mice of NMRI race were selected for mating. Since 13th day of pregnancy, the experimental group received tamoxifen with the dosage of 5 mg/kg intra-peritoneally for 7 days, wherease the control group received normal saline. After childbirth of the mated mice, male infants were selected and monitored in the standard laboratory conditions. After reaching the age of puberty (6-8Weeks, adult mice were sacrificed by the cervical dislocation, and the testes were removed for histological evaluation of spermatogenesis. After routine histological processing, the samples were studied by the light microscope. Results: Histological studies showed that spermatogenic and Sertoli cells in the seminiferous tubules in control and experimental groups were significantly different, though no difference was observed in the number of Leydig cells in the both groups. Conclusion: The findings of the present study showed that tamoxifen exposure during development can cause histological changes in the seminiferous tubules, which can lead to infertility in the male rat.

  1. Tamoxifen: an FDA approved drug with neuroprotective effects for spinal cord injury recovery

    Directory of Open Access Journals (Sweden)

    Jennifer M Colón

    2016-01-01

    Full Text Available Spinal cord injury (SCI is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inflammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and synaptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inflammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field.

  2. Tamoxifen: an FDA approved drug with neuroprotective effects for spinal cord injury recovery.

    Science.gov (United States)

    Colón, Jennifer M; Miranda, Jorge D

    2016-08-01

    Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inflammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and synaptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inflammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field.

  3. Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system

    Science.gov (United States)

    Gonzalez, Ginez A.; Hofer, Matthias P.; Syed, Yasir A.; Amaral, Ana I.; Rundle, Jon; Rahman, Saifur; Zhao, Chao; Kotter, Mark R. N.

    2016-01-01

    Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models. PMID:27554391

  4. Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen.

    Science.gov (United States)

    Snell, Cameron E; Gough, Madeline; Middleton, Kathryn; Hsieh, Michael; Furnas, Lauren; Seidl, Brenton; Gibbons, Kristen; Pyke, Christopher; Shannon, Catherine; Woodward, Natasha; Armes, Jane E

    2017-04-17

    Progesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (-) breast cancer could provide more accurate prognostic information. The retrospective cohort included 229 patients from a single institution with ER+, HER2- breast cancer who had synchronous ALN metastatic disease (2005-2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor. One patient had an ER+ primary tumour, which was ER- in the ALN metastasis. 27 (11.3%) were PR- in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR- in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse; however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR- metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR- metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312). Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  5. A five-gene model predicts clinical outcome in ER+/PR+, early-stage breast cancers treated with adjuvant tamoxifen.

    Science.gov (United States)

    Kerr, Daniel Alan; Wittliff, James L

    2011-10-01

    Primary breast carcinomas expressing both estrogen and progesterone receptors are most likely to respond to tamoxifen therapy, especially in patients with early-stage lesions. However, certain patients exhibit clinicopathologic features suggesting good prognosis relapse within 10 years, justifying a search for biomarkers identifying patients at risk for recurrence. Nine candidate genes associated with estrogen signaling were selected from microarray studies and combined with those for conventional biomarkers (ESR1, PGR, ERBB2). Expression of this 12-gene subset was analyzed by RT-qPCR in frozen tissue specimens from 60 early-stage, estrogen receptor (ER)+/progestin receptor (PR)+ breast cancers from patients treated with adjuvant tamoxifen. A multivariate model was created by Cox regression using a training data set and applied to an independent validation set. A five-gene model was developed from the training set (n = 36) that exhibited significant correlations with both relapse-free and overall survival. Applying this model to Kaplan-Meier regression, patients were separated into low-risk (100% relapse-free at 150 months) and high-risk (60% relapse-free at 150 months) groups (P = 0.03). When this model was applied to the validation set (n = 24), similar risk stratification was achieved for both relapse-free and overall survival (P = 0.01 and 0.04, respectively). We developed a five-gene model composed of PgR, BCL2, ERBB4 JM-a, RERG, and CD34 that identified early-stage, ER+/PR+ breast cancers in patients treated with tamoxifen that relapsed, although they exhibited clinicopathologic features suggesting good prognosis. Within this multivariate model, increased expression of PgR, ERBB4 JM-a, RERG, and CD34 was associated with increased survival, while increased expression of BCL2 was associated with decreased survival.

  6. An UPLC-MS/MS method for separation and accurate quantification of tamoxifen and its metabolites isomers.

    Science.gov (United States)

    Arellano, Cécile; Allal, Ben; Goubaa, Anwar; Roché, Henri; Chatelut, Etienne

    2014-11-01

    A selective and accurate analytical method is needed to quantify tamoxifen and its phase I metabolites in a prospective clinical protocol, for evaluation of pharmacokinetic parameters of tamoxifen and its metabolites in adjuvant treatment of breast cancer. The selectivity of the analytical method is a fundamental criteria to allow the quantification of the main active metabolites (Z)-isomers from (Z)'-isomers. An UPLC-MS/MS method was developed and validated for the quantification of (Z)-tamoxifen, (Z)-endoxifen, (E)-endoxifen, Z'-endoxifen, (Z)'-endoxifen, (Z)-4-hydroxytamoxifen, (Z)-4'-hydroxytamoxifen, N-desmethyl tamoxifen, and tamoxifen-N-oxide. The validation range was set between 0.5ng/mL and 125ng/mL for 4-hydroxytamoxifen and endoxifen isomers, and between 12.5ng/mL and 300ng/mL for tamoxifen, tamoxifen N-desmethyl and tamoxifen-N-oxide. The application to patient plasma samples was performed. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. In Vitro Investigations on the Toxicity and Cell Death Induced by Tamoxifen on Two Non-Breast Cancer Cell Types

    Directory of Open Access Journals (Sweden)

    S. K. Majumdar

    2001-01-01

    protein (EGFP in tamoxifen treated MEL BB-88 cells, a general feature of cells undergoing apoptosis. Tamoxifen treated cells demonstrated internucleosomal damages of the genomic DNA and DNA fragmentations, evidenced by an increase in free nucleosomes, and distinctive DNA smear patterns on the agarose gel.

  8. Direct, differential effects of tamoxifen, 4-hydroxytamoxifen, and raloxifene on cardiac myocyte contractility and calcium handling.

    Directory of Open Access Journals (Sweden)

    Michelle L Asp

    Full Text Available Tamoxifen (Tam, a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. High Tam doses have been used for treatment of gliomas and cancers with multiple drug resistance, but long QT Syndrome is a side effect. Tam is also used experimentally in mice for inducible gene knockout in numerous tissues, including heart; however, the potential direct effects of Tam on cardiac myocyte mechanical function are not known. The goal of this study was to determine the direct, acute effects of Tam, its active metabolite 4-hydroxytamoxifen (4OHT, and related drug raloxifene (Ral on isolated rat cardiac myocyte mechanical function and calcium handling. Tam decreased contraction amplitude, slowed relaxation, and decreased Ca²⁺ transient amplitude. Effects were primarily observed at 5 and 10 μM Tam, which is relevant for high dose Tam treatment in cancer patients as well as Tam-mediated gene excision in mice. Myocytes treated with 4OHT responded similarly to Tam-treated cells with regard to both contractility and calcium handling, suggesting an estrogen-receptor independent mechanism is responsible for the effects. In contrast, Ral increased contraction and Ca²⁺ transient amplitudes. At 10 μM, all drugs had a time-dependent effect to abolish cellular contraction. In conclusion, Tam, 4OHT, and Ral adversely and differentially alter cardiac myocyte contractility and Ca²⁺ handling. These findings have important implications for understanding the Tam-induced cardiomyopathy in gene excision studies and may be important for understanding effects on cardiac performance in patients undergoing high-dose Tam therapy.

  9. Comparison of tamoxifen with edible seaweed (Eucheuma cottonii L.) extract in suppressing breast tumor.

    Science.gov (United States)

    Shamsabadi, Fatemeh T; Khoddami, Ali; Fard, Samaneh Ghasemi; Abdullah, Rasedee; Othman, Hemn Hassan; Mohamed, Suhaila

    2013-01-01

    The tropical edible red seaweed (Eucheuma cottonii L.) is rich in nutrients and polyphenolic compounds that may suppress cancer through its antioxidant and antiproliferative properties. The study reports on rat mammary tumor suppression and tissue antioxidant status modulation by E. cottonii ethanol extract (ECE). The effect of orally administered ECE (100 mg/kg body-weight) was compared with that of tamoxifen (10 mg/kg body-weight). Rat was induced to develop mammary tumor with subcutaneous injection of LA-7 cells (6 × 10(6) cells/rat). The ECE was more effective than tamoxifen in suppressing tumor growth (27%), improving tissues (plasma, liver, and kidney) malondialdehyde concentrations, superoxide dismutase activity and erythrocyte glutathione concentrations (P < 0.05). Unlike tamoxifen, the ECE displayed little toxicity to the liver and kidneys. The ECE exhibited strong anticancer effect with enzyme modulating properties, suggesting its potential as a suppressing agent for mammary gland tumor.

  10. Investigational study of tamoxifen phase I metabolites using chromatographic and spectroscopic analytical techniques.

    Science.gov (United States)

    Teunissen, S F; Rosing, H; Seoane, M Dominguez; Brunsveld, L; Schellens, J H M; Schinkel, A H; Beijnen, J H

    2011-06-01

    A comprehensive overview is presented of currently known phase I metabolites of tamoxifen consisting of their systematic name and molecular structure. Reference standards are utilized to elucidate the MS(n) fragmentation patterns of these metabolites using a linear ion trap mass spectrometer. UV-absorption spectra are recorded and absorption maxima are defined. Serum extracts from ten breast cancer patients receiving 40mg tamoxifen once daily were qualitatively analyzed for tamoxifen phase I metabolites using a liquid chromatography-tandem mass spectrometry set-up. In total, 19 metabolites have been identified in these serum samples. Additionally a synthetic method for the preparation of the putative metabolite 3',4'-dihydroxytamoxifen is described. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Randomized trial of medroxyprogesterone acetate for the prevention of endometrial pathology from adjuvant tamoxifen for breast cancer: SWOG S9630.

    Science.gov (United States)

    Potkul, Ronald K; Unger, Joseph M; Livingston, Robert B; Crew, Katherine D; Wilczynski, Sharon P; Salomon, Caryl G; Smith, Barbara L; Wong, Lucas; Campbell, David L; Einspahr, David E; Anderson, Garnet L; Hershman, Dawn; Goodman, Gary E; Brown, Powel H; Meyskens, Frank L; Albain, Kathy S

    2016-01-01

    The proliferative effect of adjuvant tamoxifen on the endometrium can potentially result in endometrial abnormalities, including cancer in postmenopausal women. We conducted a randomized, controlled trial to assess endometrial pathological diagnoses in postmenopausal women with early stage, ER-positive breast cancer without endometrial pathology at baseline. They were assigned to tamoxifen alone versus tamoxifen plus cyclical medroxyprogesterone acetate (MPA 10 mg for 14 days every 3 months) for 5 years. Endovaginal sonograms (EVS) +/- endometrial biopsies (EMB) were required at baseline, 2 and 5 years. Of 313 patients registered, 296 were eligible and 169 (57%; 89, tamoxifen; 80, tamoxifen+MPA) were evaluable (completed year-2 EVS, with an EMB if stripe width was ⩾5 mm). Sixty (67%) of these in the tamoxifen arm had an endometrial stripe width ⩾5 mm (and underwent subsequent EMB) compared with 48 (60%) in the tamoxifen+MPA arm (P=0.40). There were four cases of proliferative endometrium and one simple hyperplasia on the tamoxifen arm (6% (95% confidence interval (CI): 2-13%) among evaluable patients and one proliferative endometrium on the tamoxifen+MPA arm (P=0.11). The overall fraction with benign endometrial abnormalities at year 2 was 3.6% (6/169; 95% CI: 1.3-7.6%), with only 1 (of 102) new benign proliferative event at year 5. The event rate in both arms was much lower than projected, making treatment arm comparisons less informative. A normal endometrium prior to tamoxifen may provide reassurance regarding future endometrial events. However, validation in a larger trial is needed before changing practice in asymptomatic, postmenopausal women.

  12. Tamoxifen: An alternative to clomiphene in women with polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Lakhbir Kaur Dhaliwal

    2011-01-01

    Full Text Available Background : Clomiphene citrate is commonly used for ovulation induction in women with anovulatory infertility. However, pregnancy rates with this drug are not as good as ovulation rates. Tamoxifen may be a better choice in some patients who fail to either ovulate or conceive with clomiphene due to its favorable effect on the cervical mucus and endometrium. This study was conducted to evaluate the role of tamoxifen in women with anovulatory infertility and find out the optimum dose needed for achieving the best outcome. Materials and Methods : 160 women attending the infertility clinic and suffering from anovulatory infertility were recruited for the study. Tamoxifen was administered in the dose of 40 mg daily and ovulation monitored. In case of anovulation, the dose was increased to 80 mg daily. Ovulation and pregnancy rates were calculated. Results : Twenty-three out of 160 women who received 40 mg of tamoxifen conceived, giving a pregnancy rate of 14.38% and pregnancy rate per ovulatory cycle as 14.94%. 32 out of 80 women who received 80 mg of tamoxifen conceived, giving a pregnancy rate of 40% and pregnancy rate per cycle as 33.68%. This difference in the pregnancy rate between the two groups was statistically significant. 35 women out of 90 with polycystic ovary syndrome (PCOS became pregnant with a pregnancy rate of 38.8% and 20 out of 70 women with clomiphene citrate failure conceived, giving a pregnancy rate of 28.5%. Conclusions : Tamoxifen is a good alternative to clomiphene in women with PCOS and clomiphene-resistant cases.

  13. A naringenin–tamoxifen combination impairs cell proliferation and survival of MCF-7 breast cancer cells

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    Hatkevich, Talia; Ramos, Joseph; Santos-Sanchez, Idalys; Patel, Yashomati M., E-mail: ympatel@uncg.edu

    2014-10-01

    Since over 60% of breast cancers are estrogen receptor positive (ER+), many therapies have targeted the ER. The ER is activated by both estrogen binding and phosphorylation. While anti-estrogen therapies, such as tamoxifen (Tam) have been successful they do not target the growth factor promoting phosphorylation of the ER. Other proliferation pathways such as the phosphatidylinositol-3 kinase, (PI3K) and the mitogen-activated protein kinase (MAPK) pathways are activated in breast cancer cells and are associated with poor prognosis. Thus targeting multiple cellular proliferation and survival pathways at the onset of treatment is critical for the development of more effective therapies. The grapefruit flavanone naringenin (Nar) is an inhibitor of both the PI3K and MAPK pathways. Previous studies examining either Nar or Tam used charcoal-stripped serum which removed estrogen as well as other factors. We wanted to use serum containing medium in order to retain all the potential inducers of cell proliferation so as not to exclude any targets of Nar. Here we show that a Nar–Tam combination is more effective than either Tam alone or Nar alone in MCF-7 breast cancer cells. We demonstrate that a Nar–Tam combination impaired cellular proliferation and viability to a greater extent than either component alone in MCF-7 cells. Furthermore, the use of a Nar–Tam combination requires lower concentrations of both compounds to achieve the same effects on proliferation and viability. Nar may function by inhibiting both PI3K and MAPK pathways as well as localizing ERα to the cytoplasm in MCF-7 cells. Our results demonstrate that a Nar–Tam combination induces apoptosis and impairs proliferation signaling to a greater extent than either compound alone. These studies provide critical information for understanding the molecular mechanisms involved in cell proliferation and apoptosis in breast cancer cells. - Highlights: • Nar–Tam impairs cell viability more effectively than

  14. Endometrial polyp surveillance in premenopausal breast cancer patients using tamoxifen

    Science.gov (United States)

    Jeon, Se Jeong; Lee, Jae Il; Kim, Hee Seung; Kim, Jae Weon; Park, Noh Hyun; Song, Yong Sang

    2017-01-01

    Objective To describe the endometrial pathologic lesions in premenopausal breast cancer patients with a history of tamoxifen (TMX) use. Methods We retrospectively reviewed the medical records of 120 premenopausal breast cancer patients with a history of TMX use that had undergone a gynecological examination. Results Among 120 patients, 44.2% (n=53) were asymptomatic with an endometrial thickness ≥5 mm, as assessed by transvaginal ultrasonography. Of the patients that reported abnormal uterine bleeding, 5% (n=6) had an endometrial thickness <5 mm and 20% (n=24) had an endometrial thickness ≥5 mm by transvaginal ultrasonography. The final group of patients were asymptomatic, but showed an abnormal endometrial lesion, such as an endometrial polyp, by transvaginal ultrasonography (30.8%, n=37). Of the 56 benign lesions that were histologically reviewed, 50 (41.7%) were endometrial polyps, 3 (2.5%) were submucosal myomas, 2 (1.7%) were endometrial hyperplasias, and 1 (0.8%) was chronic endometritis. There were 64 (53.3%) other non-pathologic conditions, including secreting, proliferative, and atrophic endometrium, or in some cases, there was insufficient material for diagnosis. In our data, only one case was reported as a complex hyperplasia without atypia arising from an endometrial polyp, and one patient was diagnosed with endometrioid adenocarcinoma. Conclusion For premenopausal breast cancer patients with a history of TMX use, the majority of the patients were asymptomatic, and endometrial polyps were the most common endometrial pathology observed. Therefore, we believe that endometrial assessment before starting TMX treatment, and regular endometrial screening throughout TMX treatment, are reasonable suggestions for premenopausal breast cancer patients. PMID:28217668

  15. Cyclin D-1, interleukin-6, HER-2/neu, transforming growth factor receptor-II and prediction of relapse in women with early stage, hormone receptor-positive breast cancer treated with tamoxifen.

    Science.gov (United States)

    Muss, Hyman B; Bunn, Janice Yanushka; Crocker, Abigail; Plaut, Karen; Koh, James; Heintz, Nick; Rincon, Mercedes; Weaver, Donald L; Tam, Diane; Beatty, Barbara; Kaufman, Peter; Donovan, Michael; Verbel, David; Weiss, Linda

    2007-01-01

    We hypothesized that amplification or overexpression of HER-2 (c-erbB-2), the Ki-67 antigen (Mib1), cyclin D-1 (CD1), interleukin-6 (IL-6), or the transforming growth factor beta II receptor, (TGFbetaRII), would predict relapse in women with early stage, estrogen (ER) and/or progesterone receptor (PR) positive breast cancer treated with tamoxifen. Conditional logistic regression models and a new novel analytic method - support vector machines (SVM) were used to assess the effect of multiple variables on treatment outcome. All patients had stage I-IIIa breast cancer (AJCC version 5). We paired 63 patients who were disease-free on or after tamoxifen with 63 patients who had relapsed (total 126); both disease-free and relapsed patients were matched by duration of tamoxifen therapy and time to recurrence. These 126 patients also served as the training set for SVM analysis and 18 other patients used as a validation set for SVM. In a multivariate analysis, larger tumor size, increasing extent of lymph node involvement, and poorer tumor grade were significant predictors of relapse. When HER-2 or CD1 were added to the model both were borderline significant predictors of relapse. The SVM model, after including all of the clinical and marker variables in the 126 patients as a training set, correctly predicted relapse in 78% of the 18 patient validation samples. In this trial, HER-2 and CD1 proved of borderline significance as predictive factors for recurrence on tamoxifen. An SVM model that included all clinical and biologic variables correctly predicted relapse in >75% of patients.

  16. CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH-Tamoxifen.

    Science.gov (United States)

    Prather, Paul L; FrancisDevaraj, FeAna; Dates, Centdrika R; Greer, Aleksandra K; Bratton, Stacie M; Ford, Benjamin M; Franks, Lirit N; Radominska-Pandya, Anna

    2013-11-15

    Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam can produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9-3 μM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel, efficacious, non-toxic cancer drugs acting via CB1 and/or CB2Rs.

  17. Prescribing tamoxifen in primary care for the prevention of breast cancer: a national online survey of GPs' attitudes.

    Science.gov (United States)

    Smith, Samuel G; Foy, Robbie; McGowan, Jennifer A; Kobayashi, Lindsay C; DeCensi, Andrea; Brown, Karen; Side, Lucy; Cuzick, Jack

    2017-06-01

    The cancer strategy for England (2015-2020) recommends GPs prescribe tamoxifen for breast cancer primary prevention among women at increased risk. To investigate GPs' attitudes towards prescribing tamoxifen. In an online survey, GPs in England, Northern Ireland, and Wales (n = 928) were randomised using a 2 × 2 between-subjects design to read one of four vignettes describing a healthy patient seeking a tamoxifen prescription. In the vignette, the hypothetical patient's breast cancer risk (moderate versus high) and the clinician initiating the prescription (GP prescriber versus secondary care clinician [SCC] prescriber) were manipulated in a 1:1:1:1 ratio. Outcomes were willingness to prescribe, comfort discussing harms and benefits, comfort managing the patient, factors affecting the prescribing decision, and awareness of tamoxifen and the National Institute for Health and Care Excellence (NICE) guideline CG164. Half (51.7%) of the GPs knew tamoxifen can reduce breast cancer risk, and one-quarter (24.1%) were aware of NICE guideline CG164. Responders asked to initiate prescribing (GP prescriber) were less willing to prescribe tamoxifen than those continuing a prescription initiated in secondary care (SCC prescriber) (68.9% versus 84.6%, PGPs willing to prescribe were more likely to be aware of the NICE guideline (P = 0.039) and to have acknowledged the benefits of tamoxifen (PGPs to continue the patient's care may overcome some prescribing barriers. © British Journal of General Practice 2017.

  18. A Pilot Study on Tamoxifen Sexual Side Effects and Hand Preference in Male Breast Cancer.

    Science.gov (United States)

    Motofei, Ion G; Rowland, David L; Popa, Florian; Bratucu, Eugen; Straja, Dan; Manea, Mirela; Georgescu, Simona R; Paunica, Stana; Bratucu, Mircea; Balalau, Cristian; Constantin, Vlad D

    2015-08-01

    Recent clinical and imaging studies suggest that sex hormones modulate sexuality according to a psychophysiologic process of lateralization of the brain, with androgens playing a greater role in sexual functioning of left hemibrain/right handedness and estrogens possibly for right hemibrain/left handedness. Based on this perspective, the current study attempted to specify the relationship between hand preference, estrogens, and sexual function in subjects with male breast cancer, taking into account the sexual side effects of tamoxifen as the agent for inhibiting estrogen action. Twenty-eight Romanian men-17 right-handed and 11 left-handed-undergoing treatment with tamoxifen for male breast cancer participated in this study. These men were assessed both prior to and during tamoxifen treatment using the International Index of Erectile Function, a standardized instrument used for the evaluation of various aspects of sexual functioning, including erectile function (EF), orgasmic function (OF), sexual desire (SD), and overall functioning (OF). A main effect for handedness was found on EF, OF, SD, and OS scales, with right-handed men showing higher functioning than left-handed men. Regarding interaction effects, the left-handed group of men showed greater decreased sexual functioning during tamoxifen (on three subscales: OF, SD, OS) compared to right-handed men. Further research should be conducted in order to support and refine this potential lateralized process of sexual neuromodulation within the brain.

  19. Effects of tamoxifen citrate on gene expression during nuclear chromatin condensation in male rats

    Institute of Scientific and Technical Information of China (English)

    Mukhtar Aleem; Varsha Padwal; Jyoti Choudhari; Nafisa Balasinor; Priyanka Parte; Manjeet Gill-Sharma

    2005-01-01

    Aim: To evaluate the effects of tamoxifen citrate on gene expression during nuclear chromatin condensation in male decondensation, acridine orange (AO) dye uptake, concentration of thiol-groups, levels and/or expression of transition proteins 1, 2 (TP1, TP2), protamine 1 (P1), cyclic AMP response element modulator-τ (CREMτ), androgenbinding protein (ABP) and cyclic adenosine 3', 5' monophosphate (cAMP) were evaluated after 60 days of exposure in adult male rats. Controls received the vehicle. Results: Tamoxifen citrate enhanced the rates of chromatin decondensation, increased AO dye uptake and reduced free thiols in caput epididymal sperms and reduced the levels of TP1, TP2, P1, and CREMτ in the testis, while cAMP was unaffected. P1 deposition was absent in the sperm. The transcripts of TP1, TP2 were increased, of P1 and ABP decreased, while those of CREMτ unaffected in the testis.Conclusion: Tamoxifen citrate reduced caput epididymal sperm chromatin compaction by reducing the testicular levels of proteins TP1, TP2 and P1 and the CREMτ involved in chromatin condensation during spermiogenesis.Tamoxifen citrate affects the expression of these genes at both the transcriptional and post-transcriptional levels.

  20. Potential Therapeutic Benefit of Combining Gefitinib and Tamoxifen for Treating Advanced Lung Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Chien-Ming Liu

    2015-01-01

    Full Text Available Introduction. Epidermal growth factor receptor (EGFR mutations are known as oncogene driver mutations and with EGFR mutations exhibit good response to the EGFR tyrosine kinase inhibitor Gefitinib. Some studies have shown that activation of estrogen and estrogen receptor α or β (ERα/β promote adenocarcinoma. We evaluated the relationship between the two receptors and the potential therapeutic benefit with Gefitinib and Tamoxifen. Methods. We assessed the association between EGFR mutations as well as ERα/β expression/location and overall survival in a cohort of 55 patients with LAC from a single hospital. PC9 (EGFR exon 19 deletion mutant; Gefitinib-vulnerable cells and A549 (EGFR wild type; Gefitinib-resistant cells cancer cells were used to evaluate the in vitro therapeutic benefits of combining Gefitinib and Tamoxifen. Results. We found that the cytosolic but not the nuclear expression of ERβ was associated with better OS in LAC tumors but not associated with EGFR mutation. The in vitro study showed that combined Gefitinib and Tamoxifen resulted in increased apoptosis and cytosolic expression of ERβ. In addition, combining both medications resulted in reduced cell growth and increased the cytotoxic effect of Gefitinib. Conclusion. Tamoxifen enhanced advanced LAC cytotoxic effect induced by Gefitinib by arresting ERβ in cytosol.

  1. Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer

    NARCIS (Netherlands)

    M.F.E. Godinho (Marcia F.E.); A.M. Sieuwerts (Anieta); M.P. Look (Maxime); D.N. Meijer (Dies); J.A. Foekens (John); L.C.J. Dorssers (Lambert); T.L.A. van Agthoven (Thecla)

    2010-01-01

    textabstractBackground:Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function.Me

  2. Tamoxifen inhibits astrocytic JAK2/STAT3 pathway in rats with ...

    African Journals Online (AJOL)

    Therefore, SCI has a complex pathophysiology. Because ... patients with SCI, research has been conducted ... astrocytes, various pathways involved in central nervous system ... tamoxifen on motor function in the injured rats. For this .... mechanisms, and treatment ... assessing motor deficits following traumatic brain injury.

  3. Targeted MS Assay Predicting Tamoxifen Resistance in Estrogen-Receptor-Positive Breast Cancer Tissues and Sera

    NARCIS (Netherlands)

    De Marchi, Tommaso; Kuhn, Erik; Dekker, Lennard J; Stingl, Christoph; Braakman, Rene B H; Opdam, Mark; Linn, Sabine C; Sweep, Fred C G J; Span, Paul N; Luider, Theo M; Foekens, John A; Martens, John W M; Carr, Steven A; Umar, Arzu

    2016-01-01

    We recently reported on the development of a 4-protein-based classifier (PDCD4, CGN, G3BP2, and OCIAD1) capable of predicting outcome to tamoxifen treatment in recurrent, estrogen-receptor-positive breast cancer based on high-resolution MS data. A precise and high-throughput assay to measure these

  4. EFFECT OF TAMOXIFEN ON THE SECRETORY FUNCTION OF HUMAN TROPHOBLASTIC CELLS

    Institute of Scientific and Technical Information of China (English)

    HANGui-Zhen; CHUYun-Hong; ZHOUYu-Fen

    1989-01-01

    Gu et al observed the morphological damages and the suppressed secretion of HCG in vitro cultured human placental chorionic tissues caused by tamoxifen (20ug/ml).TarnoxiFeu blood concentrations, during oral administration. 20rag, b.i.d, in early pregnant

  5. A PRELIMINARY CLINICAL STUDY OF TAMOXIFEN PRIOR TO PROSTAGLANDIN FOR TERMINATION OF EARLY PREGNANCY

    Institute of Scientific and Technical Information of China (English)

    CHENGLi-Nan; ZHOUYu-Fen; CHUYun-Hong; JINzhao-Ying

    1989-01-01

    Thirty four healthy women with amenorrhea of less than 49 daya applied for legal abortion. Each patient received tamoxifen ( Tara ) tablets 20 mg twioe a day for 4 consecutive days orally. In the morning of the Frith day they were given a vaginal sponge con-taining

  6. Global characterization of signalling networks associated with tamoxifen resistance in breast cancer

    DEFF Research Database (Denmark)

    Browne, Brigid C.; Hochgräfe, Falko; Wu, Jianmin;

    2013-01-01

    Acquired resistance to the anti‐estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen‐resistant MCF7 breast cancer cells (TamR) compa...

  7. Tamoxifen is effective in the treatment of Leishmania amazonensis infections in mice.

    Directory of Open Access Journals (Sweden)

    Danilo C Miguel

    Full Text Available BACKGROUND: Chemotherapy is still a critical issue in the management of leishmaniasis. Until recently, pentavalent antimonials, amphotericin B or pentamidine compounded the classical arsenal of treatment. All these drugs are toxic and have to be administered by the parenteral route. Tamoxifen has been used as an antiestrogen in the treatment and prevention of breast cancer for many years. Its safety and pharmacological profiles are well established in humans. We have shown that tamoxifen is active as an antileishmanial compound in vitro, and in this paper we analyzed the efficacy of tamoxifen for the treatment of mice infected with Leishmania amazonensis, an etiological agent of localized cutaneous leishmaniasis and the main cause of diffuse cutaneous leishmaniasis in South America. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c mice were infected with L. amazonensis promastigotes. Five weeks post-infection, treatment with 15 daily intraperitoneal injections of 20 mg/kg tamoxifen was administered. Lesion and ulcer sizes were recorded and parasite burden quantified by limiting dilution. A significant decrease in lesion size and ulcer development was noted in mice treated with tamoxifen as compared to control untreated animals. Parasite burden in the inoculation site at the end of treatment was reduced from 10(8.5+/-0.7 in control untreated animals to 10(5.0+/-0.0 in tamoxifen-treated mice. Parasite load was also reduced in the draining lymph nodes. The reduction in parasite number was sustained: 6 weeks after the end of treatment, 10(15.5+/-0.5 parasites were quantified from untreated animals, as opposed to 10(5.1+/-0.1 parasites detected in treated mice. CONCLUSIONS/SIGNIFICANCE: Treatment of BALB/c mice infected with L. amazonensis for 15 days with tamoxifen resulted in significant decrease in lesion size and parasite burden. BALB/c mice infected with L. amazonensis represents a model of extreme susceptibility, and the striking and sustained reduction

  8. Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

    Science.gov (United States)

    Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Benes, Vladimir; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert I; Sinn, Hans-Peter; Schneeweiss, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter

    2015-02-15

    Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer. ©2015 American Association for Cancer Research.

  9. Radiolytic oxidation of tamoxifen using the free radicals {sup .}OH and (or) HO{sub 2}{sup .}; Oxydation radiolytique du tamoxifene par les radicaux libres {sup .}OH et (ou) HO{sub 2}{sup .}

    Energy Technology Data Exchange (ETDEWEB)

    Leguene, C. [Lab. de Chimie-Physique, Centre national de la recherche scientifique, CNRS, Univ. Rene Descartes, Paris (France); Clavere, P. [Service de Radiotherapie et d' Oncologie, Centre hospitalier universitaire, CHU, Dupuytren, Limoges (France); Jore, D.; Gardes-Albert, M. [Lab. de Chimie-Physique, Centre national de la recherche scientifique, CNRS, Univ. Rene Descartes, Paris (France)

    2001-02-01

    Tamoxifen is the most widely used antiestrogen in the treatment of breast cancer. In this work, we have studied its antioxidant properties. We have investigated the ability of tamoxifen to scavenge, in vitro, {sup .}OH and (or) HO{sub 2}{sup .} free radicals that are produced by water radiolysis. Aqueous solutions of tamoxifen of concentrations ranging between 10{sup -5} and 2.5 x 10{sup -5} M have been irradiated ({gamma} {sup 137}Cs) in aerated acidic medium (H{sub 3}PO{sub 4} 10{sup -3} M or HCOOH 10{sup -1} M). The results show that tamoxifen reacts quantitatively with {sup .}OH free radicals but does not react with HO{sub 2}{sup .} free radicals under our experimental conditions. (author)

  10. Evaluation of the ability of adjuvant tamoxifen-benefit gene signatures to predict outcome of hormone-naive estrogen receptor-positive breast cancer patients treated with tamoxifen in the advanced setting

    DEFF Research Database (Denmark)

    Sieuwerts, Anieta M; Lyng, Maria Bibi; Meijer-van Gelder, Marion E

    2014-01-01

    To identify molecular markers indicative of response to tamoxifen and easily implemented in the routine setting, we recently reported three gene signatures that could stratify post-menopausal tamoxifen-treated, estrogen receptor-positive (ER+) patients according to outcome in the adjuvant setting...... exhibit predictive promise regarding the efficacy of tamoxifen treatment in recurrent disease, in addition to the previously shown favorable outcome in the adjuvant setting........ Here, we evaluated the predictive potential of the total of 14 genes included in the 3 gene signatures using 2 hormone-naïve Dutch ER+ cohorts of a total of 285 recurrent breast cancer patients treated with first-line tamoxifen. mRNA levels were measured by reverse transcriptase quantitative PCR (RT...

  11. During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor apoprotein supports cell cycling through the retinoic acid receptor α1 apoprotein.

