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Sample records for genotype-guided tamoxifen therapy

  1. Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

    Science.gov (United States)

    Empey, Philip E; Stevenson, James M; Tuteja, Sony; Weitzel, Kristin W; Angiolillo, Dominick J; Beitelshees, Amber L; Coons, James C; Duarte, Julio D; Franchi, Francesco; Jeng, Linda J B; Johnson, Julie A; Kreutz, Rolf P; Limdi, Nita A; Maloney, Kristin A; Owusu Obeng, Aniwaa; Peterson, Josh F; Petry, Natasha; Pratt, Victoria M; Rollini, Fabiana; Scott, Stuart A; Skaar, Todd C; Vesely, Mark R; Stouffer, George A; Wilke, Russell A; Cavallari, Larisa H; Lee, Craig R

    2017-12-26

    CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. © 2018, The American Society for Clinical Pharmacology and Therapeutics.

  2. 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

  3. Principles of management of recurrence of breast cancer after tamoxifen therapy (abstract)

    International Nuclear Information System (INIS)

    Rasool, I.

    1999-01-01

    The management of recurrence of breast cancer after Tamoxifen therapy needs special attention. The recurrence can be local or distant. The patient, should be thoroughly investigated to find out exact sites of recurrences. Local recurrence is managed by excision, skin grafting or various types of flaps. If extensive radiation is administrated or if not given previously. The distant recurrence in patients who have had adjuvant menopausal status, sites of recurrence while life threatening or not and previous response. The patients who are post menopausal have responded to previous Tamoxifen therapy, long DFI and soft tissues and bony metastasis are best managed by Aromatase inhibitors i.e. Letrozole. (author)

  4. National Prociency Testing Result of CYP2D6*10 Genotyping for Adjuvant Tamoxifen Therapy in China.

    Directory of Open Access Journals (Sweden)

    Guigao Lin

    Full Text Available Tamoxifen has been successfully used for treating breast cancer and preventing cancer recurrence. Cytochrome P450 2D6 (CYP2D6 plays a key role in the process of metabolizing tamoxifen to its active moiety, endoxifen. Patients with variants of the CYP2D6 gene may not receive the full benefit of tamoxifen treatment. The CYP2D6*10 variant (the most common variant in Asians was analyzed to optimize the prescription of tamoxifen in China. To ensure referring clinicians have accurate information for genotype-guided tamoxifen treatment, the Chinese National Center for Clinical Laboratories (NCCL organized a national proficiency testing (PT to evaluate the performance of laboratories providing CYP2D6*10 genotyping. Ten genomic DNA samples with CYP2D6 wild-type or CYP2D6*10 variants were validated by PCR-sequencing and sent to 28 participant laboratories. The genotyping results and pharmacogenomic test reports were submitted and evaluated by NCCL experts. Additional information regarding the number of samples tested, the accreditation/certification status, and detecting technology was also requested. Thirty-one data sets were received, with a corresponding analytical sensitivity of 98.2% (548/558 challenges; 95% confidence interval: 96.7-99.1% and an analytic specificity of 96.5% (675/682; 95% confidence interval: 97.9-99.5%. Overall, 25/28 participants correctly identified CYP2D6*10 status in 10 samples; however, two laboratories made serious genotyping errors. Most of the essential information was included in the 20 submitted CYP2D6*10 test reports. The majority of Chinese laboratories are reliable for detecting the CYP2D6*10 variant; however, several issues revealed in this study underline the importance of PT schemes in continued external assessment and provision of guidelines.

  5. Tamoxifen therapy improves overall survival in luminal A subtype of ductal carcinoma in situ: a study based on nationwide Korean Breast Cancer Registry database.

    Science.gov (United States)

    Hwang, Ki-Tae; Kim, Eun-Kyu; Jung, Sung Hoo; Lee, Eun Sook; Kim, Seung Il; Lee, Seokwon; Park, Heung Kyu; Kim, Jongjin; Oh, Sohee; Kim, Young A

    2018-06-01

    To determine the prognostic role of tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) according to molecular subtypes. Data of 14,944 patients with DCIS were analyzed. Molecular subtypes were classified into four categories based on expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Kaplan-Meier estimator was used for overall survival analysis while Cox proportional hazards model was used for univariate and multivariate analyses. Luminal A subtype (ER/PR+, HER2-) showed higher (P = .009) survival rate than triple-negative (TN) subtype. Tamoxifen therapy group showed superior (P < .001) survival than no-tamoxifen therapy group. It had survival benefit only for luminal A subtype (P = .001). Tamoxifen therapy resulted in higher survival rate in subgroups with positive ER (P = .006), positive PR (P = .009), and negative HER2 (P < .001). In luminal A subtype, tamoxifen therapy showed lower hazard ratio (HR) compared to no-tamoxifen therapy (HR, 0.420; 95% CI 0.250-0.705; P = .001). Tamoxifen therapy was a significant independent factor by multivariate analysis (HR, 0.538; 95% CI 0.306-0.946; P = .031) as well as univariate analysis. Tamoxifen therapy group showed superior prognosis than the no-tamoxifen therapy group. Its prognostic influence was only effective for luminal A subtype. Patients with luminal A subtype showed higher survival rate than those with TN subtype. Active tamoxifen therapy is recommended for DCIS patients with luminal A subtype, and routine tests for ER, PR, and HER2 should be considered for DCIS.

  6. Radiation recall dermatitis induced by Amol during tamoxifen therapy - case report

    International Nuclear Information System (INIS)

    Obtulowicz, A.; Pirowska, M.; Kosiniak-Kamysz, A.

    2011-01-01

    In the course of radiation therapy different types of adverse reactions of the skin are observed in approximately 95% of patients. Among the various complications encountered after radiotherapy, radiation recall dermatitis (RRD) deserves special attention. Radiation dermatitis is a form of delayed hypersensitivity of irradiated skin, and the direct trigger factors are medicines - most chemotherapeutics. The reaction is an inflammatory dermatosis. It is limited to previously irradiated skin and appears a number of months after radiotherapy. The aetiology of RRD is still unclear. Its clinical presentation may vary from mild erythema to necrosis and ulceration. The article presents the case of a 50-year-old patient, who after radiotherapy for breast cancer, during the hormonal therapy (tamoxifen), developed RRD type skin reactions after skin application of Amol. The article presents a detailed differential diagnosis of skin changes of RRD type, and discusses the principles of treatment and prevention. (authors)

  7. Tamoxifen- Induced Dermatomyositis

    Directory of Open Access Journals (Sweden)

    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.