    Science.gov (United States)

    Salazar, Marcela D; Ratnam, Maya; Patki, Mugdha; Kisovic, Ivana; Trumbly, Robert; Iman, Mohamed; Ratnam, Manohar

    2011-02-07

    Current hormonal adjuvant therapies for breast cancer including tamoxifen treatment and estrogen depletion are overall tumoristatic and are severely limited by the frequent recurrence of the tumors. Regardless of the resistance mechanism, development and progression of the resistant tumors requires the persistence of a basal level of cycling cells during the treatment for which the underlying causes are unclear. In estrogen-sensitive breast cancer cells the effects of hormone depletion and treatment with estrogen, tamoxifen, all-trans retinoic acid (ATRA), fulvestrant, estrogen receptor α (ER) siRNA or retinoic acid receptor α (RARα) siRNA were studied by examining cell growth and cycling, apoptosis, various mRNA and protein expression levels, mRNA profiles and known chromatin associations of RAR. RARα subtype expression was also examined in breast cancer cell lines and tumors by competitive PCR. Basal proliferation persisted in estrogen-sensitive breast cancer cells grown in hormone depleted conditioned media without or with 4-hydroxytamoxifen (OH-Tam). Downregulating ER using either siRNA or fulvestrant inhibited basal proliferation by promoting cell cycle arrest, without enrichment for ErbB2/3+ overexpressing cells. The basal expression of RARα1, the only RARα isoform that was expressed in breast cancer cell lines and in most breast tumors, was supported by apo-ER but was unaffected by OH-Tam; RAR-β and -γ were not regulated by apo-ER. Depleting basal RARα1 reproduced the antiproliferative effect of depleting ER whereas its restoration in the ER depleted cells partially rescued the basal cycling. The overlapping tamoxifen-insensitive gene regulation by apo-ER and apo-RARα1 comprised activation of mainly genes promoting cell cycle and mitosis and suppression of genes involved in growth inhibition; these target genes were generally insensitive to ATRA but were enriched in RAR binding sites in associated chromatin regions. In hormone-sensitive breast

  12. Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells

    Science.gov (United States)

    Qi, Wenwen; Sun, Mingjuan; Kong, Xiangnan; Li, Yaming; Wang, Xiaolong; Lv, Shangge; Ding, Xia; Gao, Sumei; Cun, Jinjing; Cai, Chang; Wang, Xiaoting; Chen, Junfei; Yin, Aijun; Yang, Qifeng

    2016-01-01

    Tamoxifen (TAM) is the most widely used endocrine therapy for estrogen receptor (ER)-positive breast cancer patients, but side effects and the gradual development of insensitivity limit its application. We investigated whether Huaier extract, a traditional Chinese medicine, in combination with TAM would improve treatment efficacy in ER-positive breast cancers. MTT, colony formation, and invasion and migration assays revealed that the combined treatment had stronger anticancer effects than either treatment alone. Huaier extract enhanced TAM-induced autophagy, apoptosis, and G0/G1 cell cycle arrest, as measured by acidic vesicular organelle (AVO) staining, TUNEL, flow cytometry, and western blot. Additionally, combined treatment inhibited tumorigenesis and metastasis by suppressing the AKT/mTOR signaling pathway. Huaier extract also enhanced the inhibitory effects of TAM on tumor growth in vivo in a xenograft mouse model. These results show that Huaier extract synergizes with TAM to induce autophagy and apoptosis in ER-positive breast cancer cells by suppressing the AKT/mTOR pathway. PMID:27027343

  13. Network-based approach to identify prognostic biomarkers for estrogen receptor-positive breast cancer treatment with tamoxifen.

    Science.gov (United States)

    Liu, Rong; Guo, Cheng-Xian; Zhou, Hong-Hao

    2015-01-01

    This study aims to identify effective gene networks and prognostic biomarkers associated with estrogen receptor positive (ER+) breast cancer using human mRNA studies. Weighted gene coexpression network analysis was performed with a complex ER+ breast cancer transcriptome to investigate the function of networks and key genes in the prognosis of breast cancer. We found a significant correlation of an expression module with distant metastasis-free survival (HR = 2.25; 95% CI .21.03-4.88 in discovery set; HR = 1.78; 95% CI = 1.07-2.93 in validation set). This module contained genes enriched in the biological process of the M phase. From this module, we further identified and validated 5 hub genes (CDK1, DLGAP5, MELK, NUSAP1, and RRM2), the expression levels of which were strongly associated with poor survival. Highly expressed MELK indicated poor survival in luminal A and luminal B breast cancer molecular subtypes. This gene was also found to be associated with tamoxifen resistance. Results indicated that a network-based approach may facilitate the discovery of biomarkers for the prognosis of ER+ breast cancer and may also be used as a basis for establishing personalized therapies. Nevertheless, before the application of this approach in clinical settings, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed.

  14. Targeted MS Assay Predicting Tamoxifen Resistance in Estrogen-Receptor-Positive Breast Cancer Tissues and Sera.

    Science.gov (United States)

    De Marchi, Tommaso; Kuhn, Erik; Dekker, Lennard J; Stingl, Christoph; Braakman, Rene B H; Opdam, Mark; Linn, Sabine C; Sweep, Fred C G J; Span, Paul N; Luider, Theo M; Foekens, John A; Martens, John W M; Carr, Steven A; Umar, Arzu

    2016-04-01

    We recently reported on the development of a 4-protein-based classifier (PDCD4, CGN, G3BP2, and OCIAD1) capable of predicting outcome to tamoxifen treatment in recurrent, estrogen-receptor-positive breast cancer based on high-resolution MS data. A precise and high-throughput assay to measure these proteins in a multiplexed, targeted fashion would be favorable to measure large numbers of patient samples to move these findings toward a clinical setting. By coupling immunoprecipitation to multiple reaction monitoring (MRM) MS and stable isotope dilution, we developed a high-precision assay to measure the 4-protein signature in 38 primary breast cancer whole tissue lysates (WTLs). Furthermore, we evaluated the presence and patient stratification capabilities of our signature in an independent set of 24 matched (pre- and post-therapy) sera. We compared the performance of immuno-MRM (iMRM) with direct MRM in the absence of fractionation and shotgun proteomics in combination with label-free quantification (LFQ) on both WTL and laser capture microdissected (LCM) tissues. Measurement of the 4-proteins by iMRM showed not only higher accuracy in measuring proteotypic peptides (Spearman r: 0.74 to 0.93) when compared with MRM (Spearman r: 0.0 to 0.76) but also significantly discriminated patient groups based on treatment outcome (hazard ratio [HR]: 10.96; 95% confidence interval [CI]: 4.33 to 27.76; Log-rank P < 0.001) when compared with LCM (HR: 2.85; 95% CI: 1.24 to 6.54; Log-rank P = 0.013) and WTL (HR: 1.16; 95% CI: 0.57 to 2.33; Log-rank P = 0.680) LFQ-based predictors. Serum sample analysis by iMRM confirmed the detection of the four proteins in these samples. We hereby report that iMRM outperformed regular MRM, confirmed our previous high-resolution MS results in tumor tissues, and has shown that the 4-protein signature is measurable in serum samples.

  15. Risk of skin cancer following tamoxifen treatment in more than 16,000 breast cancer patients: a cohort study.

    Science.gov (United States)

    Praestegaard, Camilla; Kjaer, Susanne K; Andersson, Michael; Steding-Jensen, Marianne; Frederiksen, Kirsten; Mellemkjaer, Lene

    2016-11-01

    Women with breast cancer are at increased risk of developing skin cancer. Little is known about how tamoxifen affects this risk. We aimed to investigate whether tamoxifen treatment following breast cancer is associated with skin cancer. A cohort consisting of 44,589 women diagnosed with breast cancer during 1977-2007 from the nationwide clinical database of the Danish Breast Cancer Cooperative Group, was followed for a primary skin cancer [basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or melanoma] in the Danish Cancer Registry supplemented by data on BCC and SCC from the Danish Pathology Register. We investigated incidence of skin cancer among 16,214 women treated with tamoxifen compared to 28,375 women not treated with tamoxifen by calculating incidence rate ratios (IRRs) in Cox regression models. Tamoxifen users were followed for a median of 2.9 years. The median duration of tamoxifen treatment increased from around 1 year among women diagnosed before 1999 to nearly 2.5 years among women diagnosed in 1999 or later. Women treated with tamoxifen had an IRR 1.06 (95 % CI 0.72-1.55) for SCC and an IRR 1.40 (95 % CI 0.95-2.08) for melanoma when compared to non-users. The observed number of these types of cancer (37 SCCs and 38 melanomas among users) did not allow stratification on calendar-period. The overall IRR for BCC was 0.96 (95 % CI 0.84-1.09), but the IRR differed by menopausal status and calendar-period at diagnosis of breast cancer. Our overall results indicate that tamoxifen is not associated with skin cancer. However, the inconsistency of results from stratifications prevents a firm conclusion.

  16. Quantification of tamoxifen and three of its phase-I metabolites in human plasma by liquid chromatography/triple-quadrupole mass spectrometry.

    Science.gov (United States)

    Binkhorst, Lisette; Mathijssen, Ron H J; Ghobadi Moghaddam-Helmantel, Inge M; de Bruijn, Peter; van Gelder, Teun; Wiemer, Erik A C; Loos, Walter J

    2011-12-15

    In view of future pharmacokinetic studies, a highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous quantification of tamoxifen and three of its main phase I metabolites in human lithium heparinized plasma. The analytical method has been thoroughly validated in agreement with FDA recommendations. Plasma samples of 200 μl were purified by liquid-liquid extraction with 1 ml n-hexane/isopropanol, after deproteination through addition of 50 μl acetone and 50 μl deuterated internal standards in acetonitrile. Tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were chromatographically separated on an Acquity UPLC(®) BEH C18 1.7 μm 2.1 mm×100 mm column eluted at a flow-rate of 0.300 ml/min on a gradient of 0.2mM ammonium formate and acetonitrile, both acidified with 0.1% formic acid. The overall run time of the method was 10 min, with elution times of 2.9, 3.0, 4.1 and 4.2 min for endoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen and tamoxifen, respectively. Tamoxifen and its metabolites were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. The multiple reaction monitoring transitions were set at 372>72 (m/z) for tamoxifen, 358>58 (m/z) for N-desmethyl-tamoxifen, 388>72 (m/z) for 4-hydroxy-tamoxifen and 374>58 (m/z) for endoxifen. The analytical method was highly sensitive with the lower limit of quantification validated at 5.00 nM for tamoxifen and N-desmethyl-tamoxifen and 0.500 nM for 4-hydroxy-tamoxifen and endoxifen, which is equivalent to 1.86, 1.78, 0.194 and 0.187 ng/ml for tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen, respectively. The method was also precise and accurate, with within-run and between-run precisions within 12.0% and accuracy ranging from 89.5 to 105.3%. The method has been applied to samples from a clinical study and cross-validated with a validated LC

  17. Determination of tamoxifen and its main metabolites in plasma samples from breast cancer patients by micellar liquid chromatography.

    Science.gov (United States)

    Peris-Vicente, Juan; Ochoa-Aranda, Enrique; Bose, Devasish; Esteve-Romero, Josep

    2015-01-01

    A method was developed for the analysis of tamoxifen and its main derivatives (4-hydroxytamoxifen, N-desmethyl-tamoxifen, tamoxifen-N-oxide and endoxifen) in human plasma, using micellar liquid chromatography coupled with fluorescence detection. Analytes were off-line derivatized by sample UV-irradiation for 20 min to form the photocycled fluorescent derivatives. Then samples were diluted, filtered and directly injected, thus avoiding extraction steps. The analytes were resolved using a mobile phase containing 0.08 M SDS-4.5% butanol at pH 3 running at 1.5 mL/min through a C18 column at 40°C, without interferences from endogenous compounds in plasma. Excitation and emission wavelengths were 260 and 380 nm, respectively. The chromatographic analysis time was less than 40 min. The analytical methodology was validated following the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines in terms of: selectivity, linear range (0.3-15 μg/mL), linearity (r(2)>0.999), sensitivity (LOD, 65-80 ng/mL; LOQ, 165-200 ng/mL), intra- and interday accuracy (-12.2-11.5%) and precision (<9.2%) and robustness (<6.3%). The method was used to quantify the tamoxifen and tamoxifen derivatives in several breast cancer patients from a local hospital, in order to study the correlation between the genotype of the patient and the ability to metabolize tamoxifen.

  18. Transformation of tamoxifen and its major metabolites during water chlorination: Identification and in silico toxicity assessment of their disinfection byproducts.

    Science.gov (United States)

    Negreira, Noelia; Regueiro, Jorge; López de Alda, Miren; Barceló, Damià

    2015-11-15

    The selective estrogen receptor modulator tamoxifen is the most commonly used drug for the treatment and prevention of breast cancer. Tamoxifen is considered as a pro-drug since it is known to exert its pharmacological effect through its major active metabolites, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen, which are mainly excreted in the urine in the days following administration. In the present work, the reactivity of tamoxifen and its major active metabolites in free chlorine-containing water was investigated for the first time. Under the studied chlorination conditions, tamoxifen was fairly stable whereas its metabolites were quickly degraded. A total of thirteen chlorinated byproducts were tentatively identified by ultra-high performance liquid chromatography coupled to high-resolution hybrid quadrupole-Orbitrap tandem mass spectrometry. Time-course profiles of the identified byproducts were followed in real wastewater samples under conditions that simulate wastewater disinfection. A preliminary assessment of their acute aquatic toxicity at two trophic levels by means of quantitative structure-activity relationship models showed that the identified byproducts were up to 110-fold more toxic than the parent compounds.

  19. Tumor specific HMG-CoA reductase expression in primary pre-menopausal breast cancer predicts response to tamoxifen

    LENUS (Irish Health Repository)

    Brennan, Donal J

    2011-01-31

    Abstract Introduction We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive\\/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as

  20. Tamoxifen affects glucose and lipid metabolism parameters, causes browning of subcutaneous adipose tissue and transient body composition changes in C57BL/6NTac mice

    Energy Technology Data Exchange (ETDEWEB)

    Hesselbarth, Nico; Pettinelli, Chiara [Department of Medicine, University of Leipzig, D-04103 Leipzig (Germany); Gericke, Martin [Institute of Anatomy, University of Leipzig, D-04103 Leipzig (Germany); Berger, Claudia [IFB Adiposity Disease, Core Unit Animal Models, University of Leipzig, D-04103 Leipzig (Germany); Kunath, Anne [German Center for Diabetes Research (DZD), Leipzig (Germany); Stumvoll, Michael; Blüher, Matthias [Department of Medicine, University of Leipzig, D-04103 Leipzig (Germany); Klöting, Nora, E-mail: nora.kloeting@medizin.uni-leipzig.de [IFB Adiposity Disease, Core Unit Animal Models, University of Leipzig, D-04103 Leipzig (Germany)

    2015-08-28

    Tamoxifen is a selective estrogen receptor (ER) modulator which is widely used to generate inducible conditional transgenic mouse models. Activation of ER signaling plays an important role in the regulation of adipose tissue (AT) metabolism. We therefore tested the hypothesis that tamoxifen administration causes changes in AT biology in vivo. 12 weeks old male C57BL/6NTac mice were treated with either tamoxifen (n = 18) or vehicle (n = 18) for 5 consecutive days. Tamoxifen treatment effects on body composition, energy homeostasis, parameters of AT biology, glucose and lipid metabolism were investigated up to an age of 18 weeks. We found that tamoxifen treatment causes: I) significantly increased HbA{sub 1c}, triglyceride and free fatty acid serum concentrations (p < 0.01), II) browning of subcutaneous AT and increased UCP-1 expression, III) increased AT proliferation marker Ki67 mRNA expression, IV) changes in adipocyte size distribution, and V) transient body composition changes. Tamoxifen may induce changes in body composition, whole body glucose and lipid metabolism and has significant effects on AT biology, which need to be considered when using Tamoxifen as a tool to induce conditional transgenic mouse models. Our data further suggest that tamoxifen-treated wildtype mice should be characterized in parallel to experimental transgenic models to control for tamoxifen administration effects. - Highlights: • Tamoxifen treatment causes significantly increased HbA{sub 1c}, triglyceride and free fatty acid serum concentrations. • Tamoxifen induces browning of subcutaneous AT and increased UCP-1 expression. • Tamoxifen changes adipocyte size distribution, and transient body composition.

  1. Tamoxifen-associated hirsutism: an unusual side effect in a 5-year-old girl with McCune-Albright syndrome.

    Science.gov (United States)

    Kırmızıbekmez, Heves; Yesiltepe Mutlu, Rahime Gül; Dursun, Fatma; İşgüven, Şükriye Pınar

    2015-09-01

    Tamoxifen, a selective estrogen receptor modulator, has been used in the treatment of peripheral precocious puberty. A 5-year and 3-month-old girl, diagnosed with McCune-Albright syndrome, came in with abnormal hair growth approximately 2 months after the initiation of tamoxifen. The pattern of terminal hair on the skin following the administration of the drug and the exclusion of other causes suggested tamoxifen-induced hirsutism.

  2. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen.

    Science.gov (United States)

    Ma, Xiao-Jun; Wang, Zuncai; Ryan, Paula D; Isakoff, Steven J; Barmettler, Anne; Fuller, Andrew; Muir, Beth; Mohapatra, Gayatry; Salunga, Ranelle; Tuggle, J Todd; Tran, Yen; Tran, Diem; Tassin, Ana; Amon, Paul; Wang, Wilson; Wang, Wei; Enright, Edward; Stecker, Kimberly; Estepa-Sabal, Eden; Smith, Barbara; Younger, Jerry; Balis, Ulysses; Michaelson, James; Bhan, Atul; Habin, Karleen; Baer, Thomas M; Brugge, Joan; Haber, Daniel A; Erlander, Mark G; Sgroi, Dennis C

    2004-06-01

    Tamoxifen significantly reduces tumor recurrence in certain patients with early-stage estrogen receptor-positive breast cancer, but markers predictive of treatment failure have not been identified. Here, we generated gene expression profiles of hormone receptor-positive primary breast cancers in a set of 60 patients treated with adjuvant tamoxifen monotherapy. An expression signature predictive of disease-free survival was reduced to a two-gene ratio, HOXB13 versus IL17BR, which outperformed existing biomarkers. Ectopic expression of HOXB13 in MCF10A breast epithelial cells enhances motility and invasion in vitro, and its expression is increased in both preinvasive and invasive primary breast cancer. The HOXB13:IL17BR expression ratio may be useful for identifying patients appropriate for alternative therapeutic regimens in early-stage breast cancer.

  3. Tamoxifen affects glucose and lipid metabolism parameters, causes browning of subcutaneous adipose tissue and transient body composition changes in C57BL/6NTac mice.

    Science.gov (United States)

    Hesselbarth, Nico; Pettinelli, Chiara; Gericke, Martin; Berger, Claudia; Kunath, Anne; Stumvoll, Michael; Blüher, Matthias; Klöting, Nora

    2015-08-28

    Tamoxifen is a selective estrogen receptor (ER) modulator which is widely used to generate inducible conditional transgenic mouse models. Activation of ER signaling plays an important role in the regulation of adipose tissue (AT) metabolism. We therefore tested the hypothesis that tamoxifen administration causes changes in AT biology in vivo. 12 weeks old male C57BL/6NTac mice were treated with either tamoxifen (n = 18) or vehicle (n = 18) for 5 consecutive days. Tamoxifen treatment effects on body composition, energy homeostasis, parameters of AT biology, glucose and lipid metabolism were investigated up to an age of 18 weeks. We found that tamoxifen treatment causes: I) significantly increased HbA1c, triglyceride and free fatty acid serum concentrations (p body composition changes. Tamoxifen may induce changes in body composition, whole body glucose and lipid metabolism and has significant effects on AT biology, which need to be considered when using Tamoxifen as a tool to induce conditional transgenic mouse models. Our data further suggest that tamoxifen-treated wildtype mice should be characterized in parallel to experimental transgenic models to control for tamoxifen administration effects.

  4. Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer.

    Directory of Open Access Journals (Sweden)

    Andrew Stone

    Full Text Available In the present study, we have taken the novel approach of using an in vitro model representative of tamoxifen-withdrawal subsequent to clinical relapse to achieve a greater understanding of the mechanisms that serve to maintain the resistant-cell phenotype, independent of any agonistic impact of tamoxifen, to identify potential novel therapeutic approaches for this disease state. Following tamoxifen withdrawal, tamoxifen-resistant MCF-7 cells conserved both drug resistance and an increased basal rate of proliferation in an oestrogen deprived environment, despite reduced epidermal growth-factor receptor expression and reduced sensitivity to gefitinib challenge. Although tamoxifen-withdrawn cells retained ER expression, a sub-set of ER-responsive genes, including pS2 and progesterone receptor (PgR, were down-regulated by promoter DNA methylation, as confirmed by clonal bisulphite sequencing experiments. Following promoter demethylation with 5-Azacytidine (5-Aza, the co-addition of oestradiol (E2 restored gene expression in these cells. In addition, 5-Aza/E2 co-treatment induced a significant anti-proliferative effect in the tamoxifen-withdrawn cells, in-contrast to either agent used alone. Microarray analysis was undertaken to identify genes specifically up regulated by this co-treatment. Several anti-proliferative gene candidates were identified and their promoters were confirmed as more heavily methylated in the tamoxifen resistant vs sensitive cells. One such gene candidate, growth differentiation factor 15 (GDF15, was carried forward for functional analysis. The addition of 5-Aza/E2 was sufficient to de-methylate and activate GDF15 expression in the tamoxifen resistant cell-lines, whilst in parallel, treatment with recombinant GDF15 protein decreased cell survival. These data provide evidence to support a novel concept that long-term tamoxifen exposure induces epigenetic silencing of a cohort of oestrogen-responsive genes whose function is

  5. Tamoxifen up-regulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms.

    Science.gov (United States)

    Grigoryants, Vladimir; Hannawa, Kevin K; Pearce, Charles G; Sinha, Indranil; Roelofs, Karen J; Ailawadi, Gorav; Deatrick, Kristopher B; Woodrum, Derek T; Cho, Brenda S; Henke, Peter K; Stanley, James C; Eagleton, Matthew J; Upchurch, Gilbert R

    2005-01-01

    Selective estrogen receptor modulators (SERMs), similar to estrogens, possess vasoprotective effects by reducing release of reactive oxygen species. Little is known about the potential effects of SERMs on the pathogenesis of abdominal aortic aneurysms (AAAs). This study's objective was to investigate the growth of experimental AAAs in the setting of the SERM tamoxifen. In the first set of experiments, adult male rats underwent subcutaneous tamoxifen pellet (delivering 10 mg/kg/day) implantation (n = 14) or sham operation (n = 16). Seven days later, all animals underwent pancreatic elastase perfusion of the abdominal aorta. Aortic diameters were determined at that time, and aortas were harvested 7 and 14 days after elastase perfusion for immunohistochemistry, real-time polymerase chain reaction, Western blot analysis, and zymography. In the second set of experiments, a direct irreversible catalase inhibitor, 3-amino-1,2,4-triazole (AT), was administered intraperitoneally (1 mg/kg) daily to tamoxifen-treated (n = 6) and control rats (n = 6), starting on day 7 after elastase perfusion. Aortic diameters were measured on day 14. In a third set of experiments, rats were perfused with catalase (150 mg/kg) after the elastase (n = 5), followed by daily intravenous injections of catalase (150 mg/kg/day) administered for 10 days. A control group of rats (n = 7) received 0.9% NaCl instead of catalase. Mean AAA diameters were approximately 50% smaller in tamoxifen-treated rats compared with sham rats 14 days after elastase perfusion (P = .002). The tamoxifen-treated group's aortas had a five-fold increase in catalase mRNA expression (P = .02) on day 7 and an eight-fold increase in catalase protein on day 14 (P = .04). Matrix metalloprotroteinase-9 activity was 2.4-fold higher (P = .01) on day 7 in the aortas of the controls compared to the tamoxifen-treated group's aortas. Tamoxifen-treated rats had approximately 40% fewer aortic polymorphonuclear neutrophils compared to

  6. Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer.

    Science.gov (United States)

    Stone, Andrew; Valdés-Mora, Fatima; Gee, Julia M W; Farrow, Lynne; McClelland, Richard A; Fiegl, Heidi; Dutkowski, Carol; McCloy, Rachael A; Sutherland, Robert L; Musgrove, Elizabeth A; Nicholson, Robert I

    2012-01-01

    In the present study, we have taken the novel approach of using an in vitro model representative of tamoxifen-withdrawal subsequent to clinical relapse to achieve a greater understanding of the mechanisms that serve to maintain the resistant-cell phenotype, independent of any agonistic impact of tamoxifen, to identify potential novel therapeutic approaches for this disease state. Following tamoxifen withdrawal, tamoxifen-resistant MCF-7 cells conserved both drug resistance and an increased basal rate of proliferation in an oestrogen deprived environment, despite reduced epidermal growth-factor receptor expression and reduced sensitivity to gefitinib challenge. Although tamoxifen-withdrawn cells retained ER expression, a sub-set of ER-responsive genes, including pS2 and progesterone receptor (PgR), were down-regulated by promoter DNA methylation, as confirmed by clonal bisulphite sequencing experiments. Following promoter demethylation with 5-Azacytidine (5-Aza), the co-addition of oestradiol (E2) restored gene expression in these cells. In addition, 5-Aza/E2 co-treatment induced a significant anti-proliferative effect in the tamoxifen-withdrawn cells, in-contrast to either agent used alone. Microarray analysis was undertaken to identify genes specifically up regulated by this co-treatment. Several anti-proliferative gene candidates were identified and their promoters were confirmed as more heavily methylated in the tamoxifen resistant vs sensitive cells. One such gene candidate, growth differentiation factor 15 (GDF15), was carried forward for functional analysis. The addition of 5-Aza/E2 was sufficient to de-methylate and activate GDF15 expression in the tamoxifen resistant cell-lines, whilst in parallel, treatment with recombinant GDF15 protein decreased cell survival. These data provide evidence to support a novel concept that long-term tamoxifen exposure induces epigenetic silencing of a cohort of oestrogen-responsive genes whose function is associated with

  7. Tamoxifen and Src kinase inhibitors as neuroprotective/neuroregenerative drugs after spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    Iris K Salgado; Aranza I Torrado; Jose M Santiago; Jorge D Miranda

    2015-01-01

    Spinal cord injury (SCI) is a devastating condition that produces signiifcant changes in the life-style of patients. Many molecular and cellular events are triggered after the initial physical impact to the cord. Two major phases have been described in the ifeld of SCI: an acute phase and late phase. Most of the therapeutic strategies are focused on the late phase because this provides an opportunity to target cellular events like apoptosis, demyelination, scar formation and axonal outgrowth. In this mini-review, we will focus on two agents (tamoxifen and a Src kinase family inhibitor known as PP2) that have been shown in our laboratory to produce neuroprotective (increase cell survival) and/or regenerative (axonal outgrowth) actions. The animal model used in our laboratory is adult female rat (~250 g) with a moderate contusion (12.5 mm) to the spinal cord at the T10 level, using the MASCIS impactor device. Tamoxifen or PP2 was administered by implantation of a 15 mg pellet (Innovative Research of America, Sarasota, FL, USA) or by intraperitoneal injections (1.5 mg/kg, every 3 days), respectively, to produce a long-term effect (28 days). Tamoxifen and the Src kinase inhibitor, PP2, are drugs that in rats with a moderate spinal cord injury promote functional locomotor recovery, increase spared white matter tissue, and stimulate axonal outgrowth. Moreover, tamoxifen reduces the formation of reactive oxygen species. Therefore, these drugs are possible therapeutic agents that have a neuroprotective/regen-erative activity in vertebrates with SCI.

  8. Hyper-reactivity of cerebral arteries from ovariectomized rats: therapeutic benefit of tamoxifen

    OpenAIRE

    2003-01-01

    An increased incidence of systemic hypertension has been documented in postmenopausal women and identified as an independent risk factor in the development of cerebrovascular stroke. The present study examined whether cerebrovascular reactivity was increased in the hypertensive ovariectomized rat, and explored the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen.Female Sprague–Dawley rats were subjected to bilateral ovariectomy (OVX, n=16) or a sham operation (...

  9. Evaluation of tamoxifen citrate efficiency on sexual inversion of Nile tilapia (Oreochromis niloticus

    Directory of Open Access Journals (Sweden)

    Marco Antonio Zanoni

    2014-09-01

    Full Text Available The experiment was conducted to evaluate the influence of tamoxifen on sexual inversion of Nile tilapia larvae from two days of life, the experimental desing was compounded of five treatments and three replicates, and fish were fed diets with different amounts of tamoxifen: 0, 25, 50, 75 and 100 mg kg-1 of feed. After 28 days of treatment, larvae were counted and transferred to water tanks of 500 liters and then which were fed with a diet containing 28% crude protein for more 60 days. After this period the fry were sexed by the “squash”. The survival 75.5 ± 5.74, 73 ± 4.76, 66 ± 11.19, 76.5 ± 4.12, 75 ± 3.46 and average percentage of male individuals 62.5 ± 5, 70 ± 8.1, 60 ± 8.2, 70 ± 0.0, 62.5 ± 9.5 for treatments 0, 25, 50, 75 and 100 mg of tamoxifenkg-1 diet, respectively, showed no statistically significant differences (p<0,05. The number of gonads in each fish experienced a significant reduction in the treatments with 75 and 100 mg of tamoxifen (89.3 and 79.3 ± 0.527 ± 0.378 when compared with treatments 0, 25 and 50 mg of tamoxifen (98, 9 ± 1.0, 97.6 ± 1.0 and 94.5 ± 1.0, respectively, the histological structure of female gonads did not differ and ovaries in all treatments showed well-defined and oocytes at several stages of maturation.

  10. Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen.

    Science.gov (United States)

    Prat, A; Parker, J S; Fan, C; Cheang, M C U; Miller, L D; Bergh, J; Chia, S K L; Bernard, P S; Nielsen, T O; Ellis, M J; Carey, L A; Perou, C M

    2012-11-01

    ER-positive (ER+) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only. Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan-Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance. All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%-100%). Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.

  11. Tamoxifen Promotes Axonal Preservation and Gait Locomotion Recovery after Spinal Cord Injury in Cats

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    Braniff de la Torre Valdovinos

    2016-01-01

    Full Text Available We performed experiments in cats with a spinal cord penetrating hemisection at T13-L1 level, with and without tamoxifen treatment. The results showed that the numbers of the ipsilateral and contralateral ventral horn neurons were reduced to less than half in the nontreated animals compared with the treated ones. Also, axons myelin sheet was preserved to almost normal values in treated cats. On the contrary, in the untreated animals, their myelin sheet was reduced to 28% at 30 days after injury (DAI, in both the ipsilateral and contralateral regions of the spinal cord. Additionally, we made hindlimb kinematics experiments to study the effects of tamoxifen on cat locomotion after the injury: at 4, 16, and 30 DAI. We observed that the ipsilateral hindlimb angular displacement (AD of the pendulum-like movements (PLM during gait locomotion was recovered to almost normal values in treated cats. Contralateral PLM acquired similar values to those obtained in intact cats. At 4 DAI, untreated animals showed a compensatory increment of PLM occurring in the contralateral hindlimb, which was partially recovered at 30 DAI. Our findings indicate that tamoxifen exerts a neuroprotective effect and preserves or produces myelinated axons, which could benefit the locomotion recovery in injured cats.

  12. Identification of influential factors on ovarian responsiveness with tamoxifen in type-2 WHO anovulatory patients

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    T. Madani

    2005-01-01

    Full Text Available Background and purpose: Chronic anovulation is a common cause of infertility in women. Most women with chronic anoulation have irregular menstural cycles and normal serum FSH concentration s(WHO-type 2.finding out influential factors on ovarian responsiveness is useful for managing the infertile patients. The objective of this study is to assess the relation of some factors on ovulation in infertile women referring to Royan institute between November 2002 to November 2003. Materials and Methods: A total of 74 normogonadotropic, oligomenorrhic, undergone ovulation induction using tamoxifen, were studied. The factors studied were pretreatment clinical sings (Hirsutism, BMI endocrine (FSH, LH, Insulin- testosterone and sonographic screening characteristics of these patients.Ovarian response and ovulation were monitored by ultrasound scans and measurement of mid-luteal progestron.Results: According to statistical analysis pretreatment Hirsutism- BMI – serum LH consentration, LH/FSH ratio and ovarian volume were identified as the significant parameters for prediction of ovulation with tamoxifen (P≤0.05.There was no statistically significant differences in age, duration of infertility, FBS/Fasting insulin ratio and ovulation between the groups. Conclusion: Ovarian responsiveness to tamoxifen in anovulatory infertile women can be predicted on the basis of some initial screening characteristics.The prediction model in this study may improve the outcome and make the treatment more safe and efficient.These approaches should be further evaluated in prospective comparative trial.