  8. Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review

    NARCIS (Netherlands)

    Lapid, Oren; van Wingerden, Jan J.; Perlemuter, Leon

    2013-01-01

    Objective: A systematic review to assess the efficacy of tamoxifen in the management of idiopathic pubertal gynecomastia. Data sources: Searches were conducted using the databases of Medline (search engine PubMed) and Web of Science (R). Study selection: Studies reporting the use of Tamoxifen for

  9. Fibroblast growth factor receptor 4 predicts failure on tamoxifen therapy in patients with recurrent breast cancer

    NARCIS (Netherlands)

    Meijer, Danielle; Sieuwerts, Anieta M.; Look, Maxime P.; van Agthoven, Ton; Foekens, John A.; Dorssers, Lambert C. J.

    2008-01-01

    Tamoxifen treatment of estrogen-dependent breast cancer ultimately loses its effectiveness due to the development of resistance. From a functional screen for identifying genes responsible for tamoxifen resistance in human ZR-75-1 breast cancer cells, fibroblast growth factor (FGF) 17 was recovered.

  10. A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study

    International Nuclear Information System (INIS)

    Gu, Ran; Long, Meijun; Chen, Kai; Chen, Lili; Xiao, Qiaozhen; Wu, Mei; Song, Erwei; Su, Fengxi; Jia, Weijuan; Zeng, Yunjie; Rao, Nanyan; Hu, Yue; Li, Shunrong; Wu, Jiannan; Jin, Liang; Chen, Lijuan

    2012-01-01

    In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen. Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups. Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer. Toremifene may be a valid and

  11. Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

    Science.gov (United States)

    Dauchy, Robert T.; Xiang, Shulin; Mao, Lulu; Brimer, Samantha; Wren, Melissa A.; Yuan, Lin; Anbalagan, Muralidharan; Hauch, Adam; Frasch, Tripp; Rowan, Brian G.; Blask, David E.; Hill, Steven M.

    2014-01-01

    Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of ERα+ MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speeds the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characters were not produced in animals where circadian rhythms were not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to re-establish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen. PMID:25062775

  12. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer

    International Nuclear Information System (INIS)

    Andersson, M.; Storm, H.H.; Mouridsen, H.T.

    1991-01-01

    The incidence of new primary cancers was evaluated in 3538 postmenopausal patients who had received surgical treatment for primary breast cancer. Of these patients, 1828 with a low risk of recurrence received no further treatment. High-risk patients were randomly assigned to one of two groups. The first group (n = 846) received postoperative radiotherapy, while the second group (n = 864) received radiotherapy plus tamoxifen at a dose of 30 mg given daily for 48 weeks. The median observation time was 7.9 years. In comparison with the number of new cancers in the general population, the number of new cancers in the three groups was elevated mostly due to a high number of cancers of the contralateral breast and of colorectal cancers in the high-risk groups. The cumulative risk of nonlymphatic leukemia was increased among patients who received postoperative radiotherapy (P = .04). Cancer incidence in the high-risk tamoxifen-treated group relative to that in the high-risk group not treated with tamoxifen was not significant (1.3). No protective effect of tamoxifen on the opposite breast was seen (rate ratio for breast cancer = 1.1), but a tendency to an elevated risk of endometrial cancer was observed (rate ratio = 3.3; 95% confidence interval = 0.6-32.4). Continued and careful follow-up of women treated with tamoxifen is necessary to clarify the potential cancer-suppressive or cancer-promoting effects of this drug

  13. 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

    -/TAM - group. Pak1 cytoplasmic intensity was not associated with breast cancer recurrence in either group (ER+/TAM + ORadj for strong vs. no cytoplasmic staining = 0.91, 95% CI 0.57, 1.5; ER-/TAM - ORadj for strong vs. no cytoplasmic staining = 0.74, 95% CI 0.39, 1.4). Associations between Pak1 nuclear......Background Adjuvant tamoxifen therapy approximately halves the risk of estrogen receptor-positive (ER+) breast cancer recurrence, but many women do not respond to therapy. Observational studies nested in clinical trial populations suggest that overexpression or nuclear localization of p21-activated...... by immunohistochemical staining of primary breast tumors from recurrence cases and matched controls from two breast cancer populations; women diagnosed with ER-positive tumors who received at least one year of tamoxifen therapy (ER+/TAM+), and women diagnosed with ER-negative tumors who survived for at least one year...

  14. Menstruation recovery after chemotherapy and luteinizing hormone-releasing hormone agonist plus tamoxifen therapy for premenopausal patients with breast cancer.

    Science.gov (United States)

    Sakurai, Kenichi; Matsuo, Sadanori; Enomoto, Katsuhisa; Amano, Sadao; Shiono, Motomi

    2011-01-01

    Little is known about the period required for menstruation recovery after long-term luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen therapy following chemotherapy. In this study we investigated the period required for menstruation recovery after the therapy. The subjects comprised 105 premenopausal breast cancer patients who had undergone surgery. All patients were administered an LH-RH agonist for 24 months and tamoxifen for 5 years following the postoperative adjuvant chemotherapy, and the status of menstruation recovery was examined. Menstruation resumed in 16 cases (15.2%) after the last LH-RH agonist treatment session. The mean period from the last LH-RH agonist treatment to the recovery of menstruation was 6.9 months. The rate of menstruation recovery was 35.5% in patients aged 40 years or younger and 8.0% in those aged 41 years or older, and it was significantly higher in those aged 40 years or younger. The period until menstruation recovery tended to be longer in older patients at the end of treatment. This study showed that menstruation resumed after treatment at higher rates in younger patients. However, because it is highly likely that ovarian function will be destroyed by the treatment even in young patients, it is considered necessary to explain the risk to patients and obtain informed consent before introducing this treatment modality.

  15. Cost Effectiveness of Genotype-Guided Warfarin Dosing in Patients with Mechanical Heart Valve Replacement Under the Fee-for-Service System.

    Science.gov (United States)

    Kim, Dong-Jin; Kim, Ho-Sook; Oh, Minkyung; Kim, Eun-Young; Shin, Jae-Gook

    2017-10-01

    Although studies assessing the cost effectiveness of genotype-guided warfarin dosing for the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism have been reported, no publications have addressed genotype-guided warfarin therapy in mechanical heart valve replacement (MHVR) patients or genotype-guided warfarin therapy under the fee-for-service (FFS) insurance system. The aim of this study was to evaluate the cost effectiveness of genotype-guided warfarin dosing in patients with MHVR under the FFS system from the Korea healthcare sector perspective. A decision-analytic Markov model was developed to evaluate the cost effectiveness of genotype-guided warfarin dosing compared with standard dosing. Estimates of clinical adverse event rates and health state utilities were derived from the published literature. The outcome measure was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed to explore the range of plausible results. In a base-case analysis, genotype-guided warfarin dosing was associated with marginally higher QALYs than standard warfarin dosing (6.088 vs. 6.083, respectively), at a slightly higher cost (US$6.8) (year 2016 values). The ICER was US$1356.2 per QALY gained. In probabilistic sensitivity analysis, there was an 82.7% probability that genotype-guided dosing was dominant compared with standard dosing, and a 99.8% probability that it was cost effective at a willingness-to-pay threshold of US$50,000 per QALY gained. Compared with only standard warfarin therapy, genotype-guided warfarin dosing was cost effective in MHVR patients under the FFS insurance system.

  16. Tamoxifen and ovarian function.

    Directory of Open Access Journals (Sweden)

    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

  17. Two years of tamoxifen or no adjuvant systemic therapy for patients with high-risk breast cancer

    DEFF Research Database (Denmark)

    Jensen, Maj-Britt; Krarup, Jens Fabricius; Palshof, Torben

    2018-01-01

    randomly assigned to two years of daily placebo or tamoxifen. Survival statistics was collected from the Danish Civil Registration System. RESULTS: The five-year invasive breast cancer recurrence (BCR) rate was 43.2% in the placebo arm and 31.9% in the tamoxifen arm. Compared with the placebo arm...... the hazard ratio for a BCR event was 0.73 in the tamoxifen arm (p = .07). With an estimated median follow-up on overall survival of 40.9 years, 154 and 145 patients had died in the placebo and tamoxifen arm, respectively. After adjustment for baseline characteristics a significant reduction in mortality...

  18. A nanomedicine based combination therapy based on QLPVM peptide functionalized liposomal tamoxifen and doxorubicin against Luminal A breast cancer.

    Science.gov (United States)

    Wang, Xiaoyou; Chen, Xianhui; Yang, Xiucong; Gao, Wei; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Dai, Zhifei; Zhang, Qiang

    2016-02-01

    Though combination chemotherapy or antitumor nanomedicine is extensively investigated, their combining remains in infancy. Additionally, enhanced delivery of estrogen or its analogs to tumor with highly-expressed estrogen-receptor (ER) is seldom considered, despite its necessity for ER-positive breast cancer treatment. Here, nanomedicine based combination therapy using QLPVM conjugated liposomal tamoxifen (TAM) and doxorubicin (DOX) was designed and testified, where the penta-peptide was derived from Ku70 Bax-binding domain. Quantitative, semi-quantitative and qualitative approaches demonstrated the enhanced endocytosis and cytotoxicity of QLPVM conjugated sterically stabilized liposomes (QLPVM-SSLs) in vitro and in vivo. Mechanism studies of QLPVM excluded the possible electrostatic, hydrophobic or receptor-ligand interactions. However, as a weak cell-penetrating peptide, QLPVM significantly induced drug release from QLPVM-SSLs during their interaction with cells, which was favorable for drug internalization. These findings suggested that the nanomedicine based combination therapy using QLPVM-SSL-TAM and QLPVM-SSL-DOX might provide a rational strategy for Luminal A breast cancer. Breast cancer remains a leading cause of mortality in women worldwide. Although combined therapy using hormonal antagonist and chemotherapy is the norm nowadays, the use of these agents together in a single delivery system has not been tested. Here, the authors investigated this approach using QLPVM conjugated liposomes in in-vitro and in-vivo models. The positive findings may provide a novel direction for breast cancer treatment in the near future. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. MR imaging of the pelvis in the diagnosis of the endometrium in breast cancer patients in tamoxifen therapy

    International Nuclear Information System (INIS)

    Hauth, E.; Libera, H.; Forsting, M.; Kimmig, R.

    2006-01-01

    Purpose: The purpose of the study was to determine the value of MR imaging of the pelvis in the diagnostic work-up of the endometrium in breast cancer patients in tamoxifen therapy. Materials and methods: MR imaging of the pelvis was performed on 24 patients (mean: 62 years, range: 51-74 years) and 30 healthy women (mean: 65 years, range: 51-73 years). The volume of the uterus and cervix and the maximal thickness of the endometrium, junctional zone and myometrium of the uterus were determined and compared to the confidence interval of the parameters in healthy women. The Mann-Whitney U-test was used to identify differences in the volume of the uterus and cervix and in the thickness of the uterine wall layers in both groups. Results: A comparison of the volume of the uterus and cervix and the thickness of the uterine wall layers in the two groups yielded no significant differences. The volume of the uterus and cervix showed no statistical differences between the two groups. The maximal height of the endometrium in the patient group showed a mean of 0.6 cm (range: 0.1-2.2 cm), and a mean of 0.4 cm (range: 0.1-1.2 cm) in the group of healthy women. The differences were not statistically significant. In all healthy women the endometrium showed homogeneous signal intensity in the sagittal T2-weighted images. In 12 of the 24 breast cancer patients, the endometrium showed inhomogeneous signal intensity. In 9 of 12 patients with an inhomogeneous endometrium with a thickness equal to or greater than 0.6 cm, histopathology confirmed polyps. In 3 patients endometrium hyperplasia was found. In one patient histopathology revealed a polyp and an endometrium carcinoma in stage T1 a N0. The endometrium carcinoma was not able to be seen via MR imaging. (orig.)