  13. Tamoxifen induced multinucleated cells (symplasts) and distortion of seminiferous tubules in rat testis

    Institute of Scientific and Technical Information of China (English)

    UrbanJ.A.D'Souza

    2003-01-01

    Aim: To evaluate the effect of tamoxifen citrate on male reproductive system of rat. Methods: Groups of male rats were gavaged with tamoxifen at doses of 200 mg.kg·-1.d-1, 400 mg·kg·-1.d-1 or 800 mg.kg-1·d-1 in 0.1 mL olive oil for 10 consecutive days. Controls were treated with 0.1 mL olive oil. Rats were anesthetized and killed on d 3, d 15 or d 35 after the last dose. Testes were collected, processed for paraffin embedding, sectioned at 5μm thickness, stained with H&E and analyzed microscopically. Results: There was a dose-dependent increase in the occurrence of seminiferous tubular distortion with germinal cell sloughing. The highest dose increased the number of multinucleated giant cells on d 3 and d 15. Conclusion: Tamoxifen citrate induces multinucleated giant cells and germinal epithelial sloughing in a dose-dependent manner and these changes are detrimental to male fertility. (Asian J Androl 2003 Sep; 5: 217-220)

  14. Generation of NSE-MerCreMer transgenic mice with tamoxifen inducible Cre activity in neurons.

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    Mandy Ka Man Kam

    Full Text Available To establish a genetic tool for conditional deletion or expression of gene in neurons in a temporally controlled manner, we generated a transgenic mouse (NSE-MerCreMer, which expressed a tamoxifen inducible type of Cre recombinase specifically in neurons. The tamoxifen inducible Cre recombinase (MerCreMer is a fusion protein containing Cre recombinase with two modified estrogen receptor ligand binding domains at both ends, and is driven by the neural-specific rat neural specific enolase (NSE promoter. A total of two transgenic lines were established, and expression of MerCreMer in neurons of the central and enteric nervous systems was confirmed. Transcript of MerCreMer was detected in several non-neural tissues such as heart, liver, and kidney in these lines. In the background of the Cre reporter mouse strain Rosa26R, Cre recombinase activity was inducible in neurons of adult NSE-MerCreMer mice treated with tamoxifen by intragastric gavage, but not in those fed with corn oil only. We conclude that NSE-MerCreMer lines will be useful for studying gene functions in neurons for the conditions that Cre-mediated recombination resulting in embryonic lethality, which precludes investigation of gene functions in neurons through later stages of development and in adult.

  15. Differential regulation of native estrogen receptor-regulatory elements by estradiol, tamoxifen, and raloxifene.

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    Levy, Nitzan; Tatomer, Dierdre; Herber, Candice B; Zhao, Xiaoyue; Tang, Hui; Sargeant, Toby; Ball, Lonnele J; Summers, Jonathan; Speed, Terence P; Leitman, Dale C

    2008-02-01

    Estrogen receptors (ERs) regulate gene transcription by interacting with regulatory elements. Most information regarding how ER activates genes has come from studies using a small set of target genes or simple consensus sequences such as estrogen response element, activator protein 1, and Sp1 elements. However, these elements cannot explain the differences in gene regulation patterns and clinical effects observed with estradiol (E(2)) and selective estrogen receptor modulators. To obtain a greater understanding of how E(2) and selective estrogen receptor modulators differentially regulate genes, it is necessary to investigate their action on a more comprehensive set of native regulatory elements derived from ER target genes. Here we used chromatin immunoprecipitation-cloning and sequencing to isolate 173 regulatory elements associated with ERalpha. Most elements were found in the introns (38%) and regions greater than 10 kb upstream of the transcription initiation site (38%); 24% of the elements were found in the proximal promoter region (tamoxifen with ERalpha or ERbeta. Tamoxifen was more effective than raloxifene at activating the elements with ERalpha, whereas raloxifene was superior with ERbeta. Our findings demonstrate that E(2), tamoxifen, and raloxifene differentially regulate native ER-regulatory elements isolated by chromatin immunoprecipitation with ERalpha and ERbeta.

  16. Targeted conjugation of breast anticancer drug tamoxifen and its metabolites with synthetic polymers.

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    Sanyakamdhorn, S; Agudelo, D; Bekale, L; Tajmir-Riahi, H A

    2016-09-01

    Conjugation of antitumor drug tamoxifen and its metabolites, 4-hydroxytamxifen and ednoxifen with synthetic polymers poly(ethylene glycol) (PEG), methoxypoly (ethylene glycol) polyamidoamine (mPEG-PAMAM-G3) and polyamidoamine (PAMAM-G4) dendrimers was studied in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize the drug binding process to synthetic polymers. Structural analysis showed that drug-polymer binding occurs via both H-bonding and hydrophobic contacts. The order of binding is PAMAM-G4>mPEG-PAMAM-G3>PEG-6000 with 4-hydroxttamoxifen forming more stable conjugate than tamoxifen and endoxifen. Transmission electron microscopy showed significant changes in carrier morphology with major changes in the shape of the polymer aggregate as drug encapsulation occurred. Modeling also showed that drug is located in the surface and in the internal cavities of PAMAM with the free binding energy of -3.79 for tamoxifen, -3.70 for 4-hydroxytamoxifen and -3.69kcal/mol for endoxifen, indicating of spontaneous drug-polymer interaction at room temperature. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Tamoxifen-independent recombination in the RIP-CreER mouse.

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    Yanmei Liu

    Full Text Available BACKGROUND: The inducible Cre-lox system is a valuable tool to study gene function in a spatial and time restricted fashion in mouse models. This strategy relies on the limited background activity of the modified Cre recombinase (CreER in the absence of its inducer, the competitive estrogen receptor ligand, tamoxifen. The RIP-CreER mouse (Tg (Ins2-cre/Esr1 1Dam is among the few available β-cell specific CreER mouse lines and thus it has been often used to manipulate gene expression in the insulin-producing cells of the endocrine pancreas. PRINCIPAL FINDINGS: Here, we report the detection of tamoxifen-independent Cre activity as early as 2 months of age in RIP-CreER mice crossed with three distinct reporter strains. SIGNIFICANCE: Evidence of Cre-mediated recombination of floxed alleles even in the absence of tamoxifen administration should warrant cautious use of this mouse for the study of pancreatic β-cells.

  18. Effect of intermittent treatment with tamoxifen on reproduction in male rats

    Institute of Scientific and Technical Information of China (English)

    M. K. Gill-Sharma; N. Balasinor; P. Parte

    2001-01-01

    Aim: To identify the antifertility effect of intrmittent oral administration of tamoxifen in male rat. Methods:Tamoxifen was administered orally at a dose of 0.4 mg@kg- 1@ d-1 with an intermittent regime for 120 days. Treated and control rats were mated with cycling female rats on days 60, 90 and 120 of treatment. The mated males were sacri riced and the weights of reproductive organs were recorded, and the semm levels of LH, FSH, testosterone and estradi ol estimated by radioimmunoassay. In the female rats, the numbers of implantation sites, corpora lutea, and numbers of normal and resorbed foetuses were recorded on d 21 of gestation. The potency, fecundity, fertility index, litter size and post-implantation loss were then calculated. Results: The fecundity of male rats was completely suppressed by tamoxifen while the potency was maintained at the control level. The fertility index was significantly decreased. No vi able litters were sired. Post implantation loss, indicative of non-viable embryos, was observed but was not significantly increased above the control level. The weights of the testes, epididymides, ventral prostate and seminal vesicles were significantly reduced. The blood LH and testosterone levels were significantly decreased, but not FSH and estradiol.Conclusion: Intermittent oral tarnoxifen administration completely suppressed the fecundity of adult male rats with reserved potency.

  19. Tamoxifen Promotes Axonal Preservation and Gait Locomotion Recovery after Spinal Cord Injury in Cats

    Science.gov (United States)

    de la Torre Valdovinos, Braniff; Duenas Jimenez, Judith Marcela; Estrada, Ismael Jimenez; Banuelos Pineda, Jacinto; Franco Rodriguez, Nancy Elizabeth; Lopez Ruiz, Jose Roberto; Osuna Carrasco, Laura Paulina; Candanedo Arellano, Ahiezer; Duenas Jimenez, Sergio Horacio

    2016-01-01

    We performed experiments in cats with a spinal cord penetrating hemisection at T13-L1 level, with and without tamoxifen treatment. The results showed that the numbers of the ipsilateral and contralateral ventral horn neurons were reduced to less than half in the nontreated animals compared with the treated ones. Also, axons myelin sheet was preserved to almost normal values in treated cats. On the contrary, in the untreated animals, their myelin sheet was reduced to 28% at 30 days after injury (DAI), in both the ipsilateral and contralateral regions of the spinal cord. Additionally, we made hindlimb kinematics experiments to study the effects of tamoxifen on cat locomotion after the injury: at 4, 16, and 30 DAI. We observed that the ipsilateral hindlimb angular displacement (AD) of the pendulum-like movements (PLM) during gait locomotion was recovered to almost normal values in treated cats. Contralateral PLM acquired similar values to those obtained in intact cats. At 4 DAI, untreated animals showed a compensatory increment of PLM occurring in the contralateral hindlimb, which was partially recovered at 30 DAI. Our findings indicate that tamoxifen exerts a neuroprotective effect and preserves or produces myelinated axons, which could benefit the locomotion recovery in injured cats. PMID:27006979

  20. Preventing the co-prescription of tamoxifen and fluoxetine in General Practice.

    Science.gov (United States)

    Stonier, Thomas; Harrison, Michael

    2013-01-01

    In 2010 a population-based cohort study showed that there was decreased efficacy of the breast cancer drug tamoxifen when used in combination with fluoxetine, a commonly used SSRI antidepressant. The aim of this project was to identify patients who may be affected by this co-prescription and suggest a change in medication. The project was conducted across two GP practices in Clevedon (The Riverside Practice & The Green Practice), Bristol. The patients were all from the active patients register at each surgery. A search was conducted to find all those on tamoxifen and fluoxetine, using the EMIS computer system. These patients would then be sent a letter to attend clinic. The new data would then be discussed with them before recommending a change of antidepressant (typically to sertraline). Three patients were found to be on both medications. They were all called into clinic and changed from fluoxetine to sertraline. Furthermore a presentation was given to all GPs at the two surgeries alerting them to the new guidelines. A message was also set up to flash on the computer system whenever an attempt was made to co-prescribe the two drugs. All the patients on tamoxifen in these two practices are now receiving the optimum treatment. Furthermore interventions have been put in place to ensure that this remains the case in future. Another data collection should be conducted in one year. This project provides a good example of how this problem could be resolved at other GP surgeries.

  1. Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan

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    Hiscox Stephen

    2012-10-01

    Full Text Available Abstract Background Acquired resistance to endocrine therapy in breast cancer is a significant problem with relapse being associated with local and/or regional recurrence and frequent distant metastases. Breast cancer cell models reveal that endocrine resistance is accompanied by a gain in aggressive behaviour driven in part through altered growth factor receptor signalling, particularly involving erbB family receptors. Recently we identified that CD44, a transmembrane cell adhesion receptor known to interact with growth factor receptors, is upregulated in tamoxifen-resistant (TamR MCF7 breast cancer cells. The purpose of this study was to explore the consequences of CD44 upregulation in an MCF7 cell model of acquired tamoxifen resistance, specifically with respect to the hypothesis that CD44 may influence erbB activity to promote an adverse phenotype. Methods CD44 expression in MCF7 and TamR cells was assessed by RT-PCR, Western blotting and immunocytochemistry. Immunofluorescence and immunoprecipitation studies revealed CD44-erbB associations. TamR cells (± siRNA-mediated CD44 suppression or MCF7 cells (± transfection with the CD44 gene were treated with the CD44 ligand, hyaluronon (HA, or heregulin and their in vitro growth (MTT, migration (Boyden chamber and wound healing and invasion (Matrigel transwell migration determined. erbB signalling was assessed using Western blotting. The effect of HA on erbB family dimerisation in TamR cells was determined by immunoprecipitation in the presence or absence of CD44 siRNA. Results TamR cells overexpressed CD44 where it was seen to associate with erbB2 at the cell surface. siRNA-mediated suppression of CD44 in TamR cells significantly attenuated their response to heregulin, inhibiting heregulin-induced cell migration and invasion. Furthermore, TamR cells exhibited enhanced sensitivity to HA, with HA treatment resulting in modulation of erbB dimerisation, ligand-independent activation of erbB2

  2. Genomic index of sensitivity to endocrine therapy for breast cancer.

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    Symmans, W Fraser; Hatzis, Christos; Sotiriou, Christos; Andre, Fabrice; Peintinger, Florentia; Regitnig, Peter; Daxenbichler, Guenter; Desmedt, Christine; Domont, Julien; Marth, Christian; Delaloge, Suzette; Bauernhofer, Thomas; Valero, Vicente; Booser, Daniel J; Hortobagyi, Gabriel N; Pusztai, Lajos

    2010-09-20

    We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy. A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively). The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET. The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.

  3. The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

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    Ribeiro, Mariana P.C. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Nunes-Correia, Isabel [Center for Neuroscience and Cell Biology, Flow Cytometry Unit, University of Coimbra, 3000-354 Coimbra (Portugal); Santos, Armanda E., E-mail: aesantos@ci.uc.pt [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Custódio, José B.A. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal)

    2014-02-15

    Recent reports suggest that N-methyl-D-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination. - Highlights: • MK-801 and memantine decrease melanoma cell proliferation. • The combination of MK-801 with antiestrogens inhibits melanoma cell proliferation. • These combinations greatly enhance the effects of the compounds individually. • MK-801 combined with tamoxifen active metabolites induces cell cycle arrest in G1. • The combination of MK-801 and antiestrogens is an innovative strategy for melanoma.

  4. The adherence and tolerance of adjuvant endocrine therapy in geriatric breast cancer patients

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    Meng-Ting Peng

    2016-09-01

    Conclusions: The completion rate for patients who underwent oral ET in our study was similar to previous studies. The switch method of adjuvant oral endocrine therapy demonstrated a better tolerance and adherence in elderly breast cancer patients, compared with tamoxifen or aromatase inhibitor alone.

  5. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer

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    Moi Line L

    2012-06-01

    Full Text Available Abstract Background Steroid receptor coactivators (SRCs may modulate estrogen receptor (ER activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs were examined in an animal model of ER positive breast cancer. Methods Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls. Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2, SRC-3/amplified in breast cancer 1 (AIB1, ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Results Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035, SRC-2/TIF-2 (P = 0.002, HER-2 (P = 0.035 and HER-3 (P = 0.006 were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001, and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P P  Conclusions The expression of SRCs and HER-2 and -3 is stimulated by tamoxifen treatment

  6. Estrogen Receptor (ER-α36 Is Involved in Estrogen- and Tamoxifen-Induced Neuroprotective Effects in Ischemic Stroke Models.

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    Wei Zou

    Full Text Available The neuroprotection by estrogen (E2 and tamoxifen is well documented in experimental stroke models; however, the exact mechanism is unclear. A membrane-based estrogen receptor, ER-α36, has been identified. Postmenopausal-levels of E2 act through ER-α36 to induce osteoclast apoptosis due to a prolonged activation of the mitogen-activated protein kinase (MAPK/extracellular signal-related kinase (ERK signaling. We hypothesized that ER-α36 may play a role in the neuroprotective activities of estrogen and tamoxifen. Here, we studied ER-α36 expression in the brain, as well as its neuroprotective effects against oxygen and glucose deprivation (OGD in PC12 cells. We found that ER-α36 was expressed in both rat and human brain. In addition, OGD-induced cell death was prevented by l nmol/L 17β-estradiol (E2β. E2β activates the MAPK/ERK signaling pathway in PC12 cells under basal and OGD conditions by interacting with ER-α36 and also induces ER-α36 expression. Low-dose of tamoxifen up-regulated ER-α36 expression and enhanced neuronal survival in an ovariectomized ischemic stroke model. Furthermore, low-dose of tamoxifen enhanced neuroprotective effects by modulating activates or suppress ER-α36. Our results thus demonstrated that ER-α36 is involved in neuroprotective activities mediated by both estrogen and tamoxifen.

  7. Low ERK phosphorylation in cancer-associated fibroblasts is associated with tamoxifen resistance in pre-menopausal breast cancer.

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    Susann Busch

    Full Text Available PURPOSE: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. PATIENTS AND METHODS: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK and smooth muscle actin-alpha expression (SMAα in cancer-associated fibroblasts (CAFs and links to clinico-pathological data and treatment-predictive values were delineated. RESULTS: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ERα-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis. In both clinical materials we further show a significant association between pERK and SMAα, a characteristic marker for activated fibroblasts. SMAα expression however was not linked to treatment-predictive information but instead had prognostic qualities. CONCLUSION: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.

  8. pH-responsive drug delivery of chitosan nanoparticles as Tamoxifen carriers for effective anti-tumor activity in breast cancer cells.

    Science.gov (United States)

    Vivek, R; Nipun Babu, V; Thangam, R; Subramanian, K S; Kannan, S

    2013-11-01

    Tamoxifen (Tam) has a broad spectrum of anticancer activity, but is limited in clinical application. The aim of this study was to explore the smart pH-responsive drug delivery system (DDS) based on chitosan (CH) nanoparticles (NPs) for its potential in enabling more intelligent controlled release and enhancing chemotherapeutic efficiency of Tamoxifen. Tamoxifen was loaded onto CH-nanoparticles by forming complexes and Tamoxifen was released from the DDS much more rapidly at pH 4.0 and 6.0 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. Tamoxifen-loaded CH nanoparticles induced remarkable improvement in anticancer activity, as demonstrated by MTT-assay, AO/EtBr and Hoechst nuclear staining. Furthermore, the possible signaling pathway was explored by RT-PCR. For instance, in human breast cancer MCF-7 cells, it was demonstrated that Tamoxifen-loaded CH nanoparticles increase intracellular concentration of Tamoxifen and enhance its anticancer efficiency by inducing apoptosis in a caspase-dependent manner, indicating that drug loaded nanoparticles could act as an efficient DDS importing Tamoxifen into target cancer cells.

  9. Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways

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    Matsuoka, Hiroshi [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Department of Pharmacy, Nara Hospital, Kinki University School of Medicine, 1248-1 Ikoma, Nara 630-0293 (Japan); Tsubaki, Masanobu [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Yamazoe, Yuzuru [Department of Pharmacy, Kinki University Hospital, Osakasayama, Osaka 589-8511 (Japan); Ogaki, Mitsuhiko [Department of Pharmacy, Higahiosaka City General Hospital, Higashi-osaka, Osaka 578-8588 (Japan); Satou, Takao; Itoh, Tatsuki [Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka 589-8511 (Japan); Kusunoki, Takashi [Department of Otolaryngology, Juntendo University School of Medicine, Tokyo (Japan); Nishida, Shozo, E-mail: nishida@phar.kindai.ac.jp [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan)

    2009-07-15

    In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities of matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKC{alpha} and PKC{delta} phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.

  10. Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation.

    NARCIS (Netherlands)

    Moerkens, M.; Zhang, Y.; Wester, L.; Water, van de B.; Meerman, J.H.N.

    2014-01-01

    BACKGROUND Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER) α -positive breast cancer patients. Although the mechanisms behind tamoxifen resistance are still not completely understood, clinical data suggests that increased expression of receptor tyrosine kinases is

  11. Genetically Guided Statin Therapy on Statin Perceptions, Adherence, and Cholesterol Lowering: A Pilot Implementation Study in Primary Care Patients

    OpenAIRE

    Li, Josephine H; Joy, Scott V.; Haga, Susanne B.; Orlando, Lori A.; Kraus, William E.; Ginsburg, Geoffrey S.; Deepak Voora

    2014-01-01

    Statin adherence is often limited by side effects. The SLCO1B1*5 variant is a risk factor for statin side effects and exhibits statin-specific effects: highest with simvastatin/atorvastatin and lowest with pravastatin/rosuvastatin. The effects of SLCO1B1*5 genotype guided statin therapy (GGST) are unknown. Primary care patients (n = 58) who were nonadherent to statins and their providers received SLCO1B1*5 genotyping and guided recommendations via the electronic medical record (EMR). The pri...

  12. PKA-induced phosphorylation of ERα at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer.

    Science.gov (United States)

    Kok, Marleen; Zwart, Wilbert; Holm, Caroline; Fles, Renske; Hauptmann, Michael; Van't Veer, Laura J; Wessels, Lodewyk F A; Neefjes, Jacques; Stål, Olle; Linn, Sabine C; Landberg, Göran; Michalides, Rob

    2011-01-01

    Phosphorylation of estrogen receptor α at serine 305 (ERαS305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ERαS305-P (PKA/ERαS305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ERαS305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ERαS305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ERαS305-P (P = 0.037). Elevated PAK1 and PKA/ERαS305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ERαS305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.

  13. Transgenic mice for a tamoxifen-induced, conditional expression of the Cre recombinase in osteoclasts.

    Directory of Open Access Journals (Sweden)

    Maria Arantzazu Sanchez-Fernandez

    Full Text Available BACKGROUND: Studies on osteoclasts, the bone resorbing cells, have remained limited due to the lack of transgenic mice allowing the conditional knockout of genes in osteoclasts at any time during development or adulthood. METHODOLOGY/PRINCIPAL FINDING: We report here on the generation of transgenic mice which specifically express a tamoxifen-inducible Cre recombinase in osteoclasts. These mice, generated on C57BL/6 and FVB background, express a fusion Cre recombinase-ERT2 protein whose expression is driven by the promoter of cathepsin K (CtsK, a gene highly expressed in osteoclasts. We tested the cellular specificity of Cre activity in CtsKCreERT2 strains by breeding with Rosa26LacZ reporter mice. PCR and histological analyses of the CtsKCreERT2LacZ positive adult mice and E17.5 embryos show that Cre activity is restricted largely to bone tissue. In vitro, primary osteoclasts derived from the bone marrow of CtsKCreERT2+/-LacZ+/- adult mice show a Cre-dependent β-galactosidase activity after tamoxifen stimulation. CONCLUSIONS/SIGNIFICANCE: We have generated transgenic lines that enable the tamoxifen-induced, conditional deletion of loxP-flanked genes in osteoclasts, thus circumventing embryonic and postnatal gene lethality and avoiding gene deletion in other cell types. Such CtsKCreERT2 mice provide a convenient tool to study in vivo the different facets of osteoclast function in bone physiology during different developmental stages and adulthood of mice.

  14. Toxicidade ocular causada pelo tamoxifeno: relato de caso Ocular toxicity caused by tamoxifen: case report

    Directory of Open Access Journals (Sweden)

    Eliane Terumi Inada

    2005-08-01

    Full Text Available O objetivo desse trabalho é relatar um caso de toxicidade ocular pelo tamoxifeno. Para isso, aferiu-se a melhor acuidade visual corrigida de ambos os olhos em tabela de Snellen. Foram realizados biomicroscopia do segmento anterior, refração, oftalmoscopia, angiofluoresceinografia e retinografia numa paciente de 63 anos, sexo feminino, cor branca, em uso de tamoxifeno 20 mg/dia há 4 anos, com acuidade visual corrigida de 20/70 e 20/40. A biomicroscopia do segmento anterior apresentava ceratopatia verticilata e catarata nuclear e cortical posterior de 1+/4 em ambos os olhos. À oftalmoscopia, foi verificado alteração do brilho macular de ambos os olhos. E a angiofluoresceinografia mostrou hiperfluorescência na área macular em fase precoce (defeito em janela. Relata-se um caso de ceratopatia e maculopatia causadas pelo tamoxifeno.To report tamoxifen ocular toxicity. The best visual acuity was measured in both eyes with Snellen chart, slit-lamp examination of anterior segment, refraction, dilated fundus examination, fluorescein angiography and retinography in a 63-year-old patient, female, white, using tamoxifen 20 mg/day for 4 years, with 20/70 and 20/40 corrected visual acuity. The anterior segment examination showed corneal linear subepithelial opacity inferior to the visual axis and nuclear and posterior cortical cataract (1+/4 in both eyes. Fundus examination showed alteration of macular color in both eyes. Fluorescein angiography presented hyperfluorescence in the macular area at an early phase (window defect. Report of keratopathy and maculopathy caused by tamoxifen.

  15. A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen.

    Science.gov (United States)

    Chia, Stephen K; Bramwell, Vivien H; Tu, Dongsheng; Shepherd, Lois E; Jiang, Shan; Vickery, Tammi; Mardis, Elaine; Leung, Samuel; Ung, Karen; Pritchard, Kathleen I; Parker, Joel S; Bernard, Philip S; Perou, Charles M; Ellis, Matthew J; Nielsen, Torsten O

    2012-08-15

    Gene expression profiling classifies breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have used material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer (NCIC CTG MA.12) to evaluate the prognostic and predictive significance of intrinsic subtypes identified by both the PAM50 gene set and by immunohistochemistry. Total RNA from 398 of 672 (59%) patients was available for intrinsic subtyping with a quantitative reverse transcriptase PCR (qRT-PCR) 50-gene predictor (PAM50) for luminal A, luminal B, HER-2-enriched, and basal-like subtypes. A tissue microarray was also constructed from 492 of 672 (73%) of the study population to assess a panel of six immunohistochemical IHC antibodies to define the same intrinsic subtypes. Classification into intrinsic subtypes by the PAM50 assay was prognostic for both disease-free survival (DFS; P = 0.0003) and overall survival (OS; P = 0.0002), whereas classification by the IHC panel was not. Luminal subtype by PAM50 was predictive of tamoxifen benefit [DFS: HR, 0.52; 95% confidence interval (CI), 0.32-0.86 vs. HR, 0.80; 95% CI, 0.50-1.29 for nonluminal subtypes], although the interaction test was not significant (P = 0.24), whereas neither subtyping by central immunohistochemistry nor by local estrogen receptor (ER) or progesterone receptor (PR) status were predictive. Risk of relapse (ROR) modeling with the PAM50 assay produced a continuous risk score in both node-negative and node-positive disease. In the MA.12 study, intrinsic subtype classification by qRT-PCR with the PAM50 assay was superior to IHC profiling for both prognosis and prediction of benefit from adjuvant tamoxifen.

  16. In Vivo Performance and Properties of Tamoxifen Metabolites for CreERT2 Control.

    Science.gov (United States)

    Felker, Anastasia; Nieuwenhuize, Susan; Dolbois, Aymeric; Blazkova, Kristyna; Hess, Christopher; Low, Larry W L; Burger, Sibylle; Samson, Natasha; Carney, Tom J; Bartunek, Petr; Nevado, Cristina; Mosimann, Christian

    2016-01-01

    Mutant Estrogen Receptor (ERT2) ligand-binding domain fusions with Cre recombinase are a key tool for spatio-temporally controlled genetic recombination with the Cre/lox system. CreERT2 is efficiently activated in a concentration-dependent manner by the Tamoxifen metabolite trans-4-OH-Tamoxifen (trans-4-OHT). Reproducible and efficient Cre/lox experimentation is hindered by the gradual loss of CreERT2 induction potency upon prolonged storage of dissolved trans-4-OHT, which potentially results from gradual trans-to-cis isomerization or degradation. Here, we combined zebrafish CreERT2 recombination experiments and cell culture assays to document the gradual activity loss of trans-4-OHT and describe the alternative Tamoxifen metabolite Endoxifen as more stable alternative compound. Endoxifen retains potent activation upon prolonged storage (3 months), yet consistently induces half the ERT2 domain fusion activity compared to fresh trans-4-OHT. Using 1H-NMR analysis, we reveal that trans-4-OHT isomerization is undetectable upon prolonged storage in either DMSO or Ethanol, ruling out isomer transformation as cause for the gradual loss of trans-4-OHT activity. We further establish that both trans-4-OHT and Endoxifen are insensitive to light exposure under regular laboratory handling conditions. We attribute the gradual loss of trans-4-OHT potency to precipitation over time, and show that heating of aged trans-4-OHT aliquots reinstates their CreERT2 induction potential. Our data establish Endoxifen as potent and reproducible complementary compound to 4-OHT to control ERT2 domain fusion proteins in vivo, and provide a framework for efficient chemically controlled recombination experiments.

  17. Benefit of low-dose tamoxifen in a large observational cohort of high risk ER positive breast DCIS.

    Science.gov (United States)

    Guerrieri-Gonzaga, Aliana; Sestak, Ivana; Lazzeroni, Matteo; Serrano, Davide; Rotmensz, Nicole; Cazzaniga, Massimiliano; Varricchio, Clara; Pruneri, Giancarlo; Leonardi, Maria Cristina; Orecchia, Roberto; Galimberti, Viviana; Bonanni, Bernardo; DeCensi, Andrea

    2016-11-01

    Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings.

  18. Tamoxifen Activation of Cre-Recombinase Has No Persisting Effects on Adult Neurogenesis or Learning and Anxiety.

    Science.gov (United States)

    Rotheneichner, Peter; Romanelli, Pasquale; Bieler, Lara; Pagitsch, Sebastian; Zaunmair, Pia; Kreutzer, Christina; König, Richard; Marschallinger, Julia; Aigner, Ludwig; Couillard-Després, Sébastien

    2017-01-01

    Adult neurogenesis is a tightly regulated process continuously taking place in the central nervous system of most mammalian species. In neuroscience research, transgenic animals bearing the tamoxifen-inducible CreER(T2)-Lox system are widely used. In this study, we made use of a Nestin-CreER(T2)/R26R-YFP transgenic mouse model in which the CreER(T2) activates the expression of YFP in multipotent neural stem cells upon tamoxifen application. Humoral factors, such as the levels of estrogens, have been reported to affect the hippocampal neurogenesis. The application of tamoxifen, a mixed agonist/antagonist of the estrogen receptor that permeates the blood-brain-barrier, could thus influence adult neurogenesis. Although the functions of adult neurogenesis are yet to be fully deciphered, a reciprocal interaction between rates of neurogenesis on the one hand and learning and mood regulation on the other hand, has been suggested. The impact of tamoxifen on neurogenesis and behavior was therefore addressed following five daily applications according to the open field test, the elevated plus maze, and Morris water maze. In addition, the impact of short-term tamoxifen application on progenitor cell proliferation, morphology, and fate in the neurogenic niche of the dentate gyrus were investigated. Finally, the influence of the route of administration (oral vs. intra-peritoneal) and gender-specific response were scrutinized. The sub-acute analysis did neither reveal significant differences in behavior, such as voluntary motor activity, anxiety behavior, and spatial learning, nor in cell proliferation, cell survival, dendritic arborization or maturation rate within the dentate gyrus between saline solution-, corn oil-, and tamoxifen-treated groups. Finally, neither the route of application, nor the gender of treated mice influenced the response to tamoxifen. We conclude that short tamoxifen treatments used to activate the CreER(T2) system in transgenic mouse models does not

  19. Tamoxifen Activation of Cre-Recombinase Has No Persisting Effects on Adult Neurogenesis or Learning and Anxiety

    Science.gov (United States)

    Rotheneichner, Peter; Romanelli, Pasquale; Bieler, Lara; Pagitsch, Sebastian; Zaunmair, Pia; Kreutzer, Christina; König, Richard; Marschallinger, Julia; Aigner, Ludwig; Couillard-Després, Sébastien

    2017-01-01

    Adult neurogenesis is a tightly regulated process continuously taking place in the central nervous system of most mammalian species. In neuroscience research, transgenic animals bearing the tamoxifen-inducible CreERT2-Lox system are widely used. In this study, we made use of a Nestin-CreERT2/R26R-YFP transgenic mouse model in which the CreERT2 activates the expression of YFP in multipotent neural stem cells upon tamoxifen application. Humoral factors, such as the levels of estrogens, have been reported to affect the hippocampal neurogenesis. The application of tamoxifen, a mixed agonist/antagonist of the estrogen receptor that permeates the blood-brain-barrier, could thus influence adult neurogenesis. Although the functions of adult neurogenesis are yet to be fully deciphered, a reciprocal interaction between rates of neurogenesis on the one hand and learning and mood regulation on the other hand, has been suggested. The impact of tamoxifen on neurogenesis and behavior was therefore addressed following five daily applications according to the open field test, the elevated plus maze, and Morris water maze. In addition, the impact of short-term tamoxifen application on progenitor cell proliferation, morphology, and fate in the neurogenic niche of the dentate gyrus were investigated. Finally, the influence of the route of administration (oral vs. intra-peritoneal) and gender-specific response were scrutinized. The sub-acute analysis did neither reveal significant differences in behavior, such as voluntary motor activity, anxiety behavior, and spatial learning, nor in cell proliferation, cell survival, dendritic arborization or maturation rate within the dentate gyrus between saline solution-, corn oil-, and tamoxifen-treated groups. Finally, neither the route of application, nor the gender of treated mice influenced the response to tamoxifen. We conclude that short tamoxifen treatments used to activate the CreERT2 system in transgenic mouse models does not have a

  20. Effect of different lipids and surfactants on formulation of solid lipid nanoparticles incorporating tamoxifen citrate

    Directory of Open Access Journals (Sweden)

    S U Upadhyay

    2012-01-01

    Full Text Available Tamoxifen Citrate (TC is an estrogen receptor antagonist and drug of choice for hormone sensitive breast cancer. Solid Lipid Nanoparticles loaded with TC were prepared by High Shear Homogenization followed by Ultrasonication. The aim of the present work is to study the effect of four different Solid Lipids and three Surfactants on Formulation and Stability of SLN. They were characterized for Particle size, Polydispersity Index and Zeta Potential by Zetasizer Nano. SLN prepared by Solid Lipid Compritol 888 (Glyceryldibehenate and Tween 80 (1% showed desired Particle Size of 206.9 nm, PDI of 0.046 and Zeta Potential of 9.32 mV.

  1. 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.

    Science.gov (United States)

    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.

  2. Study of anti-cancer drug release (tamoxifen of the nanofibers made of polycaprolactone -chitosan

    Directory of Open Access Journals (Sweden)

    Zahra Saeidi

    2016-12-01

    Full Text Available Breast cancer is a kind of cancer that begins than breast tissue. That in a kind of it, breast skin is quite involved. Than symptoms of the breast cancer is a dimple on the skin and peeling of skin and on the chest and..Natural polymers in terms of the environmental characteristics and their compatibility with the human body have vast applications in the industry: cosmetics, wound dressing, delivery of medicine scaffold, and so on.In this study, the cancer drug (tamoxifen used to complete the PCL-chitosan nanofibers made of a biocompatible polymer packag that deliver drugs will be examine. For this purpose, first the nanofibers made of PCL-chitosan-containing drugs (tamoxifen with optimal concentration of the drug was produced by electrospinning. The surface morphology of nanofibers microscopy (SEM were studied. Using infrared spectrometer instrument (FTIR evaluated the drug in nano-fibers. The effects of drug release and antimicrobial from nanofibers with standard (AATCC100 measurement and determined. According to antimicrobial test the nano-fiber manufacturing against Gram-positive and Gram-negative bacteria, Escherichia coli and Staphylococcus Cocos considerable influence along. Based on the results of tests it was found that nano-fiber PCL-chitosan-containing drug with a ratio of 70-30 and a concentration of 1 gr and 0.3 gr, speed And release better itself show compared to concentrations and the other ratios. The test results of drug release indicate a total release rate was high.