  20. MCAM/CD146 promotes tamoxifen resistance in breast cancer cells through induction of epithelial-mesenchymal transition, decreased ER alpha expression and AKT activation

    NARCIS (Netherlands)

    Liang, Yuan-Ke; Zeng, De; Xiao, Ying-Sheng; Wu, Yang; Ouyang, Yan-Xiu; Chen, Min; Li, Yao-Chen; Lin, Hao-Yu; Wei, Xiao-Long; Zhang, Yong-Qu; Kruyt, Frank A. E.; Zhang, Guo-Jun

    2017-01-01

    Tamoxifen resistance presents a prominent clinical challenge in endocrine therapy for hormone sensitive breast cancer. However, the underlying mechanisms that contribute to tamoxifen resistance are not fully understood. In this study, we established a tamoxifen resistant MCF-7 cell line

  1. 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.

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

    International Nuclear Information System (INIS)

    Arruda Viani, Gustavo; Bernardes da Silva, Lucas Godói; Stefano, Eduardo Jose

    2012-01-01

    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.

  3. 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...

  4. 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.

  5. 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......+ 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.......RNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

  6. The Efficacy of Medical Treatment of Peyronie’s Disease: Potassium Para-Aminobenzoate Monotherapy vs. Combination Therapy with Tamoxifen, L-Carnitine, and Phosphodiesterase Type 5 Inhibitor

    Directory of Open Access Journals (Sweden)

    Tae Yong Park

    2016-04-01

    Full Text Available Purpose: This study was designed to evaluate the efficacy of medical treatment of Peyronie’s disease. Materials and Methods: A total of 109 patients with Peyronie’s disease who had been treated from January 2011 to December 2014 were retrospectively reviewed in this study. Forty-four patients (Group 1 were treated with 12 mg of potassium para-aminobenzoate daily. Sixty-five patients (Group 2 were treated with combination therapy: tamoxifen (20 mg and acetyl-L-carnitine (300 mg twice daily in addition to a phosphodiesterase type 5 inhibitor. Ability to perform sexual intercourse, pain during erection, size of plaque, and penile curvature angle were assessed. Results: In Group 1, 30 of 44 patients (68.2% discontinued treatment within 12 weeks, while 5 patients (7.7% in Group 2 discontinued treatment. Pain during erection and plaque size were improved in both groups but showed no statistical difference due to the high dropout rate in Group 1. In both groups, penile curvature was improved, but demonstrated no statistical difference between the treatment groups. However, combination therapy demonstrated a better response rate in patients whose penile curvature angle was less than 30o (44.4% vs. 79.1%, p=0.048. The rate of successful sexual intercourse was significantly higher in Group 2 (42.8% vs. 78.3%, p=0.034. The number of patients who underwent surgical correction despite medical treatment was significantly higher in Group 1 (35.7% vs. 13.3%, p=0.048. Conclusions: Early medical combination therapy in Peyronie’s disease may present better results in patients whose curvature angle is less than 30o.

  7. 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...

  8. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

    Science.gov (United States)

    Gage, Brian F; Bass, Anne R; Lin, Hannah; Woller, Scott C; Stevens, Scott M; Al-Hammadi, Noor; Li, Juan; Rodríguez, Tomás; Miller, J Philip; McMillin, Gwendolyn A; Pendleton, Robert C; Jaffer, Amir K; King, Cristi R; Whipple, Brandi DeVore; Porche-Sorbet, Rhonda; Napoli, Lynnae; Merritt, Kerri; Thompson, Anna M; Hyun, Gina; Anderson, Jeffrey L; Hollomon, Wesley; Barrack, Robert L; Nunley, Ryan M; Moskowitz, Gerard; Dávila-Román, Victor; Eby, Charles S

    2017-09-26

    Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. To determine whether genotype-guided dosing improves the safety of warfarin initiation. The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0

  9. 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....

  10. Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma

    International Nuclear Information System (INIS)

    Ma, Ji; Zhang, Jian; Liu, Wenchao; Guo, Yan; Chen, Suning; Zhong, Cuiping; Xue, Yan; Zhang, Yuan; Lai, Xiaofeng; Wei, Yifang; Yu, Shentong

    2014-01-01

    Tamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy. The efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay. When metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo. The present work shows that metformin and tamoxifen additively inhibited the growth and augmented the apoptosis of ER-positive breast cancer cells. It provides leads for future research on this drug combination for the treatment of ER-positive breast cancer

  11. Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness–a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer

    International Nuclear Information System (INIS)

    Madeira, Marcelo; Mattar, André; Logullo, Ângela Flávia; Soares, Fernando Augusto; Gebrim, Luiz Henrique

    2013-01-01

    The role of estrogen receptor beta (ER-β) in breast cancer (BC) remains unclear. Some studies have suggested that ER-β may oppose the actions of estrogen receptor alpha (ER-α), and clinical evidence has indicated that the loss of ER-β expression is associated with a poor prognosis and resistance to endocrine therapy. The objective of the present study was to determine the role of ER-β and the ER-α/ER-β ratio in predicting the response to endocrine therapy and whether different regimens have any effect on ER-β expression levels. Ninety postmenopausal patients with primary BC were recruited for a short-term double-blinded randomized prospective controlled study. To determine tumor cell proliferation, we measured the expression of Ki67 in tumor biopsy samples taken before and after 26 days of treatment with anastrozole 1 mg/day (N = 25), tamoxifen 20 mg/day (N = 24) or placebo (N = 29) of 78 participants. The pre- and post-samples were placed in tissue microarray blocks and submitted for immunohistochemical assay. Biomarker statuses (ER-β, ER-α and Ki67) were obtained by comparing each immunohistochemical evaluation of the pre- and post-surgery samples using the semi-quantitative Allred’s method. Statistical analyses were performed using an ANOVA and Spearman’s correlation coefficient tests, with significance at p ≤ 0.05. The frequency of ER-β expression did not change after treatment (p = 0.33). There were no significant changes in Ki67 levels in ER-β-negative cases (p = 0.45), but in the ER-β-positive cases, the anastrozole (p = 0.01) and tamoxifen groups (p = 0.04) presented a significant reduction in post-treatment Ki67 scores. There was a weak but positive correlation between the ER-α and ER-β expression levels. Only patients with an ER-α/ER-β expression ratio between 1 and 1.5 demonstrated significant differences in Ki67 levels after treatment with anastrozole (p = 0.005) and tamoxifen (p = 0.026). Our results provide additional data that

  12. Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer

    DEFF Research Database (Denmark)

    Alkner, S; Jensen, Maj-Britt Raaby; Rasmussen, B B

    2017-01-01

    PURPOSE: To evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer. METHOD: AIB1 was analyzed...... with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group's trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs). RESULTS: Forty-six percent of the tumors had a high AIB1 expression. In line...... with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80-100 vs. 1-79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival...