  3. Shotgun ecotoxicoproteomics of Daphnia pulex: biochemical effects of the anticancer drug tamoxifen.

    Science.gov (United States)

    Borgatta, Myriam; Hernandez, Céline; Decosterd, Laurent Arthur; Chèvre, Nathalie; Waridel, Patrice

    2015-01-02

    Among pollutants released into the environment by human activities, residues of pharmaceuticals are an increasing matter of concern because of their potential impact on ecosystems. The aim of this study was to analyze differences of protein expression resulting from acute (2 days) and middle-term (7 days) exposure of aquatic microcrustacean Daphnia pulex to the anticancer drug tamoxifen. Using a liquid chromatography-mass spectrometry shotgun approach, about 4000 proteins could be identified, providing the largest proteomics data set of D. pulex published up to now. Considering both time points and tested concentrations, 189 proteins showed a significant fold change. The identity of regulated proteins suggested a decrease in translation, an increase in protein degradation and changes in carbohydrate and lipid metabolism as the major effects of the drug. Besides these impacted processes, which reflect a general stress response of the organism, some other regulated proteins play a role in Daphnia reproduction. These latter results are in accordance with our previous observations of the impact of tamoxifen on D. pulex reproduction and illustrate the potential of ecotoxicoproteomics to unravel links between xenobiotic effects at the biochemical and organismal levels. Data are available via ProteomeXchange with identifier PXD001257.

  4. Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

    Science.gov (United States)

    Butts, Arielle; Martin, Jennifer A; DiDone, Louis; Bradley, Erin K; Mutz, Mitchell; Krysan, Damian J

    2015-01-01

    Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

  5. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen.

    Science.gov (United States)

    Oktay, K; Buyuk, E; Davis, O; Yermakova, I; Veeck, L; Rosenwaks, Z

    2003-01-01

    Breast cancer chemotherapy commonly causes premature ovarian failure and infertility. Because increased estrogen levels are thought to be potentially risky in breast cancer patients, natural cycle IVF (NCIVF) has been used to preserve fertility and treat infertility in these women. Twelve women with breast cancer received 40-60 mg tamoxifen for 6.9 +/- 0.6 days beginning on days 2-3 of their menstrual cycle (15 cycles), and had IVF (TamIVF) with either fresh embryo transfer (six cycles) or cryopreservation (nine cycles). They were compared to a retrospective control group (n = 5) who had natural cycle IVF (NCIVF, nine cycles). Cycle cancellation was significantly less frequent in TamIVF, compared with NCIVF (1/15 versus 4/9, P set of twins. After a mean follow up of 15 +/- 3.6 months (range 3-54), none of the patients had a recurrence of cancer. Tamoxifen stimulation appears to result in a higher number of embryos and may provide a safe method of IVF and fertility preservation in breast cancer patients.

  6. Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

    Directory of Open Access Journals (Sweden)

    Arielle Butts

    Full Text Available Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1 the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2 an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3 electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

  7. Effects of CreERT2, 4-OH Tamoxifen, and Gender on CFU-F Assays.

    Science.gov (United States)

    McHaffie, Sophie L; Hastie, Nicholas D; Chau, You-Ying

    2016-01-01

    Gene function in stem cell maintenance is often tested by inducing deletion via the Cre-loxP system. However, controls for Cre and other variables are frequently not included. Here we show that when cultured in the presence of 4-OH tamoxifen, bone and marrow cells containing the CreERT2 construct have a reduced colony forming ability. Inactive CreERT2 recombinase, however, has the opposite effect. Young female marrow cells containing the inactive CreERT2 construct grew more colonies than cells lacking the construct altogether. Young female control marrow cells (i.e., negative for CreERT2) also produced significantly greater colony numbers when cultured with 4-OH tamoxifen, compared with the ethanol vehicle control. In conclusion, we report that the use of the Cre-loxP system is inadvisable in combination with CFU-F assays, and that appropriate controls should be in place to extend the future use of Cre-loxP in alternate assays.

  8. Tamoxifen vs Tamoxifen plus 13-cis-retinoic acid vs Tamoxifen plus Interferon alpha-2a as first-line endocrine treatments in advanced breast cancer: updated results of a phase II, prospective, randomised multicentre trial.

    Science.gov (United States)

    Chiesa, Matteo Dalla; Passalacqua, Rodolfo; Michiara, Maria; Franciosi, Vittorio; Di Costanzo, Francesco; Bisagni, Giancarlo; Camisa, Roberta; Buti, Sebastiano; Tomasello, Gianluca; Cocconi, Giorgio

    2007-12-01

    To demonstrate the efficacy of 13-cis-retinoic acid (RA) or Interferon alpha-2a (IFN alpha-2a) with Tamoxifen (TAM) in the treatment of advanced breast cancer. Ninety-nine postmenopausal patients with advanced breast cancer, and a positive or unknown estrogen (ER) or progesterone (PgR) receptor status, were randomised to receive TAM 20 mg/m2/day orally (arm A), or TAM plus RA 1 mg/kg/day orally (arm B), or TAM plus IFN alpha-2a 3 MU thrice a week intramuscular (arm C). The three treatment groups were well balanced in terms of the main prognostic factors. Response was evaluable in 32 of the patients in arm A, 32 in arm B, and 30 in arm C. Intention-to-treat analysis showed no significant difference of response rate in the three arms (44% vs 38% vs 42%). After an eight years median follow-up, there was no significant between-group difference in median overall survival: 47.4 vs 38.2 vs 45.1 months. Side effects were negligible in arm A, but cutaneous (39%) and mucosal (62%) toxicities were frequent in arm B, and flu-like syndrome and/or myalgia (46%) in arm C. The administration of RA or IFN alpha-2a does not add anything to the therapeutic effects of TAM.

  9. The study protocol for a non-randomized controlled clinical trial using a genotype-guided strategy in a dataset of patients who undergone percutaneous coronary intervention with stent

    Directory of Open Access Journals (Sweden)

    Cristina Lucía Dávila-Fajardo

    2017-02-01

    Full Text Available This article contains data related to the research article entitled “Results of genotype–guided antiplatelet therapy in patients undergone percutaneous coronary intervention with stent” (J. Sánchez-Ramos, C.L. Dávila-Fajardo, P. Toledo Frías, X. Díaz Villamarín, L.J. Martínez-González, S. Martínez Huertas, F. Burillo Gómez, J. Caballero Borrego, A. Bautista Pavés, M.C. Marín Guzmán, J.A. Ramirez Hernández, C. Correa Vilches, J. Cabeza Barrera, 2016 (1. This data article reports, for the first time, about the non-randomized clinical trial protocol that check if CYP2C19/ABCB1 genotype–guided strategy in which the choice of antiplatelet therapy is based on the genetic test, reduces the rates of cardiovascular events and bleeding compared to a non-tailored strategy in patients undergone percutaneous coronary intervention (PCI with stent. The data included in this article are: design and setting of the study, study population, inclusion and exclusion criteria, definition of the intervention, objectives, variables (baseline characteristics and during the follow-up, study procedures, collection and treatment of the biological sample, genotyping, withdrawal criteria, sample size, statistic analysis, ethical aspects, information sheet and consent form. The authors confirm that this study has been registered in Eudra CT (Eudra CT: 2016-001294-33.

  10. Therapeutic effect of tamoxifen and energy-modulating vitamins on carbohydrate-metabolizing enzymes in breast cancer.

    Science.gov (United States)

    Perumal, Selvanathan Saravana; Shanthi, Palanivelu; Sachdanandam, Panchanadham

    2005-07-01

    Cancer cells have an abnormal energetic metabolism. One of the earliest discovered hallmarks of cancer had its roots in bioenergetics, as many tumours were found in the 1920s to exhibit a high glycolytic phenotype. An animal with cancer shows significant and progressive energy loss from the host (i.e. noncancerous) tissues, which could occur by the establishment of a systemic energy-depriving cycle involving the interaction of tumour glycolysis and host gluconeogenesis. Tamoxifen (TAM) is a nonsteroidal antioestrogen that is widely used in adjuvant therapy for all stages of breast carcinoma. To improve the therapeutic efficacy of TAM and to expand its usage in the treatment of breast cancer, it is necessary to establish an energy-enhancing programme. In order to provide sufficient energy and to prevent cancer cachexia, TAM can be supplemented with energy-modulating vitamins (EMV). In this investigation the augmentation of the efficacy of TAM by the effects of EMV supplementation on carbohydrate-metabolizing enzymes, the mitochondrial Krebs cycle and respiratory enzymes was evaluated in the mammary gland of carcinoma-bearing rats. Female albino Sprague-Dawley rats were selected for the investigation. The experimental set-up included one control and four experimental groups. Mammary carcinoma was induced with 7,12- dimethyl benz(a)anthracene (25 mg), and TAM was administered orally (10 mg/kg body weight per day) along with EMV which comprised riboflavin (45 mg/kg per day), niacin (100 mg/kg per day) and coenzyme Q(10) (40 mg/kg per day). Measurements were made on tumour tissue and surrounding normal tissue in all experimental groups. Tumour tissue showed significant (P<0.05) increases in the glycolytic enzymes hexokinase, phosphoglucoisomerase and aldolase, and significant decreases in the gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-biphosphatase. In contrast, the surrounding tissue showed significant decreases in glycolytic enzymes and significant

  11. Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells.

    Science.gov (United States)

    Cutrupi, S; Reineri, S; Panetto, A; Grosso, E; Caizzi, L; Ricci, L; Friard, O; Agati, S; Scatolini, M; Chiorino, G; Lykkesfeldt, A E; De Bortoli, M

    2012-10-04

    Pharmacological resistance is a serious threat to the clinical success of hormone therapy for breast cancer. The antiproliferative response to antagonistic drugs such as tamoxifen (Tam) critically depends on the recruitment of NCoR/SMRT corepressors to estrogen receptor alpha (ERα) bound to estrogen target genes. Under certain circumstances, as demonstrated in the case of interleukin-1β (IL-1β) treatment, the protein Tab2 interacts with ERα/NCoR and causes dismissal of NCoR from these genes, leading to loss of the antiproliferative response. In Tam-resistant (TamR) ER-positive breast cancer cells, we observed that Tab2 presents a shift in mobility on sodium dodecyl sulfate--PAGE (SDS-PAGE) similar to that seen in MCF7 wt upon stimulation with IL-1β, suggesting constitutive activation. Accordingly, TamR treatment with Tab2-specific short interfering RNA, restored the antiproliferative response to Tam in these cells. As Tab2 is known to directly interact with the N-terminal domain of ERα, we synthesized a peptide composed of a 14-aa motif of this domain, which effectively competes with ERα/Tab2 interaction in pull-down and co-immunoprecipitation experiments, fused to the carrier TAT peptide to allow internalization. Treatment of TamR cells with this peptide resulted in partial recovery of the antiproliferative response to Tam, suggesting a strategy to revert pharmacological resistance in breast cancer. Silencing of Tab2 in TamR cells by siRNA caused modulation of a gene set related to the control of cell cycle and extensively connected to BRCA1 in a functional network. These genes were able to discern two groups of patients, from a published data set of Tam-treated breast cancer profiles, with significantly different disease-free survival. Altogether, our data implicate Tab2 as a mediator of resistance to endocrine therapy and as a potential new target to reverse pharmacological resistance and potentiate antiestrogen action.

  12. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer.

    Science.gov (United States)

    Vogel, Victor G; Costantino, Joseph P; Wickerham, D Lawrence; Cronin, Walter M; Cecchini, Reena S; Atkins, James N; Bevers, Therese B; Fehrenbacher, Louis; Pajon, Eduardo R; Wade, James L; Robidoux, André; Margolese, Richard G; James, Joan; Runowicz, Carolyn D; Ganz, Patricia A; Reis, Steven E; McCaskill-Stevens, Worta; Ford, Leslie G; Jordan, V Craig; Wolmark, Norman

    2010-06-01

    The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer.

  13. Tamoxifen as an effective neuroprotectant against early brain injury and learning deficits induced by subarachnoid hemorrhage: possible involvement of inflammatory signaling.

    Science.gov (United States)

    Sun, Xuebo; Ji, Chengyuan; Hu, Tong; Wang, Zhong; Chen, Gang

    2013-12-28

    Tamoxifen, a selective estrogen receptor modulator, has successfully been used to treat several animal models of brain injury, but the underlying mechanisms remain unclear. This study was undertaken to evaluate the effect of tamoxifen on the toll-like receptor 4 (TLR4)- and nuclear factor-κB (NF-κB)-related inflammatory signaling pathway and secondary brain injury in rats after subarachnoid hemorrhage (SAH). Adult male Sprague-Dawley rats were divided into four groups: (1) control group (n = 28); (2) SAH group (n = 28); (3) SAH + vehicle group (n = 28); and (4) SAH + tamoxifen group (n = 28). All SAH animals were subjected to injection of autologous blood into the prechiasmatic cistern once on day 0. In SAH + tamoxifen group, tamoxifen was administered intraperitoneally at a dose of 5 mg/kg at 2 h, 12 h, and 36 h after SAH. In the first set of experiments, brain samples were extracted and evaluated at 48 h after SAH. In the second set of experiments, the Morris water maze was used to investigate cognitive and memory changes. We found that treatment with tamoxifen markedly inhibited the protein expressions of TLR4, NF-κB and the downstream inflammatory agents, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and intercellular adhesion molecule-1 (ICAM-1). Administration of tamoxifen following SAH significantly ameliorated the early brain injury (EBI), such as brain edema, blood-brain barrier (BBB) impairment, and clinical behavior scale. Learning deficits induced by SAH were markedly alleviated after tamoxifen treatment. Post-SAH tamoxifen administration may attenuate TLR4/NF-kappaB-mediated inflammatory response in the rat brain and result in abatement of the development of EBI and cognitive dysfunction after SAH.

  14. Comparison between tamoxifen and clomiphene citrate for induction of ovulation and successful conception in polycystic ovarian syndrome

    Directory of Open Access Journals (Sweden)

    Zhyan Baker Hassan

    2015-10-01

    Conclusions: Tamoxifen has shown comparable efficacy and safety as compared to clomiphene citrate and it can be a good alternative to clomiphene citrate in patients of primary or secondary anovulatory infertility with PCOS. [Int J Reprod Contracept Obstet Gynecol 2015; 4(5.000: 1349-1352

  15. A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy.

    Science.gov (United States)

    Ishizuka, Shinji; Satou, Shizou

    2016-01-01

    In September 2000, a 32-year-old woman presented to our hospital with a right breast mass. In September 2000, she underwent pectoral muscle-preserving mastectomy for the treatment of right breast cancer. Pathologyy results revealed a mucinous carcinoma 27 × 20 × 18 mm in size accompanied by an extensive intraductal component. The tumor was staged as T2 N1M0 stage IIB and found to be estrogen receptor-positive, and 6 cycles of postoperative adjuvant chemotherapy consisting of 5-fluorouracil, epirubicin, and cyclophosphamide were carried out. Goserelin acetate plus tamoxifen was prescribed from April 2001 to March 2005. Since the patient received tamoxifen from April 2005 and eumenorrhea started in June 2006, goserelin acetate plus tamoxifen was started in August 2006. The patient was determined to be 25 weeks pregnant by abdominal ultrasonography in February 2007. This meant that she had been taking goserelin acetate plus tamoxifen for 6 months without realizing she was pregnant. She gave birth to a girl by cesarean section in May 2007. No abnormalities, including anomaly of the genitalia, were seen, and the subsequent growth of the infant was also satisfactory. We here report this case and a brief review of the literature.

  16. Hypomethylation of DNA-binding inhibitor 4 serves as a potential biomarker in distinguishing acquired tamoxifen-refractory breast cancer.

    Science.gov (United States)

    Zhang, Yonghui; Zhang, Bin; Fang, Jing; Cao, Xuchen

    2015-01-01

    To explore the methylation status of DNA-binding inhibitor 4 (ID4) in tamoxifen-refractory (TR) breast cancer. From January 2012 to December 2014, breast cancer patients managed by radical mastectomy previously and receiving tamoxifen treatment for at least 12 months were enrolled. According to the response to tamoxifen, patients were divided into TR group and tamoxifen-sensitive (TS) group. Genomic DNA was isolated from fasting venous blood, and methylight technique was applied to determine the methylation status of ID4. 43 patients with TS breast cancer and 31 patients with TR breast cancer were enrolled. No significant difference between groups was observed in term of patients' characteristics, such as age (P=0.693), progesterone receptor (P=0.970), menopausal status (P=0.784) and histological type (P=0.537), while the stage of cancer in TR group was significantly higher than TS group (Pset at 6.8% in survival analysis, log-rank test indicated the risk of disease progression was comparable between patients with ID4 hypermethylation or hypomethylation (P=0.287). ID4 hypomethylation is present in TR breast cancer, and it may serve as a potential biomarker in distinguishing TR breast cancer. However, the results need further validation in larger studies.

  17. The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

    NARCIS (Netherlands)

    L.A. Lammers (Laureen); R.H.J. Matthijsen (Ron); T. van Gelder (Teun); M.J. Bijl (Monique); A.J.M. de Graan (Anne-Joy); C.M. Seynaeve (Caroline); M.A. van Fessem (Marianne); P.M.J.J. Berns (Els); A.G. Vulto (Arnold); R.H.N. van Schaik (Ron)

    2010-01-01

    textabstractAbstract BACKGROUND: Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant

  18. Differences in Uptake, Metabolism and Clearance of Atrazine and Tamoxifen in a Fish and a Rat Species

    Science.gov (United States)

    Atrazine and tamoxifen are known endocrine-disrupting chemicals (EDCs) that have metabolites exhibiting biological activities that are equally or more potent than the parent compound. To evaluate if uptake, metabolism and clearance of such EDCs is a concern in interspecies extrap...

  19. Study on treating oligozoospermia and asthenospermia by Shengjing capsule combined with tamoxifen%生精胶囊联合他莫昔芬对男性少弱精子症治疗的研究

    Institute of Scientific and Technical Information of China (English)

    刘朝霞

    2012-01-01

      Objective:To observe the therapeutic effects of Shengjing capsule combined with tamoxifen in treating oligozoospermia and asthenospermia. Methods:80 cases with oligozoospermia or asthenospermia from out-patient clinic of sterility and infertility were randomly divided into the therapy group and the control group, 40 cases in each group. The therapy group was treated with Shengjing capsule and tamoxifen, and the control group was treated with vitamin E, vitamin C and zinc agents. The effects were assessed after 3 month treatment. Results:The total effective rate of the therapy group was 92.5%, significantly higher than the control group (P<0.01). The sperm density and the number of forward movement of sperm were significantly increased comparing with control group (P<0.01). Conclusion:Shengjing capsule combined with tamoxifen had significant effect on oligozoospermia and asthenospermia,with rare side effects.%  目的:观察生精胶囊联合他莫昔芬治疗男性少弱精子症的疗效.方法:选择不孕不育门诊确诊为少弱精子症患者80例,分为治疗组和观察组,各40例.治疗组予生精胶囊和他莫昔芬,对照组予维生素 E、维生素 C、锌剂,治疗3个月后观察疗效.结果:口服生精胶囊和他莫昔芬组治疗有效率为92.5%,明显高于对照组(P<0.01);治疗组精子密度和前向运动精子明显增多,与对照组有显著性差异(P<0.01).结论:口服生精胶囊联合他莫昔芬对男性少弱精子症疗效显著,无不良反应.

  20. Inhibition of β-Catenin to Overcome Endocrine Resistance in Tamoxifen-Resistant Breast Cancer Cell Line.

    Directory of Open Access Journals (Sweden)

    Hye Sung Won

    Full Text Available The β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K/Akt and the mammalian target of rapamycin (mTOR signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer.We established tamoxifen-resistant (TamR cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay.TamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells.These results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.

  1. 金葡球菌和肺炎链球菌在体内对莫西沙星耐药性分析%Staphylococcus auras and Streptococcus pneumatic analysis of tamoxifen resistance in vino

    Institute of Scientific and Technical Information of China (English)

    梁霞

    2016-01-01

    目的:分析金葡球菌和肺炎链球菌在体内对莫西沙星的耐药性。方法:采用大鼠肉芽肿袋模型,体内试验选用野生株、第一代耐药株以及多代耐药株,使用不同菌株感染大鼠产生肉芽肿袋后分为A、B、C3个组,用莫西沙星进行不同剂量用法治疗,每天收集肉芽肿袋的渗出物,根据耐药株的产生测定金葡球菌与肺炎链球菌对莫西沙星的耐药性。结果:由于莫西沙星对试验菌株与大鼠肉芽肿袋中分离菌的MIC相同,所以敏感性无显著变化。两种感染病原体A组与B组的试验结果相同,A组治疗1d后肺炎链球菌减少约107CFU·mL-1,A组治疗1d后金葡球菌的减少数量较慢,3d后减少数量明显。 B组的肺炎链球菌与金葡球菌的生存率都迅速下降,但减少幅度差异不明显,莫西沙星对细菌生存数量的影响可持续6d,影响期间细菌没有发生再生长,莫西沙星对肺炎链球菌的杀菌能力高于对金葡球菌的杀菌能力。同时B组与C组对比,50mg·kg-1·d-1的莫西沙星杀菌速度和程度都会明显降低,但杀菌效果仍在,治疗1d后细菌可降低103CFU·mL-1,效果持续4d,但50mg·kg-1·d-1的莫西沙星、感染后24h治疗对多代耐药株的疗效几乎为零。结论:即使人体内莫西沙星的浓度低于预期的治疗浓度,也对金葡球菌与肺炎链球菌的野生株与第一代耐药株具有良好的杀菌效果。%Objective: Staphylococcus auras and Streptococcus pneumatic in the tamoxifen resistance in vino. Methods: Rats bags granular, wild strains were selected and in vino, as well as the first generation of drug-resistant strains of drug-resistant strains of many generations after using different strains of rats infected produce granules bags into A, B, C3 groups, with different doses of tamoxifen therapy usage, gather daily granular pouch exude was measured Staphylococcus auras and Streptococcus

  2. Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials.

    Science.gov (United States)

    Saha, Poornima; Regan, Meredith M; Pagani, Olivia; Francis, Prudence A; Walley, Barbara A; Ribi, Karin; Bernhard, Jürg; Luo, Weixiu; Gómez, Henry L; Burstein, Harold J; Parmar, Vani; Torres, Roberto; Stewart, Josephine; Bellet, Meritxell; Perelló, Antonia; Dane, Faysal; Moreira, Antonio; Vorobiof, Daniel; Nottage, Michelle; Price, Karen N; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D; Colleoni, Marco; Fleming, Gini F

    2017-09-20

    Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or

  3. Preparation and in vitro characterization of poly (epsilon-caprolactone-based tamoxifen citrate-loaded cylindrical subdermal implant for breast cancer

    Directory of Open Access Journals (Sweden)

    Hiremath Jagadeesh

    2011-01-01

    Full Text Available In the present study cylindrical poly(epsilon-caprolactone (PCL-based biodegradable polymeric tamoxifen citrate-loaded subdermal implants were prepared by laboratory-based modified melt extrusion technique. The prepared implants were evaluated for their physicochemical parameters. Drug content in implants by high-performance liquid chromatographic (HPLC method, differential scanning calorimetry (DSC, X-ray diffraction (XRD and scanning electron microscope (SEM studies of tamoxifen citrate-loaded implants. Determination of in vitro hydrolytic degradation of polymeric and tamoxifen citrate-loaded implants and in vitro drug release was carried out by using indigenously developed dissolution apparatus. DSC and XRD studies proved that the drug is entrapped in the implant. The highest rate of hydrolytic degradation (weight loss was observed in blank implants when compared to tamoxifen citrate-loaded implants. The studies proved that the developed method have potential in terms of industrial feasibility.

  4. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

    Directory of Open Access Journals (Sweden)

    Chun-E Ren

    2015-03-01

    Full Text Available Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies.

  5. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

    Science.gov (United States)

    Ren, Chun-E; Zhu, Xueqiong; Li, Jinping; Lyle, Christian; Dowdy, Sean; Podratz, Karl C.; Byck, David; Chen, Hai-Bin; Jiang, Shi-Wen

    2015-01-01

    Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies. PMID:25782154

  6. Alginate/chitosan microparticles for tamoxifen delivery to the lymphatic system.

    Science.gov (United States)

    Coppi, G; Iannuccelli, V

    2009-02-09

    Oral administration of the nonsteroidal anti-estrogen tamoxifen (TMX) is the treatment of choice for metastatic estrogen receptor-positive breast cancer. With the aim to improve TMX oral bioavailability and decrease its side effects, crosslinked alginate microparticles for the targeting to the lymphatic system by Peyer's patch (PP) uptake were developed and in vitro characterized. TMX was molecularly dispersed inside the microparticles and an electrostatic interaction involving the TMX tertiary amine was detected by rheological and FT-IR assays. Microparticles showed a size less than 3mum, then suitability to be taken up by M cells in PP and a positive surface charge. Moreover, TMX loading level as well as in vitro release behaviour was affected by the polymer network connected with the mannuronic/guluronic ratio of the alginate chains.

  7. Tualang Honey Promotes Apoptotic Cell Death Induced by Tamoxifen in Breast Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Nik Soriani Yaacob

    2013-01-01

    Full Text Available Tualang honey (TH is rich in flavonoids and phenolic acids and has significant anticancer activity against breast cancer cells comparable to the effect of tamoxifen (TAM, in vitro. The current study evaluated the effects of TH when used in combination with TAM on MCF-7 and MDA-MB-231 cells. We observed that TH promoted the anticancer activity of TAM in both the estrogen receptor-(ER-responsive and ER-nonresponsive human breast cancer cell lines. Flow cytometric analyses indicated accelerated apoptosis especially in MDA-MB-231 cells and with the involvement of caspase-3/7, -8 and -9 activation as shown by fluorescence microscopy. Depolarization of the mitochondrial membrane was also increased in both cell lines when TH was used in combination with TAM compared to TAM treatment alone. TH may therefore be a potential adjuvant to be used with TAM for reducing the dose of TAM, hence, reducing TAM-induced adverse effects.

  8. Differences in Metabolite-mediated Toxicity of Tamoxifen in Rodents vs. Humans Elucidated with DNA/microsomes Electro-optical Arrays and Nanoreactors

    OpenAIRE

    2009-01-01

    Tamoxifen, a therapeutic and chemopreventive breast cancer drug, was chosen as a model compound because of acknowledged species specific toxicity differences. Emerging approaches utilizing electro-optical arrays and nanoreactors based on DNA/microsomes films were used to compare metabolite-mediated toxicity differences of tamoxifen in rodents vs. humans. “Hits” triggered by liver enzyme metabolism were first provided by arrays utilizing a DNA damage endpoint. The arrays feature thin-film spot...

  9. Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Patel, Shilpen, E-mail: Shilpenp@uw.edu [Department of Radiation Oncology, University of Washington, Seattle, WA (United States); DiBiase, Steven [Robert Wood Johnson School of Medicine, Camden, NJ (United States); Meisenberg, Barry [DeCesaris Cancer Institute, Annapolis, MD (United States); Flannery, Todd [Princeton Radiation Oncology, Princeton, NJ (United States); Patel, Ashish [Division of Radiation Oncology, Abington Memorial Hospital, Abington, PA (United States); Dhople, Anil [MIMA Cancer Center, Melbourne, FL (Australia); Cheston, Sally; Amin, Pradip [Department of Radiation Oncology, University of Maryland, Baltimore, MD (United States)

    2012-02-01

    Purpose: The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas. Methods and Materials: A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were given tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status {>=}60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m{sup 2} divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m{sup 2} increments until the MTD was reached. When {>=}2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m{sup 2}. A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered. Results: A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m{sup 2}. One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m{sup 2}. Conclusions: The MTD of tamoxifen was 100 mg/m{sup 2} when given concurrently with temozolomide 75 mg/m{sup 2} and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.

  10. Difference in extractability of estradiol- and tamoxifen-receptor complex in the nuclei from MCF-7 cells with Nonidet P-40.

    Science.gov (United States)

    Ikeda, M; Omukai, Y; Hosokawa, K; Senoo, T

    1984-05-01

    The extraction of [3H]estradiol- and [3H]tamoxifen-receptor complex in the nuclei from MCF-7 cells with the nonionic detergent Nonidet P-40 has been studied. We found that there is a striking difference in the extractability of estradiol- and tamoxifen-receptor complex from nuclei with 0.5% Nonidet P-40. The nuclear bound estradiol-receptor complex is scarcely extractable with Nonidet P-40. In contrast, almost all of the nuclear bound tamoxifen-receptor complex is extractable. The nuclear [3H]tamoxifen-receptor complex extracted in the presence of Nonidet P-40 sediments in two peaks at 7 S and 5 S. The latter sedimentation rate is the same with that of the nuclear [3H]tamoxifen-receptor complex extracted with 0.4 M KCl. The nuclear [3H]estradiol-receptor complex extracted with 0.4 M KCl sediments at 4 S. The results suggest that interaction of tamoxifen-receptor complex with chromatin is different from that of estradiol-receptor complex.

  11. FDG-PET in monitoring therapy of breast cancer

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    Biersack, H.J.; Bender, H.; Palmedo, H. [Department of Nuclear Medicine, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn (Germany)

    2004-06-01

    Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been used successfully for the staging and re-staging of breast cancer. Another significant indication is the evaluation of therapy response. Only limited data are available on the use of FDG-PET in breast cancer after radiation therapy. The same holds true for chemotherapy. Only the therapy response in locally advanced breast cancer after chemotherapy has been investigated thoroughly. Histopathological response could be predicted with an accuracy of 88-91% after the first and second courses of therapy. A quantitative evaluation is, of course, a prerequisite when FDG-PET is used for therapy monitoring. Only a small number of studies have focussed on hormone therapy. In this context, a flare phenomenon with increasing standardised uptake values after initiation of tamoxifen therapy has been observed. More prospective multicentre trials will be needed to make FDG-PET a powerful tool in monitoring chemotherapy in breast cancer. (orig.)

  12. Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

    Science.gov (United States)

    García-Becerra, Rocío; Santos, Nancy; Díaz, Lorenza; Camacho, Javier

    2013-01-01

    Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID:23344024

  13. Tailoring adjuvant endocrine therapy for postmenopausal breast cancer: a CYP2D6 multiple-genotype-based modeling analysis and validation.

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    Ke-Da Yu

    Full Text Available PURPOSE: Previous studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs. The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6. METHODS: We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS for extensive metabolizer (EM patients using annual hazard ratio (HR data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM and its frequency on survival by studying a range of estimates. RESULTS: The 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%. In the validation study, we further demonstrated that the 9-year EFS of tamoxifen-treated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4% and similar to that of patients receiving an AI (83.2%. Two-way sensitivity analyses demonstrated the robustness of the results. CONCLUSIONS: Our modeling analyses indicate that, among EM patients, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to evaluate the value of the CYP2D6 genotype in the selection of endocrine therapy.

  14. Reversed phase HPLC determination of tamoxifen in dog plasma and its pharmaco-kinetics after a single oral dose administration

    Directory of Open Access Journals (Sweden)

    Davi Pereira de Santana

    2008-01-01

    Full Text Available The analytical method developed to evaluate tamoxifen in dog plasma samples was precise, accurate, robust and linear in the range of 5-200 ng/mL. The limits of detection and quantification were 0.981 ng/mL and 2.97 ng/mL, respectively. Besides, the intra-day precision and accuracy variations were 8.78 and 10.16%, respectively. Tamoxifen concentrations were analyzed by combined reversed phase liquid chromatography and UV detection (lambda=280 nm. The study was conducted using an open randomized 2-period crossover balanced design with a 1-week washout period between the doses. This simple, rapid and selective method is suitable for pharmacokinetic, bioavailability and bioequivalence studies.

  15. Palladium-catalyzed arylation of ketone enolates: an expeditious entry to tamoxifen-related 1,2,2-triarylethanones.

    Science.gov (United States)

    Churruca, Fátima; SanMartin, Raul; Tellitu, Imanol; Domínguez, Esther

    2002-05-02

    [reaction: see text]. After a rigorous study on the effect of several catalytic systems, a simple, high yielding procedure for the preparation of 1,2,2-triarylethanones, skeletal analogues of tamoxifen, is presented. Apart from the economic and environmental advantages involved, this palladium-catalyzed arylation of deoxybenzoin enolates features a lack of ortho-arylation side reactions. In addition, an alternative approach from acetophenones to the target triarylethanone system is also announced.

  16. Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide.

    Science.gov (United States)

    Johansson, Harriet; Bonanni, Bernardo; Gandini, Sara; Guerrieri-Gonzaga, Aliana; Cazzaniga, Massimiliano; Serrano, Davide; Macis, Debora; Puccio, Antonella; Sandri, Maria Teresa; Gulisano, Marcella; Formelli, Franca; Decensi, Andrea

    2013-12-01

    Tamoxifen and fenretinide have been extensively studied and exhibit breast cancer-preventing activity. We aimed to assess their effect on sex hormones, sex hormone binding globulin (SHBG) and retinol, and their association with mammographic density (MD) and breast cancer events. In a double-blind, placebo-controlled trial, premenopausal women at risk for breast cancer were randomized to tamoxifen 5 mg/day, fenretinide, both agents, or placebo for 2 years. We measured MD and circulating concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, testosterone, androstenedione, dehydro-epiandrosteronesulfate, prolactin, SHBG, and retinol at baseline and on yearly intervals. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models. Low-dose tamoxifen markedly and enduringly increased SHBG, whereas the increases in testosterone, estradiol, and prolactin and reduction in LH weakened after 1 year. Fenretinide increased testosterone and androstenedione and decreased retinol. MD correlated directly with SHBG and inversely with retinol. After a median follow-up of 12 years, the 10-year cumulative incidence of breast cancer events was 37 % in women with SHBG ≤ 59.3 nmol/L, 22 % in women with SHBG between 59.3 and 101 nmol/L, and 19 % in women with SHBG > 101 nmol/L (P = 0.018). The difference among SHBG tertiles remained statistically significant at multivariable analysis: HR = 2.26 (95 % CI 1.04, 4.89) for the lowest versus the highest tertile. We conclude that low-dose tamoxifen or fenretinide exhibits favorable hormonal profiles as single agents, further supporting their administration for prevention of breast cancer in premenopause. Notably, SHBG levels were inversely associated with breast neoplastic events.

  17. Effect of tamoxifen on cytosolic estrogen receptor in the different parts of fallopian tube and uterus during ovum transport.

    Science.gov (United States)

    Gupta, J S; Roy, S K

    1987-12-01

    The effect of tamoxifen (ICI-46474) (alpha-[4-(beta-N-dimethylamino ethoxy)-phenyl]alpha'-ethyl trans stilbene on estrogen cytosolic receptor was observed in different parts of fallopian tube and uterus of rabbits during ovum transport. Tubal segments viz. ampulla (A), ampullary isthmic junction (AIJ), isthmus (I), uterine isthmic junction (UIJ) and uterus (U) were studied during the passage of ovum. Significant differences were observed in normal, drug treated and pregnant animals at 14, 24, 34, 48, 72, 144 and 168 h. In treated animals during 14 h post-coitum (p.c.) to 34 h p.c. the ampullary cytosol receptor concentration increased and suddenly decreased at 48 h p.c. whereas from 72 h p.c. to 144 h p.c. it increased gradually. Tamoxifen accelerated the rate of egg transport decreasing tubal cytosolic receptors at 48 h p.c. However, beyond 48 h p.c. receptors increased till 144 h p.c. Results suggest that tamoxifen modulated tubal cytosolic estrogen receptors during egg transport and prevents pregnancy.

  18. Effects of tamoxifen on the sex determination gene and the activation of sex reversal in the developing gonad of mice.

    Science.gov (United States)

    Yu, Mingxi; Wang, Jingyun; Liu, Wei; Qin, Junwen; Zhou, Quan; Wang, Yongan; Huang, Huihui; Chen, Wenli; Ma, Chao

    2014-07-03

    Tamoxifen, as well as most endocrine-disrupting chemicals, affects the reproductive system and sexual development, but little is known about its disruption of the molecular pathways regulating mammalian sex determination. In fetal mice, the expression levels and pattern of key genes involved in controlling sexually dimorphic balance were analyzed both in vivo and in vitro by using whole-mount in situ hybridization and quantitative-PCR. Developmental tamoxifen exposure induced abnormal up-regulation of the testis differentiation marker Pdfgra in Leydig cells and of Sox9 and Fgf9 in Sertoli cells in XX gonad. Immunohistochemistry analysis confirmed the over-expression of SOX9 protein. Accordingly, the ovary development marker Foxl2 was depressed at both the mRNA and protein levels. The increase in testosterone and the reduction in 17β-estradiol and progesterone were observed by using the in vitro assay with organotypic cultures. Taken together, results indicated that tamoxifen induced the ectopic expression of well-established sex-specific genes during the critical developmental period, thus resulting in abnormal testicular development in the XX gonad of mammals. This study facilitates a better understanding of the molecular mechanisms of antiestrogens and possibly of compounds that interrupt estrogen signaling by other modes of action, and the association with the pathogenesis of human sexual developmental disorders.

  19. Down-regulating causes of fibrosis with tamoxifen: a possible cellular/molecular approach to treat rhinophyma.

    Science.gov (United States)

    Payne, Wyatt G; Ko, Francis; Anspaugh, Stephanie; Wheeler, Chad K; Wright, Terry E; Robson, Martin C

    2006-03-01

    Fibrosis and proliferative scarring are prominent features of the severe forms of rhinophyma. Up-regulation of growth and fibroblast kinetics are hallmarks of fibrosis. Persistent overexpression or dysregulated activation of the fibrogenic isoforms of transforming growth factor beta (TGF-beta) is associated with the increased fibroblast function leading to fibrotic conditions such as rhinophyma. Tamoxifen, a synthetic nonsteroidal antiestrogen, can neutralize or down-regulate TGF-beta. Fibroblast-populated collagen lattices (FPCLs) were constructed from fibroblasts cultured from rhinophyma or normal nasal skin. One-half of each set of FPCLs was treated with Tamoxifen. Lattice contraction was serially measured over 5 days, and the supernatants of the cultures were analyzed for TGF-beta-2 by immunoassay. Tamoxifen significantly decreased fibroblast activity by decreasing contraction of the treated lattices (P < 0.05) and significantly decreased the production/secretion of TGF-beta-2 by rhinophyma fibroblasts (P < 0.001). These results suggest a possible new cellular/molecular approach to the treatment of the fibrotic varieties of rhinophyma.

  20. High-dosage tamoxifen as neoadjuvant treatment in minimally invasive surgery for Dupuytren disease in patients with a strong predisposition toward fibrosis: a randomized controlled trial.

    Science.gov (United States)

    Degreef, Ilse; Tejpar, Sabine; Sciot, Raf; De Smet, Luc

    2014-04-16

    Tamoxifen, a synthetic nonsteroidal anti-estrogen known to modulate the production of transforming growth factor-beta (TGF-β), has demonstrated effectiveness on fibroblast activity in vitro and in vivo. The main purpose of this study was to investigate the effect of tamoxifen on the outcome of surgery for Dupuytren contractures in patients with a strong predisposition toward fibrosis. We used a prospective, randomized, double-blind study protocol (conforming to the CONSORT standards) to investigate the influence of tamoxifen compared with placebo on the total passive extension deficit in the finger and patient satisfaction after subtotal fasciectomy in thirty patients with a strong predisposition toward fibrosis (grade, >4 according to the Abe scale). High-dosage tamoxifen (80 mg/day) was administered from six weeks prior until twelve weeks after surgery, and patients were monitored for two years. Three months after surgery, patients in the tamoxifen group had a smaller total passive extension deficit and higher satisfaction compared with the placebo group. This positive effect was lost over the two years following cessation of the medication. This study demonstrated that the short-term outcome of Dupuytren disease treatment could be influenced by use of tamoxifen as a neoadjuvant from six weeks prior to three months after subtotal fasciectomy in patients with a strong predisposition toward fibrosis. However, the beneficial effect disappeared within two years after surgery, with worsening of the contractures after the medication was discontinued. Thus, tamoxifen may have a short-term effect on the outcome of surgery for Dupuytren disease.

  1. Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance

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    Nagireddy Putluri

    2014-05-01

    Full Text Available Breast cancer (BCa molecular subtypes include luminal A, luminal B, normal-like, HER-2–enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2 alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa.

  2. Pathway-centric integrative analysis identifies RRM2 as a prognostic marker in breast cancer associated with poor survival and tamoxifen resistance.

    Science.gov (United States)

    Putluri, Nagireddy; Maity, Suman; Kommagani, Ramakrishna; Kommangani, Ramakrishna; Creighton, Chad J; Putluri, Vasanta; Chen, Fengju; Nanda, Sarmishta; Bhowmik, Salil Kumar; Terunuma, Atsushi; Dorsey, Tiffany; Nardone, Agostina; Fu, Xiaoyong; Shaw, Chad; Sarkar, Tapasree Roy; Schiff, Rachel; Lydon, John P; O'Malley, Bert W; Ambs, Stefan; Das, Gokul M; Michailidis, George; Sreekumar, Arun

    2014-05-01

    Breast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2-enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2) alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa. Copyright © 2014 Neoplasia Press, Inc. All rights reserved.

  3. Late tamoxifen in patients previously operated for breast cancer without postoperative tamoxifen: 5-year results of a single institution randomised study

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    Bidoli Ettore

    2010-05-01

    Full Text Available Abstract Background A population of breast cancer patients exists who, for various reasons, never received adjuvant post-operative tamoxifen (TAM. This study was aimed to evaluate the role of late TAM in these patients. Methods From 1997 to 2003, patients aged 35 to 75 years, operated more than 2 years previously for monolateral breast cancer without adjuvant TAM, with no signs of metastases and no contraindication to TAM were randomized to TAM 20 mg/day orally for 2 years or follow-up alone. Events were categorized as locoregional relapse, distant metastases, metachronous breast cancer, tumours other than breast cancer and death from any causes, whichever occurred first. The sample size (197 patients per arm, plus 10% allowance was based on the assumption of a 30% decrease in the number of events occurring at a rate of 5% annually in the 10 years following randomization. Four hundred and thirty-three patients were randomized in the study (TAM 217, follow-up 216. Patients characteristics (TAM/follow-up included: median age 55/55 years, median time from surgery 25/25 months (range, 25-288/25-294, in situ carcinoma 18/24, oestrogen receptor (ER positive in 75/68, negative in 70/57, unknown in 72/91 patients. Previous adjuvant treatment included chemotherapy in 131/120 and an LHRH analogue in 11/13 patients. Results Thirty-six patients prematurely discontinued TAM after a median of 1 month, mostly because of subjective intolerance. Eighty-three events (TAM 39, follow-up 44 occurred: locoregional relapse in 10/8, distant metastases in 14/16, metachronous breast cancer in 4/10, other tumours in 11/10 patients. Less ER-positive secondary breast cancers occurred in the TAM treated patients than in follow-up patients (1 vs 10, p = 0.005. Event-free survival was similar in both groups of patients. Conclusions This 5-year analysis revealed significantly less metachronous ER-positive breast cancers in the TAM treated patients. No other statistically

  4. Clinical relevance of "withdrawal therapy" as a form of hormonal manipulation for breast cancer

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    Robertson John FR

    2011-09-01

    Full Text Available Abstract Background It has been shown in in-vitro experiments that "withdrawal" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of "withdrawal therapy". Methods Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1 estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years, locally advanced or metastatic breast cancer; (2 disease deemed suitable for treatment by hormonal manipulation; (3 disease assessable by UICC criteria; (4 received "withdrawal" from a prior endocrine agent as a form of therapy; (5 on "withdrawal therapy" for ≥ 6 months unless they progressed prior. Results Seventeen patients with median age of 84.3 (53.7-92.5 had "withdrawal therapy" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10, an aromatase inhibitor (n = 5, megestrol acetate (n = 1 or fulvestrant (n = 1. Ten patients (58.8% had clinical benefit (CB (complete response/partial response/stable disease ≥ 6 months with a median duration of Clinical Benefit (DoCB of 10+ (7-27 months. Two patients remain on "withdrawal therapy" at the time of analysis. Conclusion "Withdrawal therapy" appears to produce sustained CB in a significant proportion of patients. This applies not only to "withdrawal" from tamoxifen, but also from other categories of endocrine agents. "Withdrawal" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy.

  5. Augmenting Trastuzumab Therapy against Breast Cancer through Selective Activation of NK Cells

    Science.gov (United States)

    2014-12-01

    illustrated by the protection from re-challenge(44). Recently, Bellati et al. detailed the importance of the adaptive immune response to trastuzumab therapy...Shepard, H.M., and Osborne, C.K. 1992. Estrogen -dependent, tamoxifen- resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu...Meeting Abstracts 114:2706. 40. Jiang, D., and Schwarz, H. 2010. Regulation of granulocyte and macrophage populations of murine bone marrow cells by G

  6. Tamoxifen-loaded poly(L-lactide) nanoparticles: Development, characterization and in vitro evaluation of cytotoxicity.

    Science.gov (United States)

    Altmeyer, Clescila; Karam, Thaysa Ksiaskiewcz; Khalil, Najeh Maissar; Mainardes, Rubiana Mara

    2016-03-01

    In this study, poly(L-lactide) (PLA) nanoparticles containing Tamoxifen (Tmx) were developed using an emulsion/solvent evaporation method, observing the influence of surfactants and their concentrations on mean particle size and drug entrapment. Nanoparticles were characterized in terms of size, morphology, polydispersity, interaction drug-polymer and in vitro drug release profile. Cytotoxicity over erythrocytes and tumor cells was assessed. The optimized formulation employed as surfactant 1% polyvinyl alcohol. Mean particle size was 155±4 nm (n=3) and Tmx encapsulation efficiency was 85±8% (n=3). The in vitro release profile revealed a biphasic release pattern diffusion-controlled with approximately 24% of drug released in 24 h followed by a sustained release up to 120 h (30% of Tmx released). PLA nanoparticles containing Tmx presented a very low index of hemolysis (less than 10%), in contrast to free Tmx that was significantly hemolytic. Tmx-loaded PLA nanoparticles showed IC50 value 2-fold higher than free Tmx, but considering the prolonged Tmx release from nanoparticles, cytotoxicity on tumor cells was maintained after nanoencapsulation. Thus, PLA nanoparticles are promising carriers for controlled delivery of Tmx with potential application in cancer treatment.

  7. Optimized axolotl (Ambystoma mexicanum) husbandry, breeding, metamorphosis, transgenesis and tamoxifen-mediated recombination.

    Science.gov (United States)

    Khattak, Shahryar; Murawala, Prayag; Andreas, Heino; Kappert, Verena; Schuez, Maritta; Sandoval-Guzmán, Tatiana; Crawford, Karen; Tanaka, Elly M

    2014-03-01

    The axolotl (Mexican salamander, Ambystoma mexicanum) has become a very useful model organism for studying limb and spinal cord regeneration because of its high regenerative capacity. Here we present a protocol for successfully mating and breeding axolotls in the laboratory throughout the year, for metamorphosing axolotls by a single i.p. injection and for axolotl transgenesis using I-SceI meganuclease and the mini Tol2 transposon system. Tol2-mediated transgenesis provides different features and advantages compared with I-SceI-mediated transgenesis, and it can result in more than 30% of animals expressing the transgene throughout their bodies so that they can be directly used for experimentation. By using Tol2-mediated transgenesis, experiments can be performed within weeks (e.g., 5-6 weeks for obtaining 2-3-cm-long larvae) without the need to establish germline transgenic lines (which take 12-18 months). In addition, we describe here tamoxifen-induced Cre-mediated recombination in transgenic axolotls.

  8. Interactions of tamoxifen with distearoyl phosphatidylcholine multilamellar vesicles: FTIR and DSC studies.

    Science.gov (United States)

    Bilge, Duygu; Sahin, Ipek; Kazanci, Nadide; Severcan, Feride

    2014-09-15

    Interactions of a non-steroidal antiestrogen drug, tamoxifen (TAM), with distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) multilamellar liposomes (MLVs) were investigated as a function of drug concentration (1-15 mol%) by using two noninvasive techniques, namely Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR spectroscopy results show that increasing TAM concentrations (except 1 mol%) increased the wavenumbers of the CH2 stretching modes, implying an disordering effect for DSPC MLVs both in the gel and liquid crystalline phases. The bandwidth values of the CH2 stretchings except for 1 mol% increased when TAM concentrations increased for DSPC liposomes, indicating an increase in the dynamics of liposomes. The CO stretching and PO2- antisymmetric double bond stretching bands were analyzed to study interactions of TAM with head groups of lipids. As the concentrations of TAM increased, dehydration occurred around these functional groups in the polar part of the lipids. The DSC studies on thermal properties of DSPC lipids indicate that TAM eliminated the pre transition, shifted the main phase transition to lower temperatures and broadened the phase transition curve of the liposomes.

  9. Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

    1988-01-01

    We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17..beta..-estradiol (E/sub 2/) at both low (0.1 ..mu..g/kg) and high (20 ..mu..g/kg) doses confirmed its ability to increase the number of striatal /sup 3/H-Spiperone (/sup 3/H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E/sub 2/, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity.

  10. Liver hyperplasia after tamoxifen induction of Myc in a transgenic medaka model

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    Luciana A. Menescal

    2012-07-01

    Myc is a global transcriptional regulator and one of the most frequently overexpressed oncoproteins in human tumors. It is well established that activation of Myc leads to enhanced cell proliferation but can also lead to increased apoptosis. The use of animal models expressing deregulated levels of Myc has helped to both elucidate its function in normal cells and give insight into how Myc initiates and maintains tumorigenesis. Analyses of the medaka (Oryzias latipes genome uncovered the unexpected presence of two Myc gene copies in this teleost species. Comparison of these Myc versions to other vertebrate species revealed that one gene, myc17, differs by the loss of some conserved regulatory protein motifs present in all other known Myc genes. To investigate how such differences might affect the basic biological functions of Myc, we generated a tamoxifen-inducible in vivo model utilizing a natural, fish-specific Myc gene. Using this model we show that, when activated, Myc17 leads to increased proliferation and to apoptosis in a dose-dependent manner, similar to human Myc. We have also shown that long-term Myc17 activation triggers liver hyperplasia in adult fish, allowing this newly established transgenic medaka model to be used to study the transition from hyperplasia to liver cancer and to identify Myc-induced tumorigenesis modifiers.

  11. Phthalates inhibit tamoxifen-induced apoptosis in MCF-7 human breast cancer cells.

    Science.gov (United States)

    Kim, In Young; Han, Soon Young; Moon, Aree

    2004-12-01

    Environmental estrogens represent a class of compounds that can mimic the function or activity of the endogenous estrogen 17 -estradiol (E2). Phthalates including butyl benzyl phthalate (BBP), di(n-butyl) phthalate (DBP), and di(2-ethylhexyl) phthalate (DEHP) are used as plasticizers, and also widely used in food wraps and cosmetic formulations. Phthalates have been shown to mimic estrogen and are capable of binding to the estrogen receptor (ER). It has been demonstrated that estrogen promotes drug resistance to tamoxifen (TAM) in breast cancer. In order to further evaluate the potential role of the phthalates as environmental estrogens, the effect of phthalates was investigated on TAM-induced apoptosis in MCF-7 human breast cancer cells. Our results show that phthalates, BBP (100 M), DBP (10 M), and DEHP (10 M), significantly increased cell proliferation in MCF-7, but not in MDA-MB-231 cells. In addition, BBP, DBP, and DEHP mimicked estrogen in the inhibition of TAM-induced apoptosis in MCF-7 cells. Our data suggest that the inhibitory effect of phthalates on TAM-induced apoptosis involves an increase in intracellular Bcl-2 to Bax ratio. Given that the phthalates are widely used in cosmetics mainly for women, our findings that revealed the promoting effect of BBP, DBP, and DEHP on chemotherapeutic drug resistance to TAM in breast cancer may be of biological relevance.

  12. Analysis of interaction between tamoxifen and ctDNA in vitro by multi-spectroscopic methods

    Science.gov (United States)

    Cai, Changqun; Chen, Xiaoming; Ge, Fei

    2010-07-01

    Multi-spectroscopic methods including resonance light scattering (RLS), ultraviolet spectra (UV), fluorescence spectra, 1H NMR spectroscopy, coupled with thermo-denaturation experiments were firstly used to study the interaction of antitumor drug tamoxifen (TMX) with calf thymus (ctDNA) in acetate buffer solutions (pH 4.55). The interaction of TMX with ctDNA could cause a significant enhancement of RLS intensity, the hyperchromic effect, red shift of absorption spectra and the fluorescence quenching of TMX, indicating that there is an inserting interaction between TMX and ctDNA. This inference was confirmed by 1H NMR spectroscopy. The chemical shift of the benzene proton changes significantly which indicates that TMX could insert into the base pairs of ctDNA. These studies are valuable for a better understanding the mode of TMX-ctDNA interaction further, which are important and useful for designing of new ctDNA targeted drug. And the antitumor drug TMX inserted directly into ctDNA in vitro, which can provide a lot of useful information to explore the development of new and highly effective anti-cancer drugs.

  13. Tamoxifen as an emerging endocrine disruptor. effects on fish reproduction and detoxification target genes.

    Science.gov (United States)

    Maradonna, Francesca; Batti, Stefania; Marino, Maria; Mita, Damiano Gustavo; Carnevali, Oliana

    2009-04-01

    The effect of tamoxifen (TAM) on the black goby Gobius niger exposed to different contaminants was analyzed by investigating the response of a set of biomarkers involved in reproduction and cell recovery. While the effects of TAM are well known in mammalian breast and endometrial cells (with severe consequences on physiology), few contrasting data are available for fish. In this work the expression of vitellogenin (vtg), estrogen receptor alpha (ERalpha), cytochrome P4501A1 (CYP1A1), and heat shock protein 70 (HSP70) genes was evaluated in fish treated with TAM alone or co-injected with nonylphenol, estradiol, and beta-naphtoflavone. The induction of vtg observed in male fish treated with estrogens was significantly lowered by the co-injection of TAM. ERalpha and HSP70 gene expressions were significantly upregulated in all experimental groups; however, TAM treatment did not change CYP1A1 gene expression. Together these data confirm the mixed estrogenic/anti-estrogenic action of TAM, indicating its interference in fish reproduction and physiology.

  14. PKA phosphorylation redirects ERα to promoters of a unique gene set to induce tamoxifen resistance.

    Science.gov (United States)

    de Leeuw, R; Flach, K; Bentin Toaldo, C; Alexi, X; Canisius, S; Neefjes, J; Michalides, R; Zwart, W

    2013-07-25

    Protein kinase A (PKA)-induced estrogen receptor alpha (ERα) phosphorylation at serine residue 305 (ERαS305-P) can induce tamoxifen (TAM) resistance in breast cancer. How this phospho-modification affects ERα specificity and translates into TAM resistance is unclear. Here, we show that S305-P modification of ERα reprograms the receptor, redirecting it to new transcriptional start sites, thus modulating the transcriptome. By altering the chromatin-binding pattern, Ser305 phosphorylation of ERα translates into a 26-gene expression classifier that identifies breast cancer patients with a poor disease outcome after TAM treatment. MYC-target genes and networks were significantly enriched in this gene classifier that includes a number of selective targets for ERαS305-P. The enhanced expression of MYC increased cell proliferation in the presence of TAM. We demonstrate that activation of the PKA signaling pathway alters the transcriptome by redirecting ERα to new transcriptional start sites, resulting in altered transcription and TAM resistance.

  15. In vitro effects of tamoxifen on adipose-derived stem cells.

    Science.gov (United States)

    Pike, Steven; Zhang, Ping; Wei, Zhengyu; Wu, Nan; Klinger, Aaron; Chang, Shaohua; Jones, Robert; Carpenter, Jeffrey; Brown, Spencer A; DiMuzio, Paul; Tulenko, Thomas; Liu, Yuan

    2015-09-01

    In breast reconstructive procedures, adipose-derived stem cells (ASCs) that are present in clinical fat grafting isolates are considered to play the main role in improving wound healing. In patients following chemotherapy for breast cancer, poor soft tissue wound healing is a major problem. However, it is unclear if tamoxifen (TAM) as the most widely used hormonal therapeutic agent for breast cancer treatment, affects the ASCs and ultimately wound healing. This study evaluated whether TAM exposure to in vitro human ASCs modulate cellular functions. Human ASCs were isolated and treated with TAM at various concentrations. The effects of TAM on cell cycle, cell viability and proliferation rates of ASCs were examined by growth curves, MTT assay and BrdU incorporation, respectively. Annexin V and JC-1 Mitochondrial Membrane Potential assays were used to analyze ASC apoptosis rates. ASCs were cultured in derivative-specific differentiation media with or without TAM (5 uM) for 3 weeks. Adipogenic and osteogenic differentiation levels were measured by quantitative RT-PCR and histological staining. TAM has cytotoxic effects on human ASCs through apoptosis and inhibition of proliferation in dose- and time-dependent manners. TAM treatment significantly down-regulates the capacity of ASCs for adipogenic and osteogenic differentiation (ptissue wound healing and decreased fat graft survival in cancer patients receiving TAM. © 2015 by the Wound Healing Society.

  16. The Effect and Mechanism of Tamoxifen-Induced Hepatocyte Steatosis in Vitro

    Directory of Open Access Journals (Sweden)

    Fei Zhao

    2014-03-01

    Full Text Available The aim of this study was to determine the effect and mechanism of tamoxifen (TAM-induced steatosis in vitro. HepG 2 (Human hepatocellular liver carcinoma cell line cells were treated with different concentrations of TAM for 72 h. Steatosis of hepatocytes was determined after Oil Red O staining and measurement of triglyceride (TG concentration. The expressions of genes in the TG homeostasis pathway, including sterol regulatory element-binding protein-1c (SREBP-1c, peroxisome proliferator-activated receptor γ (PPARγ, CCAAT/enhancer-binding protein α (C/EBPα, fatty acid synthase (FAS, acetyl-CoA carboxylase (ACC, stearoyl-CoA desaturase (SCD, carnitine palmitoyltransferase 1 (CPT1 and microsomal triglyceride transfer protein (MTP, were examined using quantitative real-time PCR and Western blot analysis. Cell proliferation was examined using the cell counting kit-8 (CCK-8 assay. We found that hepatocytes treated with TAM had: (1 induced hepatocyte steatosis and increased hepatocyte TG; (2 upregulation of SREBP-1c, FAS, ACC, SCD and MTP mRNA expressions (300%, 600%, 70%, 130% and 160%, respectively; (3 corresponding upregulation of protein expression; and (4 no difference in HepG 2 cell proliferation. Our results suggest that TAM can induce hepatocyte steatosis in vitro and that the enhancement of fatty acid synthesis through the upregulations of SREBP-1c and its downstream target genes (FAS, ACC and SCD may be the key mechanism of TAM-induced hepatocyte steatosis.

  17. Effect of tamoxifen in RAFT miniemulsion polymerization during the synthesis of polymer nanoparticles

    Directory of Open Access Journals (Sweden)

    Tailane Sant'Anna Moreira

    2014-01-01

    Full Text Available Tamoxifen (TXF is currently the only hormonal agent used for treatment of breast cancer. Although very effective, TXF presents low solubility in water, which affects its absorption and bioavailability. A common strategy to overcome this barrier is the formulation of a drug delivery system (DDS in order to increase the drug stability and improve the treatment effectiveness. Reversible addition-fragmentation chain transfer (RAFT polymerization is the most versatile method of controlled/living radical polymerization (CLRP, allowing for synthesis of well-defined polymers and being adapted to a wide range of polymerization systems. Miniemulsion polymerization is a dispersed system that is commonly used to prepare nanoparticles (NP with 50 to 500 nm of diameter. The aim of this work was to evaluate the effect of the in situ incorporation of TXF during miniemulsion conventional and RAFT polymerizations, using methyl methacrylate (MMA as monomer. Although the in situ addition of TXF promoted a slight reduction of the reaction rate, it did not affect the final particle size distribution of the latex or the molecular weight control exerted by the RAFT agent. The obtained results suggest that in situ incorporation of TXF during the synthesis of polymer NP via RAFT polymerization allows for production of a polymer DDS for different uses, such as the breast cancer treatment.

  18. Self-Assembling RADA16-I Peptide Hydrogel Scaffold Loaded with Tamoxifen for Breast Reconstruction

    Directory of Open Access Journals (Sweden)

    Huimin Wu

    2017-01-01

    Full Text Available More and more breast cancer patients prefer autologous fat tissue transfer following lumpectomy to maintain perfect female characteristics. However, the outcome was not satisfactory due to the transplanted fat absorption. In this study, we prepared two RADA16-I peptide scaffolds with and without tamoxifen. Both scaffolds were transparent, porous, and hemisphere-shaped. The hADSCs isolated from liposuction were attached to the scaffold. The growth inhibition of the hADSCs induced by TAM in 2-demensional (2D culture was higher than that in TAM-loaded hydrogel scaffold 3D culture (P<0.05; however, the same outcomes were not observed in MCF-7 cells. Correspondingly, the apoptosis of the hADSCs induced by TAM was significantly increased in 2D culture compared to that in scaffold 3D culture (P<0.05. Yet the outcomes of the aoptosis in MCF-7 were contrary. Apoptosis-related protein Bcl-2 was involved in the process. In vivo experiments showed that both scaffolds formed a round mass after subcutaneous implantation and it retained its shape after being pressed slightly. The implantation had no effect on the weight and activity of the animals. The results suggested that TAM-loaded RADA16-I hydrogel scaffolds both provide support for hADSCs cells attachment/proliferation and retain cytotoxic effect on MCF-7 cells, which might be a promising therapeutic breast tissue following lumpectomy.

  19. Importance of highly selective LC-MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen.

    Science.gov (United States)

    Jager, N G L; Rosing, H; Linn, S C; Schellens, J H M; Beijnen, J H

    2012-06-01

    The antiestrogenic effect of tamoxifen is mainly attributable to the active metabolites endoxifen and 4-hydroxytamoxifen. This effect is assumed to be concentration-dependent and therefore quantitative analysis of tamoxifen and metabolites for clinical studies and therapeutic drug monitoring is increasing. We investigated the large discrepancies in reported mean endoxifen and 4-hydroxytamoxifen concentrations. Two published LC-MS/MS methods are used to analyse a set of 75 serum samples from patients treated with tamoxifen. The method from Teunissen et al. (J Chrom B, 879:1677-1685, 2011) separates endoxifen and 4-hydroxytamoxifen from other tamoxifen metabolites with similar masses and fragmentation patterns. The second method, published by Gjerde et al. (J Chrom A, 1082:6-14, 2005) however lacks selectivity, resulting in a factor 2-3 overestimation of the endoxifen and 4-hydroxytamoxifen levels, respectively. We emphasize the use of highly selective LC-MS/MS methods for the quantification of tamoxifen and its metabolites in biological samples.

  20. Monitoring the effectiveness of antiplatelet therapy: opportunities and limitations

    Science.gov (United States)

    Sambu, Nalyaka; Curzen, Nick

    2011-01-01

    Previous clinical studies have shown heterogeneity in individual patient responses to antiplatelet therapy and high residual platelet reactivity is associated with increased risk of adverse clinical events. Monitoring response to antiplatelet therapy and tailoring treatment accordingly is currently not recommended in routine clinical practice largely due to the lack of a standardized definition of antiplatelet therapy hyporesponse and the need for a widely accepted point-of-care platelet function test that can be reliably utilized in frontline clinical practice. Recent data have shown that titrating the dose of clopidogrel in patients undergoing percutaneous coronary intervention significantly reduces the incidence of major adverse cardiovascular events and large-scale clinical trials are currently underway to investigate whether individually tailored treatment based on results of platelet function testing leads to improved clinical outcome. Furthermore, genetic testing has demonstrated a link between CYP2C19 genetic polymorphisms, altered clopidogrel metabolite concentrations and adverse clinical events. Clinical studies are currently underway to investigate the potential clinical benefit associated with genotype-guided tailoring of antiplatelet therapy. With the advent of newer, more potent antiplatelet agents and their associated increased bleeding risks, it will become imperative in the future to select the most appropriate, safe and effective drug. PMID:21366666

  1. Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties

    DEFF Research Database (Denmark)

    Lin, Xue; Li, Jian; Yin, Guangliang

    2013-01-01

    Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Tamoxifen resistance may be the result of acquisition of epigenetic regulation within breast cancer cells, such as DNA methylation, resulting in changed mRNA expression of genes pivotal...

  2. The role of captopril and losartan in prevention and regression of tamoxifen-induced resistance of breast cancer cell line MCF-7: an in vitro study.

    Science.gov (United States)

    Namazi, Soha; Rostami-Yalmeh, Javad; Sahebi, Ebrahim; Jaberipour, Mansooreh; Razmkhah, Mahboobeh; Hosseini, Ahmad

    2014-06-01

    Innate and acquired tamoxifen (TAM) resistance in estrogen receptor positive (ER+) breast cancer is an important problem in adjuvant endocrine therapy. The underlying mechanisms of TAM resistance is yet unknown. In the present study, we evaluated the role of renin-angiotensin system (RAS) in the acquisition of TAM resistance in human breast cancer cell line MCF-7, and the potential role of captopril and captopril+losartan combination in the prevention and reversion of the TAM resistant phenotype. MCF-7 cells were continuously exposed to 1 μmol/L TAM to develop TAM resistant cells (TAM-R). MTT cell viability assay was used to determine the growth response of MCF-7 and TAM-R cells, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess angiotensin I converting enzyme (ACE), angiotensin II receptor type-1 and type-2 (AGTR1 and AGTR2) mRNA expressions. Preventive and therapeutic effects of RAS blockers - captopril and losartan - were examined on MCF-7 and TAM-R cells. Based on qRT-PCR, TAM-R cells compared to MCF-7 cells, had a mean ± SD fold increase of 319.1 ± 204.1 (P = 0.002) in production of ACE mRNA level, 2211.8 ± 777.9 (P = 0.002) in AGTR1 mRNA level, and 265.9 ± 143.9 (P = 0.037) in production of AGTR2 mRNA level. The combination of either captopril or captopril+losartan with TAM led to the prevention and even reversion of TAM resistant phenotype.