  13. Mitotically Active Leiomyoma of the Uterus in a Postmenopausal Breast Cancer Patient Receiving Tamoxifen

    Directory of Open Access Journals (Sweden)

    I-Feng Liu

    2006-06-01

    Conclusion: Endometrial cancer is rarely noted in breast cancer patients taking tamoxifen. Further, none have reported mitotically active leiomyoma of the uterus. From this case, endometrial proliferation and mitotically active leiomyoma of the uterus may be related to tamoxifen therapy, and should not be neglected in breast cancer patients.

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

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    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

  15. 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

  16. 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

    2017-11-01

    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.

  17. 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.

  18. The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.

    Science.gov (United States)

    Johänning, Janina; Kröner, Patrick; Thomas, Maria; Zanger, Ulrich M; Nörenberg, Astrid; Eichelbaum, Michel; Schwab, Matthias; Brauch, Hiltrud; Schroth, Werner; Mürdter, Thomas E

    2018-03-01

    Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.

  19. Detection of tamoxifen metabolites by GC-MSD.

    Science.gov (United States)

    Báez, H; Camargo, C; Osorio, H; Umpiérrez, F

    2004-01-01

    Tamoxifen is an antiestrogen used in the adjuvant endocrine therapy of early breast cancer and malignant breast disorders. It is also used in women with anovulatory infertility caused by its stimulating effect on the secretion of the pituitary gonadotrophic hormones. In males it could increase the endogenous production of androgens. Because of these properties tamoxifen may be misused in some sports to treat the androgens suppression caused by the extensive abuse of anabolic androgenic steroids. A method for identification and confirmation of tamoxifen metabolites is described. Hydroxymetoxytamoxifen is detected in urine by gas chromatography and mass spectrometry in a selective ion monitoring method followed by the routine postrun in the screening of anabolic steroids. Once the hydroxymetoxytamoxifen is detected, confirmation of reported metabolites could be performed with a 5973 mass selective detector in the scan mode after solid-phase extraction by cationic exchange. This study also reports an excretion profile for a single dose of tamoxifen equivalent to 40 mg administrated orally to two males volunteers.

  20. Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

    Science.gov (United States)

    Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

    2018-04-01

    Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen

  1. C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

    Science.gov (United States)

    Li, Wei; Xu, Ling; Che, Xiaofang; Li, Haizhou; Zhang, Ye; Song, Na; Wen, Ti; Hou, Kezuo; Yang, Yi; Zhou, Lu; Xin, Xing; Xu, Lu; Zeng, Xue; Shi, Sha; Liu, Yunpeng; Qu, Xiujuan; Teng, Yuee

    2018-05-02

    Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. Our results suggested that c-Cbl can reverse tamoxifen

  2. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

    Science.gov (United States)

    Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

    2017-05-02

    Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

  3. Mullerian adenosarcoma of the uterus associated with tamoxifen treatment for breast cancer

    Directory of Open Access Journals (Sweden)

    Yasin Ceylan

    2015-12-01

    Full Text Available Mullerian adenosarcoma following tamoxifen therapy is a rare condition. Our aim was to report the youngest patient in the literature with uterine mullerian adenosarcoma who was undergoing tamoxifen therapy for breast cancer. A premenopausal woman aged 38 years who was undergoing tamoxifen therapy for breast cancer, was admitted with symptoms of lower abdominal pain and irregular vaginal bleeding and malodorous vaginal discharge that had continued for at least 6 months. A pelvic examination revealed a large and malodorous polypoid mass protruding through the cervix and an enlarged uterus. A biopsy from the protruding polypoid mass was reported as a large area of necrosis with neoplastic mesenchymal cells. The patient underwent a total abdominal hysterectomy, bilateral salpingo-oopherectomy, pelvic-paraaortic lymph node dissection, and omentectomie. The histologic diagnosis was Mullerian adenosarcoma. As a result, she was discharged to the oncology department. The woman is alive and her chemoradiotherapy treatment is ongoing. The role of tamoxifen therapy in the development of endometrial neoplasms remains unclear, but all cases of endometrial thickening and vaginal bleeding must be investigated for Mullerian adenosarcoma in tamoxifen users.

  4. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients

    International Nuclear Information System (INIS)

    Wegman, Pia; Vainikka, Linda; Stål, Olle; Nordenskjöld, Bo; Skoog, Lambert; Rutqvist, Lars-Erik; Wingren, Sten

    2005-01-01

    Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy. The patients were genotyped using PCR followed by cleavage with restriction enzymes. Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041). The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort

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

    International Nuclear Information System (INIS)

    Zheng, Kai; Chen, Maoyun; Xiang, Yangfei; Ma, Kaiqi; Jin, Fujun; Wang, Xiao; Wang, Xiaoyan; Wang, Shaoxiang; Wang, Yifei

    2014-01-01

    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

  6. 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.

  7. Therapeutic Effects of a Traditional Chinese Medicine Formula Plus Tamoxifen vs. Tamoxifen for the Treatment of Mammary Gland Hyperplasia: A Meta-Analysis of Randomized Trials

    Science.gov (United States)

    Li, Hao-Tian; Liu, Hong-Hong; Yang, Yu-Xue; Wang, Tao; Zhou, Xue-Lin; Yu, Yang; Li, Su-Na; Zheng, Yi; Zhang, Ping; Wang, Rui-Lin; Li, Jian-Yu; Wei, Shi-Zhang; Li, Kun; Li, Peng-Yan; Qian, Li-Qi

    2018-01-01

    As a common disorder that accounts for over 70% of all breast disease cases, mammary gland hyperplasia (MGH) causes a severe problem for the quality of patients' life, and confers an increased risk of breast carcinoma. However, the etiology and pathogenesis of MGH remain unclear, and the safety and efficacy of current western drug therapy for MGH still need to be improved. Therefore, a meta-analysis was conducted by our team to determine whether a TCM formula named Ru-Pi-Xiao in combination with tamoxifen or Ru-Pi-Xiao treated alone can show more prominent therapeutic effects against MGH with fewer adverse reactions than that of tamoxifen. Studies published before June 2017 were searched based on standardized searching rules in several mainstream medical databases. A total of 27 articles with 4,368 patients were enrolled in this meta-analysis. The results showed that the combination of Ru-Pi-Xiao and tamoxifen could exhibit better therapeutic effects against MGH than that of tamoxifen (OR: 3.79; 95% CI: 3.09–4.65; P < 0.00001) with a lower incidence of adverse reactions (OR: 0.35; 95% CI: 0.28–0.43; P < 0.00001). The results also suggested that this combination could improve the level of progesterone (MD: 2.22; 95% CI: 1.72–2.71; P < 0.00001) and decrease the size of breast lump (MD: −0.67; 95% CI: −0.86 to −0.49; P < 0.00001) to a greater extent, which might provide a possible explanation for the pharmacodynamic mechanism of Ru-Pi-Xiao plus tamoxifen. In conclusion, Ru-Pi-Xiao and related preparations could be recommended as auxiliary therapy combined tamoxifen for the treatment of MGH. PMID:29456506

  8. The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer

    International Nuclear Information System (INIS)

    Fowble, Barbara; Fein, Douglas A.; Hanlon, Alexandra L.; Eisenberg, Burton L.; Hoffman, John P.; Sigurdson, Elin R.; Daly, Mary B.; Goldstein, Lori J.

    1996-01-01

    Purpose: To evaluate the impact of tamoxifen on breast recurrence, cosmesis, complications, overall and cause-specific survival in women with Stage I-II breast cancer and estrogen receptor positive tumors undergoing conservative surgery and radiation. Methods and Materials: From 1982 to 1991, 491 women with estrogen receptor positive Stage I-II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median age of the patient population was 60 years with 21% < 50 years of age. The median follow-up was 5.3 years (range 0.1 to 12.8). Sixty-nine percent had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49% and the final margin of resection was negative in 64%. One hundred fifty-four patients received tamoxifen and 337 patients received no adjuvant therapy. None of the patients received adjuvant chemotherapy. Results: There were no significant differences between the two groups for age, race, clinical tumor size, histology, the use of reexcision, or median total dose to the primary. Patients who received tamoxifen were more often axillary node positive (44% tamoxifen vs. 5% no tamoxifen), and, therefore, a greater percentage received treatment to the breast and regional nodes. The tamoxifen patients less often had unknown margins of resection (9% tamoxifen vs. 22% no tamoxifen). The 5-year actuarial breast recurrence rate was 4% for the tamoxifen patients compared to 7% for patients not receiving tamoxifen (p 0.21). Tamoxifen resulted in a modest decrease in the 5-year actuarial risk of a breast recurrence in axillary node-negative patients, in those with unknown or close margins of resection, and in those who underwent a single excision. Axillary node-positive patients had a clinically significant decrease in the 5-year actuarial breast recurrence rate (21 vs. 4%; p 0.08). The 5-year actuarial rate of distant metastasis was not significantly decreased by the addition of adjuvant tamoxifen in all

  9. Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells

    Science.gov (United States)

    Wang, Qiang; Jiang, Jun; Ying, Guoguang; Xie, Xiao-Qing; Zhang, Xia; Xu, Wei; Zhang, Xuemin; Song, Erwei; Bu, Hong; Ping, Yi-Fang; Yao, Xiao-Hong; Wang, Bin; Xu, Shilei; Yan, Ze-Xuan; Tai, Yanhong; Hu, Baoquan; Qi, Xiaowei; Wang, Yan-Xia; He, Zhi-Cheng; Wang, Yan; Wang, Ji Ming; Cui, You-Hong; Chen, Feng; Meng, Kun; Wang, Zhaoyi; Bian, Xiu-Wu

    2018-01-01

    The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer. PMID:29393296

  10. 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

  11. Effect of tamoxifen on the coronary vascular reactivity of spontaneously hypertensive female rats

    Directory of Open Access Journals (Sweden)

    M.V. Borgo

    2011-08-01

    Full Text Available Tamoxifen has been associated with a reduction in the incidence of myocardial infarction. However, the effects of tamoxifen on coronary reactivity have not been fully elucidated. The objective of this study was to determine the effects of chronic treatment with tamoxifen on coronary vascular reactivity in spontaneously hypertensive rats (SHR. Female SHR were divided into four groups (N = 7 each: sham-operated (SHAM, sham-operated and treated with tamoxifen (10 mg/kg by gavage for 90 days (TAMOX, ovariectomized (OVX, and ovariectomized and treated with tamoxifen (OVX+TAMOX. Mean arterial pressure (MAP, heart rate (HR, coronary perfusion pressure (CPP, and coronary vascular reactivity were measured. MAP and HR were reduced (9.42 and 11.67%, respectively in the OVX+TAMOX group compared to the OVX group (P < 0.01. The coronary vascular reactivity of the OVX+TAMOX group presented smaller vasoconstrictor responses to acetylcholine (2-64 µg when compared to the OVX group (P < 0.01 and this response was similar to that of the SHAM group. The adenosine-induced vasodilator response was greater in the TAMOX group compared to the SHAM and OVX groups (P < 0.05. Baseline CPP was higher in OVX+TAMOX and TAMOX groups (136 ± 3.6 and 130 ± 1.5 mmHg than in OVX and SHAM groups (96 ± 2 and 119 ± 2.3 mmHg; P < 0.01. Tamoxifen, when combined with OVX, attenuated the vasoconstriction induced by acetylcholine and increased the adenosine-induced vasodilatory response, as well as reducing the MAP, suggesting beneficial effects of tamoxifen therapy on coronary vascular reactivity after menopause.