  3. Effect of varying doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome: an experimental study.

    Science.gov (United States)

    Pala, Şehmus; Atilgan, Remzi; Ozkan, Zehra Sema; Kavak, Salih Burçin; Ilhan, Nevin; Akpolat, Nusret; Sapmaz, Ekrem

    2015-01-01

    To examine the effects of low-to-high doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome (OHSS) in an experimental setting. A total of 20 female Wistar albino rats, 22 days of age, were randomly divided into four groups. Follicle-stimulating hormone 10 IU was administered subcutaneously in 15 rats on 4 consecutive days, with OHSS induction on day 5 by 30 IU of human chorionic gonadotropin. Group 1 (n=5) comprised 35-day-old control rats, group 2 (n=5) 35-day-old OHSS rats, group 3 (n=5) 27-day-old OHSS rats receiving 1 mg/kg of oral tamoxifen for 7 days, group 4 (n=5) 27-day-old OHSS rats receiving 3 mg/kg of oral tamoxifen for 7 days. All rats were decapitated on day 35. Serum VEGF, endothelin 1, and ovarian follicular reserve were assessed in all rats. Kruskal-Wallis variance analysis and the Mann-Whitney U-test were used for statistical comparisons. A Bonferroni correction was performed to control the inflation of significance, with a significance level set at a P-value of less than 0.025. Despite higher serum VEGF, endothelin 1, follicular reserve, and angiogenesis and fibrosis of the corpus luteum in the OHSS group compared to controls, these differences were not significant (P>0.025, Mann-Whitney U-test). There was a significant reduction in the ovarian follicular reserve in tamoxifen groups compared to controls (Ptamoxifen (Ptamoxifen group in comparison with rats in the high-dose tamoxifen group (P0.025, Mann-Whitney U-test). Tamoxifen 1 g and 3 g resulted in a dose-dependent increase in VEGF and endothelin 1 levels, and ovarian follicle reserves were significantly reduced in our experimental model.

  4. Evaluation of CYP2D6 enzyme activity using a Dextromethorphan Breath Test in Women Receiving Adjuvant Tamoxifen

    Science.gov (United States)

    Safgren, Stephanie L.; Suman, Vera J.; Kosel, Matthew L.; Gilbert, Judith A; Buhrow, Sarah A.; Black, John L.; Northfelt, Donald W.; Modak, Anil S.; Rosen, David; Ingle, James N.; Ames, Matthew M.; Reid, Joel M.; Goetz, Matthew P.

    2015-01-01

    Background In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady state concentrations (Endx Css). The 13Cdextromethorphan breath test (DM-BT), labeled with 13C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DMBT and Endx Css. Methods DM-BT and tamoxifen pharmacokinetics were obtained at baseline (b), 3 month (3m) and 6 months (6m) following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between bDM-BT with CYP2D6 genotype and Endx Css was determined. The association between bDM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values ≤ 11.2 known to be associated with poorer recurrence free survival) was explored. Results 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with b, 3m and 6m DMBT (r ranging from 0.457-0. 60 p 11.2 nM. Conclusions In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3m and 6 m Endx Css but did not provide better discrimination of Endx Css compared to CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css. PMID:25714002

  5. The value of high adherence to tamoxifen in women with breast cancer: a community-based cohort study.

    Science.gov (United States)

    McCowan, C; Wang, S; Thompson, A M; Makubate, B; Petrie, D J

    2013-09-03

    Low adherence to adjuvant tamoxifen is associated with worse health outcomes but little is known about the cost-effectiveness of high adherence. We conducted an economic evaluation using data for all women with incident breast cancer between 1993 and 2000 who were subsequently prescribed tamoxifen in the Tayside region of Scotland. Patient-level, lifetime Markov models evaluated the impact of high vs low adherence to tamoxifen using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records. Direct medical costs were estimated for each patient and quality-of-life weights were assigned. Recurrence information was collected by case note review and adherence calculated from prescribing records with low adherence classed below 80%. A total of 354 (28%) patients had a recorded recurrence and 504 (39%) died. Four hundred and seventy-five (38%) patients had low adherence over the treatment period, which was associated with reduced time to recurrence of 52% (Padherence was associated with a loss of 1.43 (95% CI: 1.15-1.71) discounted life years or 1.12 (95% CI: 0.91-1.34) discounted quality-adjusted life years (QALYs) and increased discounted medical costs of £5970 (95% CI: £4644-£7372). Assuming a willingness to pay threshold of £25,000 per QALY, the expected value of changing a patient from low to high adherence is £33,897 (95% CI: £28,322-£39,652). Patients with low adherence have shorter time to recurrence, increased medical costs and worse quality of life. Interventions that encourage patients to continue taking their treatment on a daily basis for the recommended 5-year period may be highly cost-effective.

  6. Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients

    DEFF Research Database (Denmark)

    Ahern, Thomas P; Hertz, Daniel L; Damkier, Per;

    2017-01-01

    -infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association....... The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women....

  7. Somatostatin Enhances the Antineoplastic Effects of Tamoxifen on Breast Carcinoma in Vitro

    Institute of Scientific and Technical Information of China (English)

    ZENGXizhi; YAOZhenxiang

    2002-01-01

    Objective:To study the antineoplastic effects of tamoxifen(TAM) in combination with a somatostain analogue(octreotide,OCT) on breast cancer.Methods:Estrogen receptor(ER)-positive(MCF-7) and ER-negative(MDA-MB-435S)human breast carcinoma cell lines were treated with TAM or OCT,or combination of both agents in vitro.Cell proliferation was evaluated by MTT assay,distribu-tion of cell cycle and rate of apoptosis were detemined by flow cytometry.Results:The inhibitory effect of OCT or TAM on proliferation of MCF-7 cells was associated with cell arrest in G0/G1 phase and induction of apoptosis.The inhibitory effect on proliferation of MCF-7 cells enhanced when treatment of TAM combined with OCT.The increased rate of apoptosis induced by combination of TAM and OCT was much higher than use of either TAM or OCT alone.TAM or OCT also had weak inhibitory effect on MDA-MB435S cell.The cells were arrested at S phase by TAM and at G0/G1 phase by OCT, but the induction of apoptosis was not identified.However,the rate of apoptosis was 22.7% if combined treatment of TAM and OCT applied.Conclusion:TAM and OCT can synergistically inhibit proliferation and induce apoptosis of ER-positive and ER-negative breast cancer cells.The synergism of TAM and OCT may be of interest in the clinical treatment of breast carcinoma.

  8. In vivo occupancy of female rat brain estrogen receptors by 17beta-estradiol and tamoxifen.

    Science.gov (United States)

    Pareto, D; Alvarado, M; Hanrahan, S M; Biegon, A

    2004-11-01

    Estrogens or antiestrogens are currently used by millions of women, but the interaction of these hormonal agents with brain estrogen receptors (ER) in vivo has not been characterized to date. Our goal was to assess, in vivo, the extent and regional distribution of brain ER occupancy in rats chronically exposed to 17beta-estradiol (E(2)) or tamoxifen (TAM). For that purpose, female ovariectomized Sprague-Dawley rats were implanted with subcutaneous pellets containing either placebo (OVX), E(2), or TAM for 3 weeks. ER occupancy in grossly dissected regions was quantified with 16alpha-[(18)F]fluoroestradiol ([(18)F]FES). Both E(2) and TAM produced significant decreases in radioligand uptake in the brain although the effect of E(2) was larger and more widespread than the effect of TAM. Detailed regional analysis of the interaction was then undertaken using a radioiodinated ligand, 11beta-methoxy-16alpha-[(125)I]iodo-estradiol ([(125)I]MIE(2)), and quantitative ex vivo autoradiography. E(2) treatment resulted in near-complete (86.6 +/- 17.5%) inhibition of radioligand accumulation throughout the brain, while ER occupancy in the TAM group showed a marked regional distribution such that percentage inhibition ranged from 40.5 +/- 15.6 in the ventrolateral part of the ventromedial hypothalamic nucleus to 84.6 +/- 4.5 in the cortical amygdala. These results show that exposure to pharmacologically relevant levels of TAM produces a variable, region-specific pattern of brain ER occupancy, which may be influenced by the regional proportion of ER receptor subtypes. These findings may partially explain the highly variable and region-specific effects observed in neurochemical, metabolic, and functional studies of the effects of TAM in the brain of experimental animals as well as human subjects.

  9. Elevation of cysteine consumption in tamoxifen-resistant MCF-7 cells.

    Science.gov (United States)

    Ryu, Chang Seon; Kwak, Hui Chan; Lee, Ji-Yoon; Oh, Soo Jin; Phuong, Nguyen Thi Thuy; Kang, Keon Wook; Kim, Sang Kyum

    2013-01-15

    Tamoxifen (TAM) resistance is a main cause of therapeutic failure in breast cancers. Although methionine dependency is a phenotypic characteristic of tumor cells, the role of sulfur amino acid metabolism in chemotherapy resistance remains to be elucidated. This study compared metabolite profiles of sulfur amino acid metabolism from methionine to taurine or glutathione (GSH) between normal MCF-7 and TAM-resistant MCF-7 (TAMR-MCF-7) cells. TAMR-MCF-7 cells showed elevated levels and activities of enzymes involved in both transsulfuration from methionine to cysteine and metabolism of cysteine to GSH and taurine. Cysteine concentrations in TAMR-MCF-7 cells and medium conditioned by cell culture for 42h were markedly decreased, while GSH, hypotaurine, and taurine concentrations in the medium were increased. These results show that TAMR-MCF-7 cells display enhanced cysteine utilization. The addition of propargylglycine, a specific cystathionine γ-lyase inhibitor, and buthionine sulfoximine, a specific γ-glutamylcysteine ligase inhibitor, to TAMR-MCF-7 cells, but not to MCF-7 cells, resulted in cytotoxicity after sulfur amino acid deprivation. These results suggest that cell viability of TAMR-MCF-7 cells is affected by inhibition of sulfur amino acid metabolism, particularly cysteine synthesis from homocysteine and GSH synthesis from cysteine. Additionally, the S-adenosylmethionine/S-adenosylhomocysteine ratio, an index of transmethylation potential, in TAMR-MCF-7 cells increased to ~3.6-fold relative to that in MCF-7 cells, a finding that may result from upregulation of methionine adenosyltransferase IIa and S-adenosylhomocysteine hydrolase. In conclusion, this study suggests that TAMR-MCF-7 cells display enhanced cysteine utilization for synthesis of GSH and taurine, and are sensitive to inhibition of cysteine metabolism.

  10. Preparation, characterization and in-vivo evaluation of microemulsions containing tamoxifen citrate anti-cancer drug.

    Science.gov (United States)

    Dehghani, Faranak; Farhadian, Nafiseh; Golmohammadzadeh, Shiva; Biriaee, Amir; Ebrahimi, Mahmoud; Karimi, Mohammad

    2017-01-01

    The aim of this study was to prepare and characterize a new nanocarrier for oral delivery of tamoxifen citrate (TMC) as a lipophilic oral administrated drug. This drug has low oral bioavailability due to its low aqueous solubility. To enhance the solubility of this drug, the microemulsion system was applied in form of oil-in-water. Sesame oil and Tween 80 were used as drug solvent oil and surfactant, respectively. Two different formulations were prepared for this purpose. The first formulation contained edible glycerin as co-surfactant and the second formulation contained Span 80 as a mixed surfactant. The results of characterization showed that the mean droplet size of drug-free samples was in the range of 16.64-64.62nm with a PDI value of <0.5. In a period of 6months after the preparation of samples, no phase sedimentation was observed, which confirmed the high stability of samples. TMC with a mass ratio of 1% was loaded in the selected samples. No significant size enlargement and drug precipitation were observed 6months after drug loading. In addition, the drug release profile at experimental environments in buffers with pH=7.4 and 5.5 showed that in the first 24h, 85.79 and 100% of the drug were released through the first formulation and 76.63 and 66.42% through the second formulation, respectively. The in-vivo results in BALB/c female mice showed that taking microemulsion form of drug caused a significant reduction in the growth rate of cancerous tumor and weight loss of the mice compared to the consumption of commercial drug tablets. The results confirmed that the new formulation of TMC could be useful for breast cancer treatment.

  11. A toxicity study of simultaneous administration of Tamoxifen and Diazepam to female Wistar rats.

    Science.gov (United States)

    D'Mello, D; Mehta, D; Pereira, J; Rao, C V

    1999-11-01

    Tamoxifen (TAM) is used in the treatment of breast cancer and decreases the incidence of breast cancer when given to healthy women for different therapeutic purposes. This expansion of its use calls for further studies of its own potential side effects and those in combination with other prescription drugs. Diazepam (DP) is one such drug normally administered to patients who are under cancer treatment and those who suffer from insomnia. The present study examines the effect of individual and simultaneous administration of TAM and DP at therapeutic dose level of 0.8 mg/Kg/day of TAM and 0.3 mg/Kg/day of DP to normal female Wistar rats for a period of 12 weeks. The drugs were administered orally by mixing it in pellet made by wheat dough. There was no significant change in the terminal body weight and liver weights of animals. The ovary weights in TAM + DP treated animals were significantly decreased. The serum succinate dehydrogenase (SDH) levels were significantly lower in TAM, DP and TAM + DP treated rats and comparatively were lowest in TAM and TAM + DP treated animal groups. Serum glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT), acid and alkaline phosphatase (ACP & ALP) levels were significantly higher in the three treated groups, but comparatively lower in TAM + DP treated animals when compared to TAM or DP alone treated rats. There was marked increase in liver triglyceride and cholesterol levels in the three treated groups but remarkable decrease in liver glycogen. Total serum cholesterol levels were significantly high in DP and TAM + DP treated rats and total serum triglyceride levels were significantly high only in TAM treated rats. As a whole it can be concluded that DP does not enhance TAM toxicity on simultaneous administration, but on its own when administered individually brings about perturbation in lipid storage and metabolism.

  12. In vitro and in vivo effects of combination of Trastuzumab (Herceptin) and Tamoxifen in breast cancer.

    Science.gov (United States)

    Wang, Chun-Xia; Koay, Debbie C; Edwards, Andrea; Lu, Zhao; Mor, Gil; Ocal, Idris T; Digiovanna, Michael P

    2005-08-01

    Extensive interactions between estrogen receptor alpha (ERalpha) and HER2 signaling pathways have been described. Using BT-474 human breast cancer cells, we have previously shown that the combination of tamoxifen (TAM) and Herceptin results in strong synergistic growth inhibition, enhancement of G(0)-G(1) cell cycle accumulation, inhibition of HER2 activity and a cytostatic effect without cell death. To further examine the underlying mechanism of synergy, we investigated the effect of this drug combination on ERalpha function and growth factor downstream signaling. TAM caused a small increase in ERalpha levels while Herceptin had no effect, and both drugs caused an increase in the level of Ser118-phosphorylated ERalpha. However, both TAM and Herceptin individually inhibited ERalpha transcriptional activity, although the combination did not have a greater effect than either single agent. Herceptin inhibited MAPK and Akt activity, while TAM had no effect on these either as a single agent or when added to Herceptin. Using a BALB/c athymic BT-474 in vivo xenograft model, the drug combination (Herceptin 0.3 mg/kg i.p. twice weekly, TAM 1.0 mg/mouse i.p. three times per week) showed a greater inhibition of tumor growth compared to either single agent. Tumor extracts and fixed sections were examined at the end of the treatment period for treatment-specific alterations: we noted a paradoxical proliferation-inducing effect of TAM that was reversed by the addition of Herceptin. Our results indicate that combined targeting of both peptide growth factor receptors and ERalpha represents a promising breast cancer treatment strategy.

  13. From tamoxifen to dendrogenin A: The discovery of a mammalian tumor suppressor and cholesterol metabolite.

    Science.gov (United States)

    Silvente-Poirot, Sandrine; de Medina, Philippe; Record, Michel; Poirot, Marc

    2016-11-01

    Tamoxifen (Tam) was developed as a ligand and modulator of estrogen receptor α (ERα) and is one of the main drugs used globally for the hormonotherapy of breast cancers. Besides ERα, Tam also binds with high affinity to the microsomal antiestrogen binding site (AEBS). The AEBS is a hetero-oligomeric proteinaceous complex with cholesterol-5,6-epoxide hydrolase (ChEH) activity that is associated with an intracellular histamine (HA) binding site. The enzymatic activities of the ChEH subunits control developmental programs in mammals and transform cholesterol-5,6-epoxides (5,6-EC) into cholestane-3β,5α,6β-triol. Inhibition of the ChEH activity by pharmacological agents such as Tam induce cancer cell re-differentiation through the accumulation of 5,6-EC. A few years ago, the putative chemical reactivity of the 5,6-EC epoxide group towards nucleophiles led our group to hypothesize that 5,6-EC could react with HA that was co-localized at the AEBS to give a new molecule involved in cell differentiation. This hypothesis was chemically tested and the conjugation of 5,6α-EC: with HA was found possible but only under catalytic conditions. It gave a stereo-selective single product of transformation which was named dendrogenin A (DDA). DDA was found to display potent cancer cell differentiation and anticancer properties in vitro and in vivo, suggesting that it was a tumor suppressor metabolite. The presence of DDA was then established in several mammalian tissues, providing the first evidence of a steroidal alkaloid metabolite in mammals. The discovery of DDA highlights a new metabolic pathway in mammals which lies at the crossroads of cholesterol and histamine metabolism and produces this tumor suppressor metabolite.

  14. Potentiation of the antiproliferative activity of MKT-077 by loperamide, diltiazem and tamoxifen.

    Science.gov (United States)

    Abdul, Mansoor; Hoosein, Naseema

    2003-01-01

    MKT-077, a delocalized lipophilic cation, selectively targets cancer cells. MKT-077 has been reported to inhibit the growth of several tumor types and has undergone phase I clinical testing. We have examined the effect of MKT-077, alone and in combination with the antidiarrheal drug loperamide. Ten human cancer cell lines, four prostate (PC3, DU145, LNCaP, MDA-PCA-2B), two breast (MCF-7 and MDA-MB-231) and four colon (LoVo, Colo320DM, SW1116 and LS174t) were tested in vitro. Cells were grown to confluency prior to treatment. Loperamide potentiated the antiproliferative effect of MKT-077 in all ten cell lines, in a dose-dependent manner. The sensitivity of MDA-PCA-2B cells, the two breast and four colon cancer cell lines to MKT-077 was relatively low (>2.5 microg/ml MKT-077 required to inhibit growth by 95%). In these cell lines, 0.5-5 microg/ml (1-10 microM) loperamide caused a marked increase in the response to MKT-077. Loperamide is known to activate micro-opioid receptors at nanomolar concentrations and block voltage-gated calcium channels at micromolar doses. We found that calcium channel-blockers diltiazem and nifedipine (10-20 microg/ml), as well as tamoxifen (1.5-2.5 microg/ml) can also potentiate the growth-inhibitory effects of MKT-077. These synergistic interactions could be exploited for therapeutic benefit.

  15. Evaluation of three commercial progesterone receptor assays in a single tamoxifen-treated breast cancer cohort.

    Science.gov (United States)

    Kornaga, Elizabeth N; Klimowicz, Alexander C; Guggisberg, Natalia; Ogilvie, Travis; Morris, Don G; Webster, Marc; Magliocco, Anthony M

    2016-12-01

    Estrogen receptor and progesterone receptor status are routinely assessed using immunohistochemistry assays to assist in patient prognosis and clinical management. Three commonly utilized autostainer vendors-Dako, Leica and Ventana-provide ready-to-use progesterone receptor assays; however, they have never been directly compared in a single breast cancer cohort. We looked at three immunohistochemical progesterone receptor assays, in addition to original ligand-binding assay results, in a single retrospective, tamoxifen-treated breast cancer cohort to investigate inter- and intra-observer agreement, concordance, prognostic ability and measures of test performance. All immunohistochemical assays utilized the manufacturer's specified protocols. Five-year disease-free survival was the endpoint of interest, and multivariate models were adjusted for lymph node status, tumor grade, tumor size and human epidermal growth factor 2 status. All assays showed substantial to almost perfect agreement between the three observers (Dako κ=0.69-0.90; Leica κ=0.70-0.89; and Ventana κ=0.78-0.94) and concordance (Dako/Leica κ=0.81; Dako/Ventana κ=0.78; and Leica/Ventana κ=0.82). Univariate survival analyses showed that only the ligand-binding assay, Dako and Ventana assays achieved statistical significance. No statistically significant results were seen in multivariate models, although a strong trend was seen with the Ventana progesterone receptor assay. All assays performed similarly with regards to measures of test performance with ligand-binding assay set as the reference, and all immunohistochemical assays outperformed the ligand-binding assay in regards to 5-year disease-free survival. Despite similar agreement and concordance with the progesterone receptor assays, clear differences were noted with regards to 5-year disease-free survival. Additional survival analyses suggest that clinical utility of estrogen receptor assays vary when investigated in combination with

  16. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial.

    Science.gov (United States)

    Masuda, Norikazu; Sagara, Yasuaki; Kinoshita, Takayuki; Iwata, Hiroji; Nakamura, Seigo; Yanagita, Yasuhiro; Nishimura, Reiki; Iwase, Hirotaka; Kamigaki, Shunji; Takei, Hiroyuki; Noguchi, Shinzaburo

    2012-04-01

    Aromatase inhibitors have shown increased efficacy compared with tamoxifen in postmenopausal early breast cancer. We aimed to assess the efficacy and safety of anastrozole versus tamoxifen in premenopausal women receiving goserelin for early breast cancer in the neoadjuvant setting. In this phase 3, randomised, double-blind, parallel-group, multicentre study, we enrolled premenopausal women with oestrogen receptor (ER)-positive, HER2-negative, operable breast cancer with WHO performance status of 2 or lower. Patients were randomly assigned (1:1) to receive goserelin 3·6 mg/month plus either anastrozole 1 mg per day and tamoxifen placebo or tamoxifen 20 mg per day and anastrozole placebo for 24 weeks before surgery. Patients were randomised sequentially, stratified by centre, with randomisation codes. All study personnel were masked to study treatment. The primary endpoint was best overall tumour response (complete response or partial response), assessed by callipers, during the 24-week neoadjuvant treatment period for the intention-to-treat population. The primary endpoint was analysed for non-inferiority (with non-inferiority defined as the lower limit of the 95% CI for the difference in overall response rates between groups being 10% or less); in the event of non-inferiority, we assessed the superiority of the anastrozole group versus the tamoxifen group. We included all patients who received study medication at least once in the safety analysis set. We report the primary analysis; treatment will also continue in the adjuvant setting for 5 years. This trial is registered with ClinicalTrials.gov, number NCT00605267. Between Oct 2, 2007, and May 29, 2009, 204 patients were enrolled. 197 patients were randomly assigned to anastrozole (n=98) or tamoxifen (n=99), and 185 patients completed the 24-week neoadjuvant treatment period and had breast surgery (95 in the anastrazole group, 90 in the tamoxifen group). More patients in the anastrozole group had a complete or

  17. Automated discovery of drug treatment patterns for endocrine therapy of breast cancer within an electronic medical record.

    Science.gov (United States)

    Savova, Guergana K; Olson, Janet E; Murphy, Sean P; Cafourek, Victoria L; Couch, Fergus J; Goetz, Matthew P; Ingle, James N; Suman, Vera J; Chute, Christopher G; Weinshilboum, Richard M

    2012-06-01

    To develop an algorithm for the discovery of drug treatment patterns for endocrine breast cancer therapy within an electronic medical record and to test the hypothesis that information extracted using it is comparable to the information found by traditional methods. The electronic medical charts of 1507 patients diagnosed with histologically confirmed primary invasive breast cancer. The automatic drug treatment classification tool consisted of components for: (1) extraction of drug treatment-relevant information from clinical narratives using natural language processing (clinical Text Analysis and Knowledge Extraction System); (2) extraction of drug treatment data from an electronic prescribing system; (3) merging information to create a patient treatment timeline; and (4) final classification logic. Agreement between results from the algorithm and from a nurse abstractor is measured for categories: (0) no tamoxifen or aromatase inhibitor (AI) treatment; (1) tamoxifen only; (2) AI only; (3) tamoxifen before AI; (4) AI before tamoxifen; (5) multiple AIs and tamoxifen cycles in no specific order; and (6) no specific treatment dates. Specificity (all categories): 96.14%-100%; sensitivity (categories (0)-(4)): 90.27%-99.83%; sensitivity (categories (5)-(6)): 0-23.53%; positive predictive values: 80%-97.38%; negative predictive values: 96.91%-99.93%. Our approach illustrates a secondary use of the electronic medical record. The main challenge is event temporality. We present an algorithm for automated treatment classification within an electronic medical record to combine information extracted through natural language processing with that extracted from structured databases. The algorithm has high specificity for all categories, high sensitivity for five categories, and low sensitivity for two categories.

  18. Effect of selective serotonin reuptake inhibitors use on endocrine therapy adherence and breast cancer mortality: a population-based study.

    Science.gov (United States)

    Valachis, Antonis; Garmo, Hans; Weinman, John; Fredriksson, Irma; Ahlgren, Johan; Sund, Malin; Holmberg, Lars

    2016-09-01

    The purpose of the study was to investigate whether the concomitant use of selective serotonin reuptake inhibitors (SSRI) with tamoxifen influences the risk of death due to breast cancer, and we also investigated the association between SSRI use and adherence to oral endocrine therapy (ET). We analyzed data from BCBaSe Sweden, which is a database created by the data linkage of Registries from three different regions of Sweden. To investigate the association between ET adherence and SSRI use, we included all women who were diagnosed with non-distant metastatic ER-positive invasive breast cancer from July 2007 to July 2011 and had at least one dispensed prescription of oral tamoxifen or aromatase inhibitor. To investigate the role of concurrent administration of SSRI and tamoxifen on breast cancer prognosis, we performed a nested case-control study. In the adherence cohort, 9104 women were included in the analyses. Women who received SSRI, either before or after breast cancer diagnosis, were at higher risk for low adherence to ET. However, when the overlapping period between SSRI use and ET was >50 %, no excess risk for low adherence was observed. Non-adherence (breast cancer survival (OR 4.07; 95 % CI 3.27-5.06). In the case-control study, 445 cases and 11125 controls were included. The concomitant administration of SSRI and tamoxifen did not influence breast cancer survival, neither in short-term (OR 1.41; 95 % CI 0.74-2.68) nor in long-term SSRI users (OR 0.85; 95 % CI 0.35-2.08). Concomitant SSRI and tamoxifen use does not seem to increase risk for death due to breast cancer. Given the positive association between continuing antidepressive pharmacotherapy for a longer period of time and adherence to ET, it is essential to capture and treat depression in breast cancer patients to secure adherence to ET.

  19. Pak1, adjuvant tamoxifen therapy, and breast cancer recurrence risk in a Danish population-based study

    DEFF Research Database (Denmark)

    Ahern, Thomas P; Cronin-Fenton, Deirdre P; Lash, Timothy L

    2016-01-01

    as well as novel approaches e.g. remote sensing using UAV’s (Unmanned Aerial Vehicles commonly known as drones), a newly developed redox probe, and novel uses of geophysical methods. More information about TReNDS can be found at www.nitrat.dk. The project is funded by Innovation Fund Denmark...

  20. Ribavirin restores ESR1 gene expression and tamoxifen sensitivity in ESR1 negative breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Sappok Anne

    2011-12-01

    Full Text Available Abstract Tumor growth is estrogen independent in approximately one-third of all breast cancers, which makes these patients unresponsive to hormonal treatment. This unresponsiveness to hormonal treatment may be explained through the absence of the estrogen receptor alpha (ESR1. The ESR1 gene re-expression through epigenetic modulators such as DNA methyltransferase inhibitors and/or histone deacetylase inhibitors restores tamoxifen sensitivity in ESR1 negative breast cancer cell lines and opens new treatment horizons in patients who were previously associated with a poor prognosis. In the study presented herein, we tested the ability of ribavirin, which shares some structural similarities with the DNA-methyltransferase inhibitor 5-azacytidine and which is widely known as an anti-viral agent in the treatment of hepatitis C, to restore ESR1 gene re-expression in ESR1 negative breast cancer cell lines. In our study we identified ribavirin to restore ESR1 gene re-expression alone and even more in combination with suberoylanilide hydroxamic acid (SAHA - up to 276 fold induction. Ribavirin and analogs could pave the way to novel translational research projects that aim to restore ESR1 gene re-expression and thus the susceptibility to tamoxifen-based endocrine treatment strategies.

  1. Antiproliferation and apoptosis induced by tamoxifen in human bile duct carcinoma QBC939 cells via upregulated p53 expression

    Energy Technology Data Exchange (ETDEWEB)

    Han, Peng; Kang, Jin-He; Li, Hua-Liang [Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005 (China); Hu, Su-Xian [First Hospital Attached to Fujian Medical University, Xiamen 361004 (China); Lian, Hui-Hui; Qiu, Ping-Ping; Zhang, Jian [Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005 (China); Li, Wen-Gang, E-mail: lwg11861@163.com [First Hospital Attached to Fujian Medical University, Xiamen 361004 (China); Chen, Qing-Xi, E-mail: chenqx@xmu.edu.cn [Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005 (China); Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005 (China)

    2009-07-24

    Tamoxifen (TAM) is a nonsteroidal antiestrogen that has been used in the treatment of breast cancer for over 30 years. Recently, it was shown that TAM also has efficacy on gastrointestinal neoplasms such as hepatocarcinoma and pancreatic carcinoma, and that the chemopreventive activities of TAM might be due to its abilities to inhibit cell growth and induce apoptosis. In the present study, we investigated the effects of tamoxifen on growth and apoptosis in the human bile duct carcinoma (BDC) cell line QBC939 using MTT assay, inverted microscopy, fluorescence microscopy, transmission electron microscopy, classic DNA fragmentation agarose gel electrophoresis assay, PI single- and FITC/PI double-staining flow cytometry, and Western blotting. Our data revealed that TAM could significantly inhibit growth and induce apoptosis in QBC939 cells. Increased expression of p53 was observed in TAM-treated cells, indicating that p53 might play an important role in TAM-induced apoptosis in QBC939 cells. These results provide significant insight into the anticarcinogenic action of TAM on BDC.

  2. Evaluation of Effects of Quercetin (3, 3’, 4’, 5, 7-pentohidroxyflavon on Apoptosis and Telomerase Enzyme Activity in MCF-7 and NIH-3T3 Cell Lines Compared with Tamoxifen

    Directory of Open Access Journals (Sweden)

    Ayşe Ak

    2011-09-01

    Full Text Available Objective: Quercetin has been shown to inhibit the proliferation of cancer cells. Tamoxifen is used for breast cancer. In this study, we have aimed to investigate the effects of quercetin and tamoxifen on telomerase enzyme activity and apoptosis in two cell lines.Methods: In this study, 10, 50 and 100 µM of quercetin and tamoxifen were used to treat MCF-7 and NIH-3T3. Apoptosis was determined by the TUNEL method (Terminal Deoxynucleotide Transferase dUTP Nick End Label and telomerase enzyme activity was determined by ELISA (Enzyme-Linked Immunosorbent Assay. Results: In the NIH3T3 cell line, only 100 µM quercetin and tamoxifen induced significant apoptosis. In the MCF-7 cell line 10 µM and 100 µM quercetin in the 24th hour and 100 µM quercetin in the 72nd hour induce apoptosis. In 24th and 48th hours, 50 µM tamoxifen and 100 µM tamoxifen in the 24th and 48th hours induce apoptosis in the MCF-7 cell line. In MCF-7 and NIH-3T3 cell lines, all doses of quercetin and tamoxifen reduced telomerase enzyme activity compared to the control group. Conclusion: In this study, it was shown that quercetin has similar effects to tamoxifen. However quercetin induces apoptosis more than decreasing telomerase enzyme activities, being different from tamoxifen. We hope that the findings will assist in developing new therapeutic pathways for preventing breast cancer. However, there should be many more studies in order to discover quercetin and other potential drugs.

  3. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen

    NARCIS (Netherlands)

    ter Heine, Rob; Binkhorst, Lisette; de Graan, Anne Joy M; de Bruijn, Peter; Beijnen, Jos H; Mathijssen, Ron H J; Huitema, Alwin D R

    2014-01-01

    AIMS: Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clin

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

    DEFF Research Database (Denmark)

    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 ov...

  5. Effect of tamoxifen on fatty degeneration and atrophy of rotator cuff muscles in chronic rotator cuff tear: An animal model study.

    Science.gov (United States)

    Cho, Edward; Zhang, Yue; Pruznak, Anne; Kim, H Mike

    2015-12-01

    Fatty degeneration of the rotator cuff muscles is an irreversible change resulting from chronic rotator cuff tear and is associated with poor clinical outcomes following rotator cuff repair. We evaluated the effect of Tamoxifen, a competitive estrogen receptor inhibitor, on fatty degeneration using a mouse model for chronic rotator cuff tear. Sixteen adult mice were divided into two diet groups (Tamoxifen vs. Regular) and subjected to surgical creation of a large rotator cuff tear and suprascapular nerve transection in their left shoulder with the right shoulder serving as a control. The rotator cuff muscles were harvested at 16 weeks and subjected to histology and RT-PCR for adipogenic and myogenic markers. Histology showed substantially decreased atrophy and endomysial inflammation in Tamoxifen group, but no significant differences in the amount of intramuscular adipocytes and lipid droplets compared to the Regular group. With RT-PCR, the operated shoulders showed significant upregulation of myogenin and PPAR-γ, and downregulation of myostatin compared to the nonsurgical shoulder. No significant differences of gene expression were found between the two diet groups. Our study demonstrated that tamoxifen diet leads to decreased muscle atrophy and inflammatory changes following chronic rotator cuff tear, but has no apparent effect on adipogenesis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  6. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial

    DEFF Research Database (Denmark)

    Rabaglio, M; Sun, Z; Price, K N

    2009-01-01

    with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone...

  7. Optimizing high-performance liquid chromatography method with fluorescence detection for quantification of tamoxifen and two metabolites in human plasma: application to a clinical study.