  12. 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.

  13. 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/tam...oxifen.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/tam...oxifen.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/tam...open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/tamoxifen.Rat.in_vivo.Liver.Repeat.zip ...

  14. Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells.

    Science.gov (United States)

    Ambrosio, Maria Rosaria; D'Esposito, Vittoria; Costa, Valerio; Liguoro, Domenico; Collina, Francesca; Cantile, Monica; Prevete, Nella; Passaro, Carmela; Mosca, Giusy; De Laurentiis, Michelino; Di Bonito, Maurizio; Botti, Gerardo; Franco, Renato; Beguinot, Francesco; Ciccodicola, Alfredo; Formisano, Pietro

    2017-12-12

    Type 2 diabetes and obesity are negative prognostic factors in patients with breast cancer (BC). We found that sensitivity to tamoxifen was reduced by 2-fold by 25 mM glucose (High Glucose; HG) compared to 5.5 mM glucose (Low Glucose; LG) in MCF7 BC cells. Shifting from HG to LG ameliorated MCF7 cell responsiveness to tamoxifen. RNA-Sequencing of MCF7 BC cells revealed that cell cycle-related genes were mainly affected by glucose. Connective Tissue Growth Factor (CTGF) was identified as a glucose-induced modulator of cell sensitivity to tamoxifen. Co-culturing MCF7 cells with human adipocytes exposed to HG, enhanced CTGF mRNA levels and reduced tamoxifen responsiveness of BC cells. Inhibition of adipocyte-released IL8 reverted these effects. Interestingly, CTGF immuno-detection in bioptic specimens from women with estrogen receptor positive (ER + ) BC correlated with hormone therapy resistance, distant metastases, reduced overall and disease-free survival. Thus, glucose affects tamoxifen responsiveness directly modulating CTGF in BC cells, and indirectly promoting IL8 release by adipocytes.

  15. 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.

  16. 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%, P preventive therapy in secondary care before asking GPs to continue the patient's care may overcome some prescribing barriers. © British Journal of General Practice 2017.

  17. 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.

  18. 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...

  19. Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials.

    Science.gov (United States)

    Brentnall, Adam R; Cuzick, Jack; Byers, Helen; Segal, Corrinne; Reuter, Caroline; Detre, Simone; Sestak, Ivana; Howell, Anthony; Powles, Trevor J; Newman, William G; Dowsett, Mitchell

    2016-08-01

    A case-control study from two randomised breast cancer prevention trials of tamoxifen and raloxifene (P-1 and P-2) identified single-nucleotide polymorphisms (SNPs) in or near genes ZNF423 and CTSO as factors which predict which women will derive most anti-cancer benefit from selective oestrogen receptor modulator (SERM) therapy. In this article, we further examine this question using blood samples from two randomised tamoxifen prevention trials: the International Breast Cancer Intervention Study I (IBIS-I) and the Royal Marsden trial (Marsden). A nested case-control study was designed with 2:1 matching in IBIS-I and 1:1 matching in Marsden. The OncoArray was used for genotyping and included two SNPs previously identified (rs8060157 in ZNF423 and rs10030044 near CTSO), and 102 further SNPs within the same regions. Overall, there were 369 cases and 662 controls, with 148 cases and 268 controls from the tamoxifen arms. Odds ratios were estimated by conditional logistic regression, with Wald 95 % confidence intervals. In the tamoxifen arms, the per-allele odds ratio for rs8060157 was 0.99 (95 %CI 0.73-1.34) and 1.00 (95 %CI 0.76-1.33) for rs10030044. In the placebo arm, the odds ratio was 1.10 (95 %CI 0.87-1.40) for rs8060157 and 1.01 (95 %CI 0.79-1.29) for rs10030044. There was no evidence to suggest that other SNPs in the surrounding regions of these SNPs might predict response to tamoxifen. Results from these two prevention trials do not support the earlier findings. rs8060157 in ZNF423 and rs10030044 near CTSO do not appear to predict response to tamoxifen.

  20. Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L; Costantino, Joseph P; Baehner, Frederick L; Baker, Joffre; Cronin, Maureen T; Watson, Drew; Shak, Steven; Bohn, Olga L; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L; Vogel, Victor G; McCaskill-Stevens, Worta; Ford, Leslie G; Geyer, Charles E; Wickerham, D Lawrence; Wolmark, Norman; Paik, Soonmyung

    2011-11-01

    Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

  1. Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

    Science.gov (United States)

    Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L.; Costantino, Joseph P.; Baehner, Frederick L.; Baker, Joffre; Cronin, Maureen T.; Watson, Drew; Shak, Steven; Bohn, Olga L.; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L.; Vogel, Victor G.; McCaskill-Stevens, Worta; Ford, Leslie G.; Geyer, Charles E.; Wickerham, D. Lawrence; Wolmark, Norman; Paik, Soonmyung

    2011-01-01

    Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors. PMID:21947828

  2. 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

    , the compound is now also recognized as a multitargeting drug with diverse potential applications, for example, it has antiproliferative properties and it can reverse resistance toward antibiotics in bacteria. Furthermore, chlorpromazine can reverse multidrug resistance caused by overexpression of P......Tamoxifen resistance is a major clinical problem in the treatment of estrogen receptor a-positive breast tumors. It is, at present, unclear what exactly causes tamoxifen resistance. For decades, chlorpromazine has been used for treating psychotic diseases, such as schizophrenia. However......-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...

  3. Tamoxifen and CYP2D6

    DEFF Research Database (Denmark)

    Cronin-Fenton, Deirdre P.; Damkier, Per

    2018-01-01

    Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2...

  4. 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.