    Science.gov (United States)

    Zhu, Yu-Bing; Zhang, Qian; Zou, Jian-Jun; Yu, Cui-Xia; Xiao, Da-Wei

    2008-01-22

    We set an improved high-performance liquid chromatography method with fluorescence detection HPLC-FLU assay with more sensitivity and precision for the quantification of tamoxifen and two metabolites: 4-hydroxytamoxifen and N-desmethyltamoxifen. The compounds and internal standard, mexiletine, were separated with an Agilent Extend C18 column set at 65 degrees C and a mobile phase of methanol-1% triethylamine aqueous solution (pH 11; 82:18, v/v). The detection system utilized offline ultraviolet irradiation to convert the analytes to their respective photocyclisation products, followed by fluorescence detection (lambda ex=260 nm and lambda em=375 nm). The limits of quantification for tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen in plasma were improved to 0.5, 0.5 and 0.1 ng/ml, respectively. And the retention times for tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen were minimized to 11, 10 and 3.9 min, respectively. A single stage liquid-liquid extraction method for determination of these triphenylethylene drugs in plasma was developed, with high extraction efficiency and rapid sample treatment for target compounds. The method has been validated for use in a clinical bioavailability research of tamoxifen.

  8. Effect of tamoxifen on the receptor-positive T61 and the receptor-negative T60 human breast carcinomas grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Vindeløv, L;

    1985-01-01

    to a transformed Gompertz function, and the effect on the cell cycle distributions was estimated by flow cytometric DNA analysis on tumour tissue obtained by fine-needle aspirations at intervals after the treatment. The results showed that in the T61 tumour, tamoxifen induced a dose-related growth inhibition...

  9. Randomized Double-Blind 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in High-Risk Premenopausal Women

    Science.gov (United States)

    Decensi, Andrea; Robertson, Chris; Guerrieri-Gonzaga, Aliana; Serrano, Davide; Cazzaniga, Massimiliano; Mora, Serena; Gulisano, Marcella; Johansson, Harriet; Galimberti, Viviana; Cassano, Enrico; Moroni, Simona M.; Formelli, Franca; Lien, Ernst A.; Pelosi, Giuseppe; Johnson, Karen A.; Bonanni, Bernardo

    2009-01-01

    Purpose Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. Patients and Methods A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk ≥ 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. Results During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% ± 1.0%, 2.1% ± 0.8%, 4.7% ± 1.3%, and 5.2% ± 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen × fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. Conclusion Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated. PMID:19597031

  10. Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response.

    Science.gov (United States)

    Lehn, Sophie; Tobin, Nicholas P; Sims, Andrew H; Stål, Olle; Jirström, Karin; Axelson, Håkan; Landberg, Göran

    2014-02-22

    Yes-associated protein (YAP1) is frequently reported to function as an oncogene in many types of cancer, but in breast cancer results remain controversial. We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen. YAP1 protein intensity was scored as absent, weak, intermediate or strong in two primary breast cancer cohorts (n = 144 and n = 564) and mRNA expression of YAP1 was evaluated in a gene expression dataset (n = 1107). Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence. WST-1 assay was employed to measure cell viability and a luciferase ERE (estrogen responsive element) construct was used to study the effect of tamoxifen, following downregulation of YAP1 using siRNAs. In the ER+ (Estrogen Receptor α positive) subgroup of the randomised cohort, YAP1 expression was inversely correlated to histological grade and proliferation (p = 0.001 and p = 0.016, respectively) whereas in the ER- (Estrogen Receptor α negative) subgroup YAP1 expression correlated positively to proliferation (p = 0.005). Notably, low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset, specifically for the luminal A subgroup (p tamoxifen, extensively used for luminal A breast cancers. In a tamoxifen randomised patient material, absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis (p = 0.042). YAP1 downregulation resulted in increased progesterone receptor (PgR) expression and a delayed and weaker tamoxifen in support of the clinical data. Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup, likely due to the decreased

  11. MCF7/LCC9: an antiestrogen-resistant MCF-7 variant in which acquired resistance to the steroidal antiestrogen ICI 182,780 confers an early cross-resistance to the nonsteroidal antiestrogen tamoxifen

    DEFF Research Database (Denmark)

    Brünner, N; Boysen, B; Jirus, S;

    1997-01-01

    variant designated MCF7/LCC9. In contrast to 4-hydroxytamoxifen-selected MCF7/LCC2 cells, MCF7/LCC9 cells exhibit full cross-resistance to tamoxifen, despite never having been exposed to this drug. Significantly, tamoxifen cross-resistance arose early in the selection, appearing following selection...... growth of MCF7/LCC9 tumors is not affected by treatment with ICI 182,780. Although there is some evidence of tamoxifen stimulation of tumor growth, this did not reach statistical significance. If this pattern of cross-resistance occurs in some breast cancer patients, administering triphenylethylene...

  12. 1α,25-dihydroxyvitamin D3 inhibits cell growth and NFκB signaling in tamoxifen-resistant breast cancer cells.

    Science.gov (United States)

    Lundqvist, Johan; Yde, Christina W; Lykkesfeldt, Anne E

    2014-07-01

    Resistance to antiestrogens is a major clinical problem in current breast cancer treatment and development of new treatment strategies for these tumors is highly prioritized. In this study, we have investigated the effects of 1α,25-dihydroxyvitamin D3 on the proliferation of tamoxifen-resistant cells. Further, we have investigated on a molecular level the effects of vitamin D on NFkB signaling in tamoxifen-resistant breast cancer cells. Parental human breast cancer MCF-7 cells and four tamoxifen-resistant sublines have been used to investigate the effects of 1α,25-dihydroxyvitamin D3 on cell proliferation using a colorimetric method, gene expression using quantitative PCR, protein phosphorylation using Western blot analysis and cellular localization of proteins using immunofluorescence microscopy. We found that 1α,25-dihydroxyvitamin D3 is able to strongly decrease the growth of both tamoxifen-sensitive and -resistant breast cancer cells and that this antiproliferative effect of 1α,25-dihydroxyvitamin D3 might be mediated via inhibition of the NFκB pathway. We found that 1α,25-dihydroxyvitamin D3 stimulates the gene expression of IkB, an NFκB-inhibiting protein, and that cells pretreated with 1α,25-dihydroxyvitamin D3 have a decreased sensitivity to TNFα stimulation. Further, we show that 1α,25-dihydroxyvitamin D3 treatment strongly decreases the TNFα-induced translocation of p65 into the nucleus. This manuscript reports novel findings regarding the effects of 1α,25-dihydroxyvitamin D3 on NFκB signaling in tamoxifen-resistant breast cancer cells and suggests that vitamin D might be interesting for further evaluation as a new strategy to treat antiestrogen-resistant breast cancers.

  13. Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: their antioxidant effect and role of estrogen receptor alpha.

    Science.gov (United States)

    Mosquera, Laurivette; Colón, Jennifer M; Santiago, José M; Torrado, Aranza I; Meléndez, Margarita; Segarra, Annabell C; Rodríguez-Orengo, José F; Miranda, Jorge D

    2014-05-01

    17β-Estradiol is a multi-active steroid that imparts neuroprotection via diverse mechanisms of action. However, its role as a neuroprotective agent after spinal cord injury (SCI), or the involvement of the estrogen receptor-alpha (ER-α) in locomotor recovery, is still a subject of much debate. In this study, we evaluated the effects of estradiol and of Tamoxifen (an estrogen receptor mixed agonist/antagonist) on locomotor recovery following SCI. To control estradiol cyclical variability, ovariectomized female rats received empty or estradiol filled implants, prior to a moderate contusion to the spinal cord. Estradiol improved locomotor function at 7, 14, 21, and 28 days post injury (DPI), when compared to control groups (measured with the BBB open field test). This effect was ER-α mediated, because functional recovery was blocked with an ER-α antagonist. We also observed that ER-α was up-regulated after SCI. Long-term treatment (28 DPI) with estradiol and Tamoxifen reduced the extent of the lesion cavity, an effect also mediated by ER-α. The antioxidant effects of estradiol were seen acutely at 2 DPI but not at 28 DPI, and this acute effect was not receptor mediated. Rats treated with Tamoxifen recovered some locomotor activity at 21 and 28 DPI, which could be related to the antioxidant protection seen at these time points. These results show that estradiol improves functional outcome, and these protective effects are mediated by the ER-α dependent and independent-mechanisms. Tamoxifen׳s effects during late stages of SCI support the use of this drug as a long-term alternative treatment for this condition.

  14. Moderate and high amounts of tamoxifen in αMHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death

    Directory of Open Access Journals (Sweden)

    Kevin Bersell

    2013-11-01

    Numerous mouse models have utilized Cre-loxP technology to modify gene expression. Adverse effects of Cre recombinase activity have been reported, including in the heart. However, the mechanisms associated with cardiac Cre toxicity are largely unknown. Here, we show that expression of Cre in cardiomyocytes induces a DNA damage response, resulting in cardiomyocyte apoptosis, cardiac fibrosis and cardiac dysfunction. In an effort to increase the recombination efficiency of a widely used tamoxifen-sensitive Cre transgene under control of the α-myosin-heavy-chain promoter (αMHC-MerCreMer, we observed myocardial dysfunction and decreased survival, which were dependent on the dose of tamoxifen injected. After excluding a Cre-independent contribution by tamoxifen, we found that Cre induced myocardial fibrosis, activation of pro-fibrotic genes and cardiomyocyte apoptosis. Examination of the molecular mechanisms showed activation of DNA damage response signaling and p53 stabilization in the absence of loxP sites, suggesting that Cre induced illegitimate DNA breaks. Cardiomyocyte apoptosis was also induced by expressing Cre using adenoviral transduction, indicating that the effect was not dependent on genomic integration of the transgene. Cre-mediated homologous recombination at loxP sites was dose-dependent and had a ceiling effect at ∼80% of cardiomyocytes showing recombination. By titrating the amount of tamoxifen to maximize recombination while minimizing animal lethality, we determined that 30 μg tamoxifen/g body weight/day injected on three consecutive days is the optimal condition for the αMHC-MerCreMer system to induce recombination in the Rosa26-lacZ strain. Our results further highlight the importance of experimental design, including the use of appropriate genetic controls for Cre expression.

  15. Structure-function relationships of hydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitro.

    Science.gov (United States)

    Murphy, C S; Langan-Fahey, S M; McCague, R; Jordan, V C

    1990-11-01

    Several hydroxylated derivatives of tamoxifen were tested for their effects on the growth of T47D human breast cancer cells in vitro. Compounds containing a fused seven-membered ring were used to prevent isomerization of the triphenyl-ethylenes at the double bond. This stable structure permitted the determination of the activity of the cis and trans forms of tamoxifen and the true activity of two of its metabolites, 4-hydroxytamoxifen and metabolite E. Estradiol stimulates the growth of T47D cells 3-4-fold over control after 6 days of treatment (EC50 = congruent to 3 x 10(-12) to 3 x 10(-11) M, depending upon the particular experiment). The fixed ring form of the trans isomer of tamoxifen is an antiestrogen, whereas the cis isomer is estrogenic. Fixed ring-trans-4-hydroxytamoxifen is a potent antiestrogen, and its cis isomer is a weak antiestrogen (IC50 congruent to 4 x 10(-8) to 2 x 10(-7) M). The fixed ring form of trans-metabolite E (tamoxifen without the dimethylaminoethane side chain) is only a weak partial estrogen agonist, whereas the fixed ring derivative of its cis isomer is a potent estrogen agonist (EC50 congruent to 4 x 10(-12) to 1 x 10(-11) M). These studies have determined the true biological activities of the hydroxylated derivatives of tamoxifen. This information will be valuable for the development of drug receptor models and will be particularly useful when the three-dimensional structure of the receptor complex is determined.

  16. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

    2012-10-01

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

  17. Effect of varying doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome: an experimental study

    Directory of Open Access Journals (Sweden)

    Pala S

    2015-03-01

    Full Text Available Sehmus Pala,1 Remzi Atilgan,1 Zehra Sema Ozkan,1 Salih Burçin Kavak,1 Nevin Ilhan,2 Nusret Akpolat,3 Ekrem Sapmaz1 1Department of Obstetrics and Gynecology, 2Department of Biochemistry, 3Department of Pathology, Firat University School of Medicine, Elazig, Turkey Objective: To examine the effects of low-to-high doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome (OHSS in an experimental setting.Materials and methods: A total of 20 female Wistar albino rats, 22 days of age, were randomly divided into four groups. Follicle-stimulating hormone 10 IU was administered subcutaneously in 15 rats on 4 consecutive days, with OHSS induction on day 5 by 30 IU of human chorionic gonadotropin. Group 1 (n=5 comprised 35-day-old control rats, group 2 (n=5 35-day-old OHSS rats, group 3 (n=5 27-day-old OHSS rats receiving 1 mg/kg of oral tamoxifen for 7 days, group 4 (n=5 27-day-old OHSS rats receiving 3 mg/kg of oral tamoxifen for 7 days. All rats were decapitated on day 35. Serum VEGF, endothelin 1, and ovarian follicular reserve were assessed in all rats. Kruskal–Wallis variance analysis and the Mann–Whitney U-test were used for statistical comparisons. A Bonferroni correction was performed to control the inflation of significance, with a significance level set at a P-value of less than 0.025.Results: Despite higher serum VEGF, endothelin 1, follicular reserve, and angiogenesis and fibrosis of the corpus luteum in the OHSS group compared to controls, these differences were not significant (P>0.025, Mann–Whitney U-test. There was a significant reduction in the ovarian follicular reserve in tamoxifen groups compared to controls (P<0.025, Mann–Whitney U-test, while angiogenesis of the corpus luteum, number of atretic follicles, fibrosis, and serum VEGF were significantly higher in rats receiving tamoxifen (P<0.025, Mann–Whitney U-test. Also, significantly lower follicular reserve and

  18. Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer

    DEFF Research Database (Denmark)

    Larsen, Sarah L; Yde, Christina W; Laenkholm, Anne-Vibeke

    2015-01-01

    treatment targets. METHODS: Antiestrogen sensitive and resistant T47D breast cancer cell lines were used as model systems. Parental and fulvestrant resistant cell lines were subjected to a kinase inhibitor library. Kinase inhibitors preferentially targeting growth of fulvestrant resistant cells were...... for endocrine resistance, immunohistochemistry was performed on archival primary tumor tissue from breast cancer patients who have received adjuvant endocrine treatment with tamoxifen. RESULTS: The selective Aurora kinase B inhibitor barasertib was identified to preferentially inhibit growth of fulvestrant...... resistant T47D breast cancer cell lines. Compared with parental cells, phosphorylation of Aurora kinase B was higher in the fulvestrant resistant T47D cells. Barasertib induced degradation of Aurora kinase B, caused mitotic errors, and induced apoptotic cell death as measured by accumulation of SubG1 cells...

  19. Effects of tamoxifen dose and nutrition scheme during growth on stimulation of the reproductive system in cornish breed cocks.

    Science.gov (United States)

    Lisowski, Mirosław; Bednarczyk, Marek

    2005-01-01

    The effects of tamoxifen (TAM) antiestrogen dose as well as protein and energy content in feed on stimulation of the reproductive system development in meat type cocks were studied. The experiment was conducted on males of the Dominant White Cornish chicken breed. The optimum TAM dose for stimulation of reproductive system development was at the level of 5 mg per kg body weight. The effects of TAM administration on the following traits were investigated: body weight, breast muscle thickness, age at sexual maturity, egg fertilization and hatchability. No effect of TAM on breast muscle thickness was found. It was also noted that semen obtained from 11 to 12 week old males of the Dominant White Cornish breed could be used successfully in the insemination of females.

  20. Preparation and in vitro characterization of the transdermal drug delivery system containing tamoxifen citrate for breast cancer

    Directory of Open Access Journals (Sweden)

    Adhyapak Anjana

    2011-01-01

    Full Text Available A matrix-type transdermal drug delivery system of tamoxifen citrate was developed by using a different ratio of eudragit-RL100, hydroxypropyl methyl cellulose (HPMC-K15, and ethyl cellulose (EC, by the solvent evaporation technique. The effect of the binary mixture of polymers with a penetration enhancer on the physical chemical parameters including, thickness, folding endurance, uniformity of drug content, moisture content, moisture uptake, tensile strength, and in vitro drug permeation were evaluated. The in vitro drug permeation studies were conducted by using modified Keshary-Chein diffusion cells through female Sprague Dawley rat skin using pH 7.4 phosphate buffer saline (PBS. The selected formulation′s stability studies were conducted as per the International Conference on Harmonization (ICH guidelines, and did not show any degradation of the drug.

  1. Penetration of tamoxifen citrate loaded ethosomes and liposomes across human skin: a comparative study with confocal laser scanning microscopy.

    Science.gov (United States)

    Sarwa, Khomendra K; Suresh, Preeti K; Rudrapal, Mithun; Verma, Vinod K

    2014-01-01

    In the present study, ethosomal and liposomal formulations containing tamoxifen citrate were prepared and evaluated for their penetration properties in human cadaver skin using Franz diffusion cell and confocal laser scanning microscope (CLSM). The results clearly revealed that ethosomal vesicles showed a better drug permeation profile than that of liposomal vesicles. In addition, low fluorescence intensity in CLSM was recorded with liposomes as compared to ethosomes, indicating lower cumulative amount of drug permeation from liposomal vesicles. Furthermore, CLSM showed uniform fluorescence intensity across the entire depth of skin in ethosomal treatment, indicating high penetrability of ethosomal vesicles through human cadaver skin. In contrast, low penetrability of conventional liposomal vesicles was recorded as penetration was limited to the 7(th) section (i.e. upper epidermis layer) of skin as evident from visualization of intact liposomal vesicles in CLSM.

  2. Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486 as detected by RNA-sequencing.

    Directory of Open Access Journals (Sweden)

    Karin Tamm-Rosenstein

    Full Text Available BACKGROUND: Estrogen (E2 and progesterone (P4 are key players in the maturation of the human endometrium. The corresponding steroid hormone modulators, tamoxifen (TAM and mifepristone (RU486 are widely used in breast cancer therapy and for contraception purposes, respectively. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profiling of the human endometrial Ishikawa cancer cell line treated with E2 and P4 for 3 h and 12 h, and TAM and RU486 for 12 h, was performed using RNA-sequencing. High levels of mRNA were detected for genes, including PSAP, ATP5G2, ATP5H, and GNB2L1 following E2 or P4 treatment. A total of 82 biomarkers for endometrial biology were identified among E2 induced genes, and 93 among P4 responsive genes. Identified biomarkers included: EZH2, MDK, MUC1, SLIT2, and IL6ST, which are genes previously associated with endometrial receptivity. Moreover, 98.8% and 98.6% of E2 and P4 responsive genes in Ishikawa cells, respectively, were also detected in two human mid-secretory endometrial biopsy samples. TAM treatment exhibited both antagonistic and agonistic effects of E2, and also regulated a subset of genes independently. The cell cycle regulator cyclin D1 (CCND1 showed significant up-regulation following treatment with TAM. RU486 did not appear to act as a pure antagonist of P4 and a functional analysis of RU486 response identified genes related to adhesion and apoptosis, including down-regulated genes associated with cell-cell contacts and adhesion as CTNND1, JUP, CDH2, IQGAP1, and COL2A1. CONCLUSIONS: Significant changes in gene expression by the Ishikawa cell line were detected after treatments with E2, P4, TAM, and RU486. These transcriptome data provide valuable insight into potential biomarkers related to endometrial receptivity, and also facilitate an understanding of the molecular changes that take place in the endometrium in the early stages of breast cancer treatment and contraception usage.

  3. Development of erythropoietin receptor-targeted drug delivery system against breast cancer using tamoxifen-loaded nanostructured lipid carriers

    Directory of Open Access Journals (Sweden)

    Beh CY

    2017-03-01

    Full Text Available Chaw Yee Beh,1 Chee Wun How,1,2 Jhi Biau Foo,2 Jia Ning Foong,3 Gayathri Thevi Selvarajah,3 Abdullah Rasedee1,3 1Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 2Faculty of Pharmacy, MAHSA University, Jenjarom, 3Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia Abstract: Tamoxifen (TAM has been used in the treatment of breast cancers and is supplemented with erythropoietin (EPO to alleviate the cancer-related anemia. The purported deleterious effects caused by the use of EPO with chemotherapeutic agents in the treatment of cancer-related anemia vary across studies and remain controversial. The use of nanoparticles as a drug delivery system has the potential to improve the specificity of anticancer drugs. In this study, we simultaneously incorporated two pharmacological active ingredients in one nanocarrier to develop EPO-conjugated TAM-loaded lipid nanoparticles (EPO-TAMNLC, a targeted delivery system, to enhance the cytotoxic activity while reducing the side effects of the ingredients. The effect of temperature in modulating the thermodynamic parameters associated with the binding of EPO and TAMNLC was assessed using isothermal titration calorimetry, while the unfolding of EPO structure was determined using fluorescence-quenching approach. The association efficiency of EPO and TAMNLC was 55.43%. Unlike binding of albumin to TAMNLC, the binding of EPO to TAMNLC occurred through endothermic and entropy-driven reaction. The EPO-TAMNLC formulation was stable because of the hydrophobic interaction and the high free energy, suggesting the spontaneity of the interactions between EPO and TAMNLC. The EPO-TAMNLC enhanced the in vitro cytotoxicity of TAM to MCF-7 cells. The EPO surface-functionalized TAMNLC could sequentially deliver EPO and TAM as well as improving site-specific delivery of these therapeutic compounds. Keywords: tamoxifen, thermodynamic interaction

  4. Biopolymer mediated nanoparticles synthesized from Adenia hondala for enhanced tamoxifen drug delivery in breast cancer cell line

    Science.gov (United States)

    Varadharajaperumal, Pradeepa; Subramanian, Balakumar; Santhanam, Amutha

    2017-09-01

    Silver nanoparticles (AgNPs) are an important class of nanomaterials, which have used as antimicrobial and disinfectant agents due to their detrimental effect on target cells. In the present study it was explored to deliver a novel tamoxifen drug system that can be used in breast cancer treatment, based on chitosan coated silver nanoparticles on MCF-7 human breast cancer cells. AgNPs synthesized from Adenia hondala tuber extract were used to make the chitosan coated AgNPs (Ch-AgNPs), in which the drug tamoxifen was loaded on chitosan coated silver nanoparticles (Tam-Ch-AgNPs) to construct drug loaded nanoparticles as drug delivery system. The morphology and characteristics of the Ch-AgNPs were investigated by UV, FTIR, zeta potential and FESEM. Furthermore, the toxicity of AgNPs, Ch-AgNPs, Tam-Ch-AgNPs was evaluated through cell viability, lactate dehydrogenase leakage, reactive oxygen species generation, caspase-3, DNA laddering, and TUNEL assay in human breast cancer cells (MCF-7) and HBL-100 continuous cell line as a control. Treatment of cancer cells with various concentrations of AgNPs, Ch-AgNPs, Tam-Ch-AgNPs for 24 h revealed that Tam-Ch-AgNPs could inhibit cell viability and induce significant membrane leakage in a dose-dependent manner. Cells exposed to Tam-Ch-AgNPs showed increased reactive oxygen species and hydroxyl radical production when compared to AgNPs, Ch-AgNPs. Furthermore, the apoptotic effects of AgNPs, Ch-AgNPs, Tam-Ch-AgNPs were confirmed by activation of caspase-3 and DNA nuclear fragmentation. The present findings suggest that Tam-Ch-AgNPs could contribute to the development of a suitable anticancer drug delivery.

  5. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients.

    Science.gov (United States)

    Borges, Silvana; Desta, Zeruesenay; Jin, Yan; Faouzi, Azzouz; Robarge, Jason D; Philips, Sanosh; Philip, Santosh; Nguyen, Anne; Stearns, Vered; Hayes, Daniel; Rae, James M; Skaar, Todd C; Flockhart, David A; Li, Lang

    2010-04-01

    Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. The overall performance of the 3 gene scoring systems without consideration of CYP2D6-inhibiting medications in predicting CYP2D6 phenotype was poor in both the training set (R(2) = 0.24, 0.22, and 0.18) and the validation set (R(2) = 0.30, 0.24, and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R(2) values in the training and validation data sets were nearly twice as high as the genotype-only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41), respectively. The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 activity score doubled the ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, as yet unidentified factors must be involved in tamoxifen activation.

  6. Generation and characterization of transgenic mice expressing tamoxifen-inducible cre-fusion protein specifically in mouse liver.

    Science.gov (United States)

    Zhu, Huan-Zhang; Chen, Jian-Quan; Cheng, Guo-Xiang; Xue, Jing-Lun

    2003-08-01

    To establish transgenic mice expressing tamoxifen-inducible Cre-ERt recombinase specifically in the liver and to provide an efficient animal model for studying gene function in the liver and creating various mouse models mimicking human diseases. Alb-Cre-ERt transgenic mice were produced by microinjecting the construct with Cre-ERt fusion gene of DNA fragments into fertilized eggs derived from inbred C57BL/6 strain. Transgenic mice were identified by using PCR and Southern blotting. Expression of Cre-ERt fusion gene was analyzed in the liver, kidney, brain and lung from F1 generation transgenic mice at 8 weeks of age by reverse transcription (RT)-PCR. Four hundred and fourteen fertilized eggs of C57 BL/6 mice were microinjected with recombinant Alb-Cre-ERt DNA fragments, and 312 survival eggs injected were transferred to the oviducts of 12 pseudopregnant recipient mice, 6 of 12 recipient mice became pregnant and gave birth to 44 offsprings. Of the 44 offsprings, two males and one female carried the hybrid Cre-ERt fusion gene. Three mice were determined as founders, and were back crossed to set up F1 generations with other inbred C57BL/6 mice. Transmission of Cre-ERt fusion gene in F1 offspring followed Mendelian rules. The expression of Cre-ERt mRNA was detected only in the liver of F1 offspring from two of three founder mice. Transgenic mice expressing tamoxifen-inducible Cre-ERt recombinase under control of the liver-specific promoter are preliminary established.

  7. Comparative study of estrogenic potencies of estradiol, tamoxifen, bisphenol-A and resveratrol with two in vitro bioassays.

    Science.gov (United States)

    Li, Wen; Seifert, Martin; Xu, Ying; Hock, Bertold

    2004-05-01

    This study was undertaken to compare the sensitivity of two in vitro screening test methods and to determine the accuracy of predicted response to spiked laboratory water samples. A newly developed enzyme-linked receptor assay (ELRA) and a widely used yeast estrogen screen (YES) assay were selected to evaluate the estrogenic responses. Four natural, pharmaceutical, xenobiotic or phytobiotic chemicals: 17beta-estradiol (E2), tamoxifen, bisphenol-A and resveratrol were examined, and 17beta-E2 was used as a positive control. 17beta-E2 can strongly induce estrogenic response in both test systems, however, ELRA was found to be more sensitive to 17beta-E2 with a detection limit of 0.07 microg/l compared to 0.88 microg/l in YES assay. Similar results were obtained for bisphenol-A and resveratrol, and their estrogen potencies relative to E2 (100%) determined by ELRA were at least 5.6 times greater than produced by YES assay. ELRA was unable to distinguish the anti-estrogen tamoxifen and YES assay is also poor at distinguishing. Comparison of response to spiked laboratory water samples show that ELRA can give accurate determination to all four chemicals with recoveries among 70-120%, while YES can only give accurate determination to 17beta-E2 and bisphenol-A with recoveries among 69-112%. The comparative results provide evidence that ELRA is more suitable for rapid screening estrogenic potency of the environmental samples. Combination of ELRA and mammalian cellular assay will constitute an advantageous test to specify agonistic or antagonistic effects.

  8. Vegetable intake is associated with reduced breast cancer recurrence in tamoxifen users: a secondary analysis from the Women's Healthy Eating and Living Study.

    Science.gov (United States)

    Thomson, Cynthia A; Rock, Cheryl L; Thompson, Patricia A; Caan, Bette J; Cussler, Ellen; Flatt, Shirley W; Pierce, John P

    2011-01-01

    The protective effect of vegetables on the risk of breast cancer recurrence is uncertain. We sought to evaluate the association between breast cancer recurrence and vegetable intake including analyses stratified on tamoxifen use. Experimental evidence of anti-carcinogenic activity of phytochemicals in cruciferous vegetables in combination with tamoxifen led to specific evaluation of this class of vegetables as well. To assess the association between vegetable intake and breast cancer recurrence, vegetable intake from repeat 24-h dietary recalls were examined as a secondary analysis of 3,080 breast cancer survivors enrolled in the Women's Healthy Eating and Living (WHEL) Study. At the time of enrollment women were, on average, 23.5 months post-diagnosis. The hazard of recurrence, controlling for relevant and significant clinical and demographic variables, with vegetable intake was assessed overall and separately for women taking tamoxifen. WHEL participants reported mean baseline intakes (⁻x, SE) of 3.1 ± 0.05 and 0.5 ± 0.02 servings/day of total and cruciferous vegetables, respectively. Baseline vegetable intake in the highest as compared to lowest tertiles was associated with an overall lower adjusted hazard ratios (HR) for recurrence of 0.69, 95% CI 0.55-0.87. Among women taking tamoxifen, the HRs were 0.56, 95% CI 0.41-0.77 for total vegetables and 0.65, 95% CI 0.47-0.89 for cruciferous vegetable intake. The hazard in women using tamoxifen who reported cruciferous vegetable intake above the median and who were within the highest tertile of total vegetable intake was HR 0.48; 95% CI 0.32-0.70. This secondary analysis in over 3,000 breast cancer survivors suggests that baseline vegetable intake may be associated with a reduction in the risk of breast cancer recurrent or new events particularly for those using tamoxifen. Such associations should be explored further as the possibility that vegetable intake is simply a surrogate for other health

  9. The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause

    DEFF Research Database (Denmark)

    Chirgwin, Jacquie; Sun, Zhuoxin; Smith, Ian

    2012-01-01

    subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen......) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤ 55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither...... of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤ 55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients...

  10. Development and validation of a simple and sensitive high performance liquid chromatographic method for the simultaneous determination of anastrozole, bicalutamide, tamoxifen, and their synthetic impurities.

    Science.gov (United States)

    Gomes, Fabio Pereira; Garcia, Pedro Lopez

    2012-11-15

    A simple and sensitive analytical method for simultaneous determination of anastrozole, bicalutamide, and tamoxifen as well as their synthetic impurities, anastrozole pentamethyl, bicalutamide 3-fluoro-isomer, and tamoxifen e-isomer, was developed and validated by using high performance liquid chromatography (HPLC). The separation was achieved on a Symmetry(®) C-8 column (100×4.6 mm i.d., 3.5 μm) at room temperature (±24 °C), with a mobile phase consisting of acetonitrile/water containing 0.18% N,N dimethyloctylamine and pH adjusted to 3.0 with orthophosphoric acid (46.5/53.5, v/v) at a flow rate of 1.0 mL min(-1) within 20 min. The detection was made at a wavelength of 270 nm by using ultraviolet (UV) detector. No interference peaks from excipients and relative retention time indicated the specificity of the method. The calibration curve showed correlation coefficients (r) >0.99 calculated by linear regression and analysis of variance (ANOVA). The limit of detection (LOD) and limit of quantitation (LOQ), respectively, were 2.2 and 6.7 μg mL(-1) for anastrozole, 2.61 and 8.72 μg mL(-1) for bicalutamide, 2.0 and 6.7 μg mL(-1) for tamoxifen, 0.06 and 0.22 μg mL(-1) for anastrozole pentamethyl, 0.02 and 0.07 μg mL(-1) for bicalutamide 3-fluoro-isomer, and 0.002 and 0.007 μg mL(-1) for tamoxifen e-isomer. Intraday and interday relative standard deviations (RSDs) were <2.0% (drugs) and <10% (degradation products) as well as the comparison between two different analysts, which were calculated by f test.

  11. The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review

    OpenAIRE

    Fleeman, N.; Martín Saborido, Carlos; Payne, K; Boland, A; Dickson, R.; Dundar, Y.; Fernández Santander, Ana; Howell, S J; Newman, W G; Oyee, J.; Walley, T

    2011-01-01

    Background: Objectives: Data Sources: Review Methods: Results: Conclusion: Breast cancer is the most common cancer affecting women in the UK. Tamoxifen (TAM) is considered as the standard of care for many women with oestrogen receptor positive breast cancer. However, wide variability in the response of individuals to drugs at the same doses may occur, which may be a result of interindividual genetic differences (pharmacogenetics). TAM is known to be metabolised to its active metabolites N-des...

  12. The multidrug resistance proteins Pgp, MRP, and BCRP as markers for lowering the efficacy of tamoxifen in the treatment of breast cancer

    Directory of Open Access Journals (Sweden)

    T. A. Bogush

    2011-01-01

    Full Text Available The antiestrogen tamoxifen was examined for its effect on the interaction of monoclonal antibodies with the multidrug resistance markers: with Pgp and MRP1 in the cultured T-lymphoblast leukemia cell line Jurkat and with BCRP in the cultured cervical cancer cell line HeLa. The investigation used immunofluorescence and flow cytofluorimetric assays, primary monoclonal and isotypic antibodies labeled with the fluorescent dyes FITS and PE. After tamoxifen use, there was an increase in specific fluorescence and the number of specifically fluorescent cells on incubation with Pgp and BCRP antibodies and a reduction in those on incubation with MRP1 antibodies. This directly indicates that tomoxifen binds to Pgp, BCRP, and MRP1, which inevitably results in a decrease in the intracellular concentration of the antiestrogen available for the interaction with other cellular targets, including that with estrogen receptors. The authors consider that there is every reason to consider Pgp, BCRP, and MRP1 as markers for lowering the efficacy of tamoxifen in the treatment of breast cancer with the positive estrogen receptor status.

  13. The salubrious effect of tamoxifen [correction of Tamaxifen] on serum marker enzymes, glycoproteins, and lysosomal enzymes level in breast cancer woman.

    Science.gov (United States)

    Thangaraju, M; Rameshbabu, J; Vasavi, H; Ilanchezhian, S; Vinitha, R; Sachdanandam, P

    1998-08-01

    Tumour markers correlate strongly with prognosis based on tumour burden and surgical resectability. If chemotherapy is extremely effective in certain stage of the disease, the sensitive marker may be of great use in monitoring disease response and drug treatment. Hence, this study was launched to evaluate the changes in tumour marker enzymes like lactate dehydrogenase (LDH), glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase, and acid phosphatase in before and after 3 and 6 months tamoxifen treated breast cancer patients. In addition, the changes in serum glycoproteins viz., hexose, hexosamine, and sialic acid and lysosomal enzymes such as N-acetyl-beta-D-glucosaminidase, beta-D-galactosidase, and beta-D-glucuronidase were analysed in these patients. These values were compared with their age matched healthy control subjects. At 6 months evaluation, the tamoxifen treated postmenopausal breast cancer women showed a statistically significant decreased (p sialic acid and N-acetyl-beta-D-glucosaminidase, beta-D-galactosidase, and beta-D-glucuronidase were decreased significantly (p breast cancer as well as the bone demineralisation in postmenopausal breast cancer women. Thus, tamoxifen may also have its antitumour activity through its beneficial effects on tumour marker enzymes and serum proteins in breast cancer women.

  14. Interest of molecularly imprinted polymers in the fight against doping. Extraction of tamoxifen and its main metabolite from urine followed by high-performance liquid chromatography with UV detection.

    Science.gov (United States)

    Claude, Bérengère; Morin, Philippe; Bayoudh, Sami; de Ceaurriz, Jacques

    2008-07-04

    A molecular imprinted polymer (MIP) has been synthesized in order to specifically extract tamoxifen, a nonsteroidal antiestrogen, and its metabolites from urine by solid-phase extraction (SPE) before HPLC-UV analysis. Clomiphene, a chlorinated tamoxifen analogue, was selected as template for MIP synthesis. Polymerisation was achieved by thermal polymerisation of methacrylic acid (MAA) as functional monomer, ethylene glycol dimethacrylate (EDMA) as cross-linking agent and acetonitrile as porogen. The efficient elimination of the urinary matrix has been obtained by MIP-SPE but the elution recovery of tamoxifen was initially too low ( approximately 14%). This problem has been overcome following two ways. At first, a preliminary HLB-SPE of the urine has enabled to discard endogenous salts and to percolate an organic sample through the MIP cartridge. Extraction recoveries are equal to 56 and 74% for tamoxifen and 4-hydroxytamoxifen, respectively. Then, a second MIP has been prepared with styrene and MAA as functional co-monomers. Strong pi-pi interactions occurring between phenyl groups of styrene and tamoxifen promote rebinding of the analyte by the specific sites. The enhanced hydrophobic character of the imprinted polymer has enabled the direct percolation of urine through MIP-SPE and the easy elimination of endogenous salts from urine with only one aqueous washing step. HPLC-UV analysis has confirmed high extraction recoveries (85%) for tamoxifen and its metabolite with an enrichment factor of 8. This analytical protocol can selectively detect the presence of tamoxifen metabolites in urines and be useful as a proof of doping in competitive sports.

  15. Comparative Study on the Curative Effect of Clomifene and Tamoxifen in Infertile Patients With Polycystic Ovary Syndrome%氯米芬与他莫昔芬治疗多囊卵巢综合征不孕患者疗效对比研究

    Institute of Scientific and Technical Information of China (English)

    孙春凤; 王木森

    2016-01-01

    Objective To compare the clinical efficacy of polycystic ovary syndrome infertile patients treated with Clomifene and tamoxifen therapy.Methods There were 76 patients with polycystic ovary syndrome infertile patients in this study, al the patients were selected from January 2014 to April 2015 in our hospital, according to the different treatment methods they were divided into group I, group II,there were 38 cases in each group. The patients of group I were given tamoxifen for treatment, patients of the group II received Clomifene treatment, LH, FSH, T levels and ovulation rate, pregnancy rate of two group after three courses were compared.Results LH, T levels of two groups after treatment decreased, FSH levels began to increase significantly, the degree of raise or lower in group I was significantly greater than group II, the difference was statisticaly significant (P<0.05). The ovulation rate and pregnancy rate of group I was higher than group II, the difference was statisticaly significant(P<0.05). ConclusionClomifene and tamoxifen in treatment of Polycystic Ovary Syndrome have a therapeutic effect, but the use of tamoxifen therapy in improving the breakdown of estrogen levels in patients and significantly improve the pregnancy rate convenience advantages, it is recommended in clinical application.%目的:对比分析氯米芬与他莫昔芬治疗多囊卵巢综合征不孕患者临床疗效。方法本次研究中的76例多囊卵巢综合征不孕患者均为2014年1月~2015年4月我院收治,按照治疗方法的不同分为I组,II组,每组患者38例,I组给予他莫昔芬进行治疗,II组给予氯米芬治疗,治疗3个疗程后对比两组患者的LH、FSH、T水平及排卵率、妊娠率。结果治疗后两组LH、T水平出现下降,FSH水平出现升高,I组升高或降低的程度大于II组,两组差异有统计学意义(P<0.05)。I组患者的排卵率及妊娠率高于II组,两组差异有统计学意义(P<0.05

  16. Structure-activity relationships of nonisomerizable derivatives of tamoxifen: importance of hydroxyl group and side chain positioning for biological activity.

    Science.gov (United States)

    Murphy, C S; Parker, C J; McCague, R; Jordan, V C

    1991-03-01

    The antiestrogen tamoxifen [(Z)-1(p-beta-dimethylaminoethoxy-phenyl)-1,2-diphenylbut-1-ene] is an effective anticancer agent against estrogen receptor (ER)-positive breast cancer. The alkylaminoethane side chain is essential for antiestrogenic activity, but the potency of the antiestrogen can be increased by para hydroxylation of the phenyl ring on carbon 1 of but-1-ene. This compound, 4-hydroxytamoxifen, is a metabolite of tamoxifen and has a very high binding affinity for ER [J. Endocrinol. 75:305-316 (1977)] because the hydroxyl is located in the equivalent position as the 3-phenolic hydroxyl of 17 beta-estradiol. In this study, we have examined the relationship between the relative positions of the hydroxyl and the alkyl-aminoethane side chain and the pharmacological activity of the ligand. A fixed seven-membered ring derivative of the triphenylethylene was used to prevent isomerization. All compounds were tested, with and without 17 beta-estradiol, for their effects on the growth of estrogen-responsive T47D and MCF-7 human breast cancer cells in vitro. The growth of MDA-MB-231 ER-negative breast cancer cells was not affected by any of the compounds tested, at a concentration (1 microM) that had a profound estrogenic or antiestrogenic action in ER-positive cell lines. The relative binding affinity of the compounds was determined using rat uterine ER and was found to be consistent with the observed potencies in vitro. The compounds found to be antiestrogens in vitro were antiestrogenic against estradiol (0.08 micrograms daily) in the 3-day immature rat uterine weight test. All compounds were partial agonists in vivo. In general, the estrogenic and antiestrogenic results obtained in vivo were consistent with the potency estimates obtained with the breast cancer cells in vitro. The results of this extensive structure-activity relationship study demonstrate that the substitution for 4-hydroxytamoxifen appears to be optimal to produce a potent antiestrogen; all

  17. Hormone therapy for patients with advanced or recurrent endometrial cancer.

    Science.gov (United States)

    Lee, Wen-Ling; Yen, Ming-Shyen; Chao, Kuan-Chong; Yuan, Chiou-Chung; Ng, Heung-Tat; Chao, Hsiang-Tai; Lee, Fa-Kung; Wang, Peng-Hui

    2014-05-01

    The "gold standard" treatment for endometrial cancer is completely staged surgery, followed by radiation or chemotherapy, based on the final pathological surgical stage and requirements. In the primary treatment of endometrial cancers, hormones are rarely taken into consideration after primary surgery. Primary treatment with hormones to preserve fertility in younger women with endometrial cancer is an attractive option, and many successful cases have been reported, although the majority of them finally received definite therapy, including total hysterectomy. The role of hormone therapy is often delayed in recurrent disease; response rates to progestins and tamoxifen or aromatase inhibitors in advanced/recurrent endometrial cancers are approximately 15-20% and nearly ≤ 10%, respectively. This review is focused on updated information and recent knowledge on the use of hormones in the management of women with advanced or recurrent endometrial cancers.

  18. Expressions of Ki67,estrogen receptor,and progestogen receptor in endometrium of patients with breast cancer after oral administration of Tamoxifen and the changes of sex hormones levels%Ki67ER及PR在乳腺癌患者服用他莫昔芬后子宫内膜的表达及其性激素水平的变化

    Institute of Scientific and Technical Information of China (English)

    樊艺; 韩克

    2012-01-01

    Objective: To explore the characteristics and significances of expressions of Ki67 , estrogen receptor, and progestogen receptor in endometrium, the relationship between the thickness of endometrium and time, age in patients with breast cancer after oral administration of Tamoxifen. Methods: A total of 48 patients with breast cancer who were treated with Tamoxifen were selected, then routine trans-vaginal ultrasonography was performed to examine the situations of bilateral uterine appendages, diagnostic curettage was conducted when ul-trasonogiaphy indicated that the thickness of endometrium was more than 5 mm; the endometrial tissues of 16 patients after curettage deceived pathological examination, estrogen receptor, progestogen receptor, and Ki67 were detected by immunohistochemical method. Thirty patients without drug therapy were selected as control group, pathological examination showed there was no endometrial lesions, and the samples received immunohistochetnical staining, the expressions of estrogen receptor, progestogen receptor, and Ki67 in endometrium were detected, the thickness of endometrium was detected by ultrasonography. Results; The results of ultrasonography in the patients with breast cancer; 23 patients were found with hysteromyoma (47. 92% ) , 9 patients were found with ovarian cyst (18. 75% ) , one patient was found with endometrial polyps (2. 08% ) , 4 patients were found with adenomyosis. In Tamoxifen group, the expression levels of estrogen receptor and progestogen receptor in glands of endometrium were higher than those in normal endometrium ( secretory phase) . The correlation between expression of progestogen receptor in glands and positive rate of Ki67 in Tamoxifen group and control group was the strongest Conclusion; There was a positive correlation between estrogen receptor expression, progestogen receptor expression and Ki67 expression. The endometrium of patients with breast cancer who were treated with oral administration of

  19. Topotecan-tamoxifen duple PLGA polymeric nanoparticles: investigation of in vitro, in vivo and cellular uptake potential.

    Science.gov (United States)

    Khuroo, Tahir; Verma, Devina; Talegaonkar, Sushama; Padhi, Santwana; Panda, Amulya K; Iqbal, Zeenat

    2014-10-01

    The dual drug loaded poly(dl-lactic-co-glycolic acid) (PLGA(1)) nanoparticles (TOP-TAM NPs(2)) concurrently delivering topotecan hydrochloride (TOP(3)) and tamoxifen citrate (TAM(4)) were developed to achieve synergism for the treatment of breast cancer by enhancing the permeation of TOP through the gut and the cells present in the breast. TAM acted as P-glycoprotein (P-gp(5)) inhibitor, reduced the side effects of individual drugs by reducing the dose. The NPs were prepared by double emulsion (w/o/w) method. The optimized TOP-TAM NPs were found to have smooth and spherical morphology by using SEM(6) and TEM(7) technique. Similarly size of nanoparticles was found to be 151.2 ± 1.6 nm with 0.147 ± 0.03 polydispersity index (PDI(8)). The percentage entrapment efficiency of 95.17 ± 3.57 and 57.77 ± 2.2 was found for TAM and TOP respectively. The lyophillized nanoparticles under DSC(9) showed amorphous nature of both TOP and TAM. In an in vitro release study the release of drugs from TOP-TAM NPs was found to follow the Higuchi pattern. The ex vivo gut permeation study revealed that the TAM enhanced the permeation of TOP and increased its bioavailability by 1.9 folds. The permeation and activity of combination of drugs were further confirmed by carrying out cell line studies on MCF-7 cells.

  20. The Influences of Mifepristone, Norethisterone and Tamoxifen on the Glycosphingolipids Compositions from Human Chorionic Tissue during Early Pregnancy

    Institute of Scientific and Technical Information of China (English)

    孙翠翔; 周剑萍; 于传鑫; 张俊慧; 张厦英; 刘银刊

    1996-01-01

    By using the Ladisch partitioning and microscale-analysis of HPTLC the comparative quantitative and qualitative studies of gangtiosides (Gg) and neutral gtycosphingotipids ( N-GSL ) compositions from human chorionic villi tissues of normal early pregnant women and women treated with mifepristone, norethisterone (NET) and tamoxifen (TAM) were reported in this paper. The patterns of Gg and N-GSL in three treated groups were similar to those in normal pregnant group, The total values of Gg from the ckorionic villi tissues reduced significantly in three treated groups (P<0. 01), In all treated groups, the amounts of NeuNAC-Gal-Glc-cer (GM3) , NeuNAC-NeuNAC-Gal-Gtc-cer ( GD3) and Gal-GalNAC-(NeuNAC)-Gal-Glc-eer(GM1 ) were decreased significantly compared with those in normal (P<0. 01 or P<0. 05), In NET and TAM groups, Neu NAC-Gal-GalNAC-(NeuNAC-NeuNAC )-Gal-Glc-cer( GT16 ) was markedly lower than that in normal (P<0. 01), The total values of N-GSL extracted from the chorionic villi tissues were obviously higher in mifepristone and TAM groups than those in normal (P<0. 01). The Gal-Gte-cer(LacCer) (CDH) and Gal-Gal-Glc-cer(Gat-LacCer) (CTH)were greatly increased in mifepristone group as compared with normal (P<0. 05 ), Paragloboside : Gat-GalNAC-Gal-Gtc-cer (PG) in NETgroup was significantly higher than that in normal (P<0. 01 ).

  1. Acid-base cosolvent method for determining aqueous permeability of amiodarone, itraconazole, tamoxifen, terfenadine and other very insoluble molecules.

    Science.gov (United States)

    Ruell, Jeffrey Alan; Tsinman, Oksana; Avdeef, Alex

    2004-05-01

    A high-throughput, UV-detection PAMPA (parallel artificial membrane permeability assay) cosolvent procedure is described, based on the use of 20% v/v acetonitrile in aqueous buffer. A training set of 32 drugs (17 bases, 13 acids, 2 ampholytes) was studied both in aqueous buffer and in cosolvent-buffer solutions. A procedure was devised, where intrinsic permeability values, log P(o)(COS), measured in cosolvent solution, are converted to values expected under cosolvent-free conditions, using an in silico model based on Abraham H-bond acidity (alpha) and basicity (beta) descriptors, developed with the Algorithm Builder computer program, to obtain aqueous intrinsic permeability values: log P(o)=0.738+0.885 log P(o)(COS)-1.262alpha+0.436beta, r(2)=0.97, q(2)=0.96, s=0.38, n=32, F=279. Five sparingly-soluble weak bases (solubility tamoxifen 28 cm/s; terfenadine 162 cm/s.

  2. Slingshot: a PiggyBac based transposon system for tamoxifen-inducible 'self-inactivating' insertional mutagenesis.

    Science.gov (United States)

    Kong, Jun; Wang, Feng; Brenton, James D; Adams, David J

    2010-10-01

    We have developed a self-inactivating PiggyBac transposon system for tamoxifen inducible insertional mutagenesis from a stably integrated chromosomal donor. This system, which we have named 'Slingshot', utilizes a transposon carrying elements for both gain- and loss-of-function screens in vitro. We show that the Slingshot transposon can be efficiently mobilized from a range of chromosomal loci with high inducibility and low background generating insertions that are randomly dispersed throughout the genome. Furthermore, we show that once the Slingshot transposon has been mobilized it is not remobilized producing stable clonal integrants in all daughter cells. To illustrate the efficacy of Slingshot as a screening tool we set out to identify mediators of resistance to puromycin and the chemotherapeutic drug vincristine by performing genetrap screens in mouse embryonic stem cells. From these genome-wide screens we identified multiple independent insertions in the multidrug resistance transporter genes Abcb1a/b and Abcg2 conferring resistance to drug treatment. Importantly, we also show that the Slingshot transposon system is functional in other mammalian cell lines such as human HEK293, OVCAR-3 and PE01 cells suggesting that it may be used in a range of cell culture systems. Slingshot represents a flexible and potent system for genome-wide transposon-mediated mutagenesis with many potential applications.

  3. Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells.

    Science.gov (United States)

    Nair, Binoj C; Vallabhaneni, Sreeram; Tekmal, Rajeshwar R; Vadlamudi, Ratna K

    2011-08-11

    Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)α functions and aromatase inhibitors that decrease local and systemic estrogen production. Both of these strategies improve outcomes for ERα-positive breast cancer patients, however, development of therapy resistance remains a major clinical problem. Divergent molecular pathways have been described for this resistant phenotype and interestingly, the majority of downstream events in these resistance pathways converge upon the modulation of cell cycle regulatory proteins including aberrant activation of cyclin dependent kinase 2 (CDK2). In this study, we examined whether the CDK inhibitor roscovitine confers a tumor suppressive effect on therapy-resistant breast epithelial cells. Using various in vitro and in vivo assays, we tested the effect of roscovitine on three hormonal therapy-resistant model cells: (a) MCF-7-TamR (acquired tamoxifen resistance model); (b) MCF-7-LTLTca (acquired letrozole resistance model); and (c) MCF-7-HER2 that exhibit tamoxifen resistance (ER-growth factor signaling cross talk model). Hormonal therapy-resistant cells exhibited aberrant activation of the CDK2 pathway. Roscovitine at a dose of 20 μM significantly inhibited the cell proliferation rate and foci formation potential of all three therapy-resistant cells. The drug treatment substantially increased the proportion of cells in G2/M cell cycle phase with decreased CDK2 activity and promoted low cyclin D1 levels. Interestingly, roscovitine also preferentially down regulated the ERα isoform and ER-coregulators including AIB1 and PELP1. Results from xenograft studies further showed that roscovitine can attenuate growth of therapy-resistant tumors in vivo. Roscovitine can reduce cell proliferation and survival of hormone therapy-resistant breast cancer cells. Our results support the emerging concept that inhibition of CDK2 activity has the potential to

  4. Combination of low-concentration of novel phytoestrogen (8,9)-furanyl-pterocarpan-3-ol from Pachyrhizus erosus attenuated tamoxifen-associated growth inhibition on breast cancer T47D cells

    Institute of Scientific and Technical Information of China (English)

    Arief Nurrochmad; Endang Lukitaningsih; Ameilinda Monikawati; Dita Brenna Septhea; Edy Meiyanto

    2013-01-01

    Objective: To investigate the estrogenic effect of (8,9)-furanyl-pterocarpan-3-ol (FPC) on growth of human breast cancer T47D cells and the interactions between the FPC and tamoxifen (TAM), on the growth of estrogen receptor-dependent breast cancer T47D cells.Methods:T47D cells were treated with FPC alone (0.01-200 μmol/L) or in combination with TAM 20 nmol/L. The proliferation effect of FPC were conducted on T47D cells in vitro by MTT test. Furthermore, the expression of ERα or c-Myc were also determined by immunohistochemistry.Results:inhibitory effect on T47D cells, wheraes co-administered with low concentration (less than 1μmol/L) of FPC attenuated to promote cell proliferation. In contrast, the combination of TAM with higher doses (more than 20 μmol/L) of FPC showed growth inhibitory. This result was supported by immunocytochemistry studies that the administration of 20 nmol/L TAM down-regulated ER-αand c-Myc, but the combination of 20 nmol/L TAM and 1 μmol/L FPC robustly up-regulated expression of ER-α. Thus, the reduced growth inhibition of TAM 20 nmol/L by FPC 1 μmol/L on T47D cells may act via the modulation of ER-α.Conclusions:The findings indicate and suggest that FPC had estrogenic activity at low The results indicated that administration of an anti-estrogen TAM showed growth concentrations and anti-estrogenic effect that are likely to be regulated by c-Myc and estrogen receptors. We also confirm that low concentration of FPC attenuated the growth-inhibitory effects of TAM on mammary tumor prevention. Therefore, the present study suggests that caution is warranted regarding the consumption of dietary FPC by breast cancer patients while on TMA therapy.

  5. Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells.

    Science.gov (United States)

    Yu, Xinfeng; Li, Ruilian; Shi, Wenna; Jiang, Tao; Wang, Yufei; Li, Cong; Qu, Xianjun

    2016-02-01

    Tamoxifen (TAM) and fulvestrant (FUL) represent the major adjuvant therapy to estrogen receptor-alpha positive (ER(+)) breast cancer patients. However, endocrine resistance to TAM and FUL is a great impediment for successful treatment. We hypothesized that miR-21 might alter the sensitivity of breast cancer cells to TAM or FUL by regulating cell autophagy. Using the ER(+) breast cancer cells, we knockdown miR-21.by transfection with miR-21 inhibitor, then the cells were exposed to TAM or FUL and the percentages of apoptosis and autophagy were determined. Knockdown of miR-21 significantly increased the TAM or FUL-induced apoptosis in ER(+) breast cancer cells. Further, silencing of miR-21 in MCF-7 cells enhanced cell autophagy at both basal and TAM or FUL-induced level. The increase of autophagy in miR-21-knockdown MCF-7 cells was also indicated by increase of beclin-1, LC3-II and increased GFP-LC3 dots. Importantly, knockdown of miR-21 contributed to autophagic cell death, which is responsible for part of TAM induced cell death in miR-21 inhibitor-transfected cells. Further analysis suggested that miR-21 inhibitor enhance autophagic cell death through inhibition of PI3K-AKT-mTOR pathway. MiR-21 coordinated the function of autophagy and apoptosis by targeting Phosphatase and tensin homolog (PTEN) through inhibition of PI3K-AKT-mTOR pathway. In conclusion, silencing of miR-21 increased the sensitivity of ER(+) breast cancer cells to TAM or FUL by increasing autophagic cell death. Targeting autophagy-related miRNAs is a potential strategy for overcoming endocrine resistance to TAM and FUL.

  6. Thioredoxin-mediated redox regulation of resistance to endocrine therapy in breast cancer.

    Science.gov (United States)

    Penney, Rosalind Brigham; Roy, Deodutta

    2013-08-01

    Resistance to endocrine therapy in breast carcinogenesis due to the redox regulation of the signal transduction system by reactive oxygen species (ROS) is the subject of this review article. Both antiestrogens and aromatase inhibitors are thought to prevent cancer through modulating the estrogen receptor function, but other mechanisms cannot be ruled out as these compounds also block metabolism and redox cycling of estrogen and are free radical scavengers. Endocrine therapeutic agents, such as, tamoxifen and other antiestrogens, and the aromatase inhibitor, exemestane, are capable of producing ROS. Aggressive breast cancer cells have high oxidative stress and chronic treatment with exemestane, fulvestrant or tamoxifen may add additional ROS stress. Breast cancer cells receiving long-term antiestrogen treatment appear to adapt to this increased persistent level of ROS. This, in turn, may lead to the disruption of reversible redox signaling that involves redox-sensitive phosphatases, protein kinases, such as, ERK and AKT, and transcription factors, such as, AP-1, NRF-1 and NF-κB. Thioredoxin modulates the expression of estrogen responsive genes through modulating the production of H2O2 in breast cancer cells. Overexpressing thioredoxine reductase 2 and reducing oxidized thioredoxin restores tamoxifen sensitivity to previously resistant breast cancer cells. In summary, it appears that resistance to endocrine therapy may be mediated, in part, by ROS-mediated dysregulation of both estrogen-dependent and estrogen-independent redox-sensitive signaling pathways. Further studies are needed to define the mechanism of action of thioredoxin modifiers, and their effect on the redox regulation that contributes to restoring the antiestrogen-mediated signal transduction system and growth inhibitory action.

  7. Tamoxifen-regulated adenoviral E1A chimeras for the control of tumor selective oncolytic adenovirus replication in vitro and in vivo.

    Science.gov (United States)

    Sipo, I; Wang, X; Hurtado Picó, A; Suckau, L; Weger, S; Poller, W; Fechner, H

    2006-01-01

    Pharmacological control is a desirable safety feature of oncolytic adenoviruses (oAdV). It has recently been shown that oAdV replication may be controlled by drug-dependent transcriptional regulation of E1A expression. Here, we present a novel concept that relies on tamoxifen-dependent regulation of E1A activity through functional linkage to the mutated hormone-binding domain of the murine estrogen receptor (Mer). Four different E1A-Mer chimeras (ME, EM, E(DeltaNLS)M, MEM) were constructed and inserted into the adenoviral genome under control of a lung-specific surfactant protein B promoter. The highest degree of regulation in vitro was seen for the corresponding oAdVs Ad.E(DeltaNLS)M and Ad.MEM, which exhibited an up to 100-fold higher oAdV replication in the presence as compared with the absence of 4-OH-tamoxifen. Moreover, destruction of nontarget cells was six- and 13-fold reduced for Ad.E(DeltaNLS)M and Ad.MEM, respectively, as compared with Ad.E. Further investigations supported tamoxifen-dependent regulation of Ad.E(DeltaNLS)M and Ad.MEM in vivo. Induction of Ad.E(DeltaNLS)M inhibited growth of H441 lung tumors as efficient as a control oAdV expressing E1A. E(DeltaNLS)M and the MEM chimeras can be easily inserted into a single vector genome, which extends their application to existing oAdVs and strongly facilitates in vivo application.

  8. A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node-positive breast cancer

    OpenAIRE

    De Placido, S.; DE LAURENTIIS M; De Lena, M; LORUSSO V; Paradiso, A; DAPRILE M; Pistillucci, G; Farris, A; SAROBBA MG; Palazzo, S.; Manzione, L; Adamo, V.; Palmeri, S; FERRAU F; Lauria, R.

    2005-01-01

    The sequential doxorubicin → CMF (CMF=cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF × 6 cycles (CMF); (b) doxorubicin × 4 cycles followed by CMF × 6 cycles (A → CMF); (c) CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (CMF → GT); and (d) doxorubicin × 4 cycles followed...

  9. Expression of a phosphorylated p130Cas substrate domain attenuates the phosphatidylinositol 3-kinase/Akt survival pathway in tamoxifen resistant breast cancer cells

    OpenAIRE

    Soni, Shefali; Lin, Bor-Tyh; August, Avery; Nicholson, Robert I; Kirsch, Kathrin H.

    2009-01-01

    Elevated expression of p130Cas/BCAR1 (breast cancer anti estrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. Specifically, p130Cas signaling has been associated with antiestrogen resistance, for which the mechanism is currently unknown. TAM-R cells, which were established by long-term exposure of estrogen (E2)-dependent MCF-7 cells to tamoxifen, displayed elevated levels of total and activated p130Cas. Here we have investigated the effects of...

  10. Interaction of calf thymus dsDNA with anti-tumor drug tamoxifen studied by zero current potentiometry.

    Science.gov (United States)

    Guo, Xiao-xia; Song, Zhang-jun; Sun, Jie-juan; Song, Jun-feng

    2011-06-15

    Since the electrochemical oxidation peaks of both DNA and anti-tumor drug tamoxifen (TAM) overlapped with each other, the known electrochemical methods were limited in the study of the interactions between DNA and TAM. In this paper, zero current potentiometry, a new electrochemical method, was used to study the interaction of calf thymus dsDNA with TAM. The dsDNA was immobilized on the surface of carbon paste (dsDNA/CP). The dsDNA/CP connected in series between the clips of working and counter electrodes of a potentiostat and a reference electrode were immersed in aqueous solution containing TAM, the interaction of dsDNA with TAM produced a change in interfacial potential at the dsDNA/CP/solution interface. When linear sweep potential was applied to the dsDNA/CP and the corresponding I-E curve was recorded, interfacial potential offset applied potential partially, making the I-E curve displace along potential axis. Zero current potential where circuit current I was equal to zero in the I-E curve was measured to check the displacement of the I-E curve. Based on the displacement, the thermodynamic constants of the interaction between dsDNA and TAM were determined. The binding ratio of dsDNA with TAM was found to be 1:1 and the apparent binding constant was (6.85±0.20)×10(6) M(-1). As zero current potentiometry was independent of the changes in redox potential or current of both dsDNA and TAM themselves, the interaction was studied in their natural forms without damage. Moreover, TAM can be determined. The detection limit was 1.1×10(-7) M.

  11. Estradiol and its membrane-impermeable conjugate estradiol-BSA inhibit tamoxifen-stimulated prolactin secretion in incubated rat pituitaries.

    Science.gov (United States)

    Aguilar, R; Bellido, C; Garrido-Gracia, J C; Alonso, R; Sánchez-Criado, J E

    2006-04-01

    In the absence of estrogen (E), the selective E receptor modulator tamoxifen (TX) has two agonist effects in the rat pituitary: induction of progesterone receptor (PR)-dependent GnRH self-priming in the gonadotrope, and stimulation of prolactin (PRL) secretion in the lactotrope. TX-induced gonadotropin (GnRH) self-priming is absent when 10(-8) M estradiol-17beta (E2) is added to the incubation medium of pituitaries from TX-treated rats. The present experiments investigated whether PR-independent PRL release into the incubation medium of pituitaries from TX-treated ovariectomized (OVX) rats was affected by E2, and the effect of different ER ligands (ICI182780, TX, estradiol-17alpha, E2 -BSA) on TX-stimulated PRL secretion. Moreover, the effect of E2 on TRH-stimulated PRL secretion in pituitaries collected from estradiol benzoate- and TX-treated OVX rats was studied. It was found that: i) incubation with E2 supressed the PRL releasing effect of injected TX; ii) whereas coincubation with the pure anti-E type II ICI182780 antagonized the inhibitory effect of E2, coincubation with the anti-E type I TX did not; iii) estradiol-17alpha lacked inhibitory action, whereas a dose-dependent inhibitory effect of both E2 and E2 -BSA was noticed; and iv) TRH stimulatory effect on PRL release in pituitaries from TX-treated rats was blocked by addition of E2 to the medium. Taken together, these data argue in favor of the presence of specific membrane recognition sites for E in the lactotrope involved in steroid-specific E2 inhibition of TX-stimulated PRL secretion.

  12. Thymoquinone Could Increase The Efficacy of Tamoxifen Induced Apoptosis in Human Breast Cancer Cells: An In Vitro Study

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    Sedigheh Ganji-Harsini

    2016-07-01

    Full Text Available Objective Thymoquinone (TQ, as the main component of Nigella Sativa plant, shows anticancer properties. This study was aimed to evaluate the combined effect of TQ and Tamoxifen (TAM on viability and apoptosis of human breast cancer cell lines. Materials and Methods In this experimental study, estrogen positive MCF-7 and estrogen negative MDA-MB-231 human breast cancer cell lines were induced by TAM (2 µM or different doses of TQ (50, 75, 100, 150 µM, individually or in combination. Cell viability and apoptosis were investigated by MTT assay and TdT-mediated deoxy-uracil nick end labeling (TUNEL assay; Acridine orange (AO/Ethidium bromide (EB staining respectively. Data were analyzed by one way ANOVA and P<0.05 was considered significant. Results In 24 hours treatment, TAM and all doses of TQ, solely or in combination, significantly reduced cell viability of both cell lines, except in MCF-7 cells treated with 50 µM TQ, and MDA-MB-231 cells treated with 50 or 75 µM TQ (P<0.01. After 48 hours treatment, cell viability of both cell lines was reduced in all treated groups (P<0.05. Remarkable apoptotic index was observed in combination treatment of MCF-7 or MDA-MB-231 cell lines with TAM and TQ (P<0.001. Conclusion The synergistic effect of TQ and TAM on human breast cancer cell lines showed cell viability reduction as well as apoptosis induction, independent to estrogen.

  13. Reactivity and antiproliferative activity of ferrocenyl-tamoxifen adducts with cyclodextrins against hormone-independent breast-cancer cell lines.

    Science.gov (United States)

    Buriez, Olivier; Heldt, Jan Martin; Labbé, Eric; Vessières, Anne; Jaouen, Gerard; Amatore, Christian

    2008-01-01

    Hydroxyferrocifen compounds are a new and promising class of ferrocifen-type breast-cancer drug candidates. They possess both endocrine-modulating properties and cytotoxic activity, which come from the tamoxifen skeleton and the presence of a ferrocene moiety, respectively. However, they suffer from reduced solubility in water, which presents a problem for their eventual therapeutic use. Herein, we examined the interactions of hydroxyferrocifen compounds with cyclodextrins (CDs) to evaluate whether or not their electron-transfer oxidation pathways were affected by their inclusion. It has been demonstrated that these inclusion complexes are soluble in pure water, which shows that CDs can be used to deliver these biologically active molecules. Therefore, a series of these compounds has been investigated by cyclic voltametry in various media in the presence of CDs (beta-CD and Me-beta-CD). In methanol, the hydroxyferrocifen compounds exhibited a weak interaction with the CD cavity. These interactions became stronger as the amount of added water increased. The complexation effect between the hydroxyferrocifen compounds and beta-CD was found to be stronger if the CD was partially methylated, which is probably due to hydrophobic effects between the cyclopentadienyl ring and/or the aromatic rings and the methoxy groups. Moreover, it appears that the structure of the hydroxyferrocifen compounds affects both their solubility and their complexation dynamics. Investigations in the presence of pyridine show that the base kinetically favors the dissociation of the ferrocifen-CD complex during the electron transfer step, but does not affect the follow-up reactivity of the electrogenerated ferrocenium cation, which leads eventually to the corresponding quinone methide, as reported in the absence of CD. Accordingly, the cytotoxicity of these beta-CD-encapsulated organometallic complexes in hormone-independent breast-cancer cells (MDA-MB231) were confirmed to be similar to those

  14. let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in breast cancer.

    Science.gov (United States)

    Zhao, Yingchun; Deng, Caishu; Lu, Weida; Xiao, Jing; Ma, Danjun; Guo, Mingxi; Recker, Robert R; Gatalica, Zoran; Wang, Zhaoyi; Xiao, Gary Guishan

    2011-01-01

    MicroRNAs (miRNAs) play an important regulatory role in breast tumorigenesis. Previously, we found that let-7 miRNAs were downregulated significantly in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. In this study, we further found that endogenous levels of let-7b and let-7i miRNA