  5. FGFR2-Driven Signaling Counteracts Tamoxifen Effect on ERα-Positive Breast Cancer Cells

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    Lukasz Turczyk

    2017-10-01

    Full Text Available Signaling mediated by growth factors receptors has long been suggested as one of the key factors responsible for failure of endocrine treatment in breast cancer (BCa. Herein we present that in the presence of tamoxifen, FGFs (Fibroblast Growth Factors promote BCa cell growth with the strongest effect being produced by FGF7. FGFR2 was identified as a mediator of FGF7 action and the FGFR2-induced signaling was found to underlie cancer-associated fibroblasts-dependent resistance to tamoxifen. FGF7/FGFR2-triggered pathway was shown to induce ER phosphorylation, ubiquitination and subsequent ER proteasomal degradation which counteracted tamoxifen-promoted ER stabilization. We also identified activation of PI3K/AKT signaling targeting ER-Ser167 and regulation of Bcl-2 expression as a mediator of FGFR2-promoted resistance to tamoxifen. Analysis of tissue samples from patients with invasive ductal carcinoma revealed an inversed correlation between expression of FGFR2 and ER, thus supporting our in vitro data. These results unveil the complexity of ER regulation by FGFR2-mediated signaling likely to be associated with BCa resistance to endocrine therapy.

  6. Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines.

    Science.gov (United States)

    Attia, Yasmin M; El-Abhar, Hanan S; Al Marzabani, Mahmoud M; Shouman, Samia A

    2015-11-03

    Tamoxifen is the standard endocrine therapy for ER+ breast cancer; however, many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3-bromopyruvate. An in vitro screening of antitumor activity as well as the apoptotic, anti-metastatic, and anti-angiogenic potentials of the combination therapy were carried out using different techniques on breast cancer cell lines MCF7and T47D. In addition the antitumor effect of the combined therapy was done on mice bearing tumor. Our results showed modulation in apoptosis, angiogenesis and metastatic potential by either drug alone; however, their combination has surpassed that of the individual one. Combination regimen enhanced activated caspases-3, 7 and 9, as well as oxidative stress, signified by increased malondialdehyde and decreased glutathione level. Additionally, the angiogenesis and metastasis markers, including hypoxia inducing factor-1α, vascular endothelia growth factor, and metaloproteinases-2 and 9 were decreased after using the combination regimen. These results were further confirmed by the in vivo study, which depicted a decrease in the tumor volume and angiogenesis and an increase in oxidative stress as well. 3-bromopyruvate could be a valuable compound when added with tamoxifen in breast cancer treatment.

  7. Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines

    International Nuclear Information System (INIS)

    Attia, Yasmin M.; EL-Abhar, Hanan S.; Al Marzabani, Mahmoud M.; Shouman, Samia A.

    2015-01-01

    Tamoxifen is the standard endocrine therapy for ER+ breast cancer; however, many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3-bromopyruvate. An in vitro screening of antitumor activity as well as the apoptotic, anti-metastatic, and anti-angiogenic potentials of the combination therapy were carried out using different techniques on breast cancer cell lines MCF7and T47D. In addition the antitumor effect of the combined therapy was done on mice bearing tumor. Our results showed modulation in apoptosis, angiogenesis and metastatic potential by either drug alone; however, their combination has surpassed that of the individual one. Combination regimen enhanced activated caspases-3, 7 and 9, as well as oxidative stress, signified by increased malondialdehyde and decreased glutathione level. Additionally, the angiogenesis and metastasis markers, including hypoxia inducing factor-1α, vascular endothelia growth factor, and metaloproteinases-2 and 9 were decreased after using the combination regimen. These results were further confirmed by the in vivo study, which depicted a decrease in the tumor volume and angiogenesis and an increase in oxidative stress as well. 3-bromopyruvate could be a valuable compound when added with tamoxifen in breast cancer treatment

  8. Genotoxic, epigenetic, and transcriptomic effects of tamoxifen in mouse liver

    International Nuclear Information System (INIS)

    Conti, Aline de; Tryndyak, Volodymyr; Churchwell, Mona I.; Melnyk, Stepan; Latendresse, John R.; Muskhelishvili, Levan; Beland, Frederick A.; Pogribny, Igor P.

    2014-01-01

    Highlights: • Treatment of female mice with tamoxifen caused genotoxic changes in the livers. • Tamoxifen treatment did not affect the hepatic epigenome. • Tamoxifen caused over-expression of hepatic Lcn13 and Pparγ genes. • Mice are resistant to tamoxifen-induced liver carcinogenesis and fatty liver injury. - Abstract: Tamoxifen is a non-steroidal anti-estrogenic drug widely used for the treatment and prevention of breast cancer in women; however, there is evidence that tamoxifen is hepatocarcinogenic in rats, but not in mice. Additionally, it has been reported that tamoxifen may cause non-alcoholic fatty liver disease (NAFLD) in humans and experimental animals. The goals of the present study were to (i) investigate the mechanisms of the resistance of mice to tamoxifen-induced hepatocarcinogenesis, and (ii) clarify effects of tamoxifen on NAFLD-associated liver injury. Feeding female WSB/EiJ mice a 420 p.p.m. tamoxifen-containing diet for 12 weeks resulted in an accumulation of tamoxifen-DNA adducts, (E)-α-(deoxyguanosin-N 2 -yl)-tamoxifen (dG-TAM) and (E)-α-(deoxyguanosin-N 2 -yl)-N-desmethyltamoxifen (dG-DesMeTAM), in the livers. The levels of hepatic dG-TAM and dG-DesMeTAM DNA adducts in tamoxifen-treated mice were 578 and 340 adducts/108 nucleotides, respectively, while the extent of global DNA and repetitive elements methylation and histone modifications did not differ from the values in control mice. Additionally, there was no biochemical or histopathological evidence of NAFLD-associated liver injury in mice treated with tamoxifen. A transcriptomic analysis of differentially expressed genes demonstrated that tamoxifen caused predominantly down-regulation of hepatic lipid metabolism genes accompanied by a distinct over-expression of the lipocalin 13 (Lcn13) and peroxisome proliferator receptor gamma (Pparγ), which may prevent the development of NAFLD. The results of the present study demonstrate that the resistance of mice to tamoxifen

  9. Tumorigenic Effects of Tamoxifen on the Female Genital Tract

    Directory of Open Access Journals (Sweden)

    Kaei Nasu M.D., Ph.D.

    2008-01-01

    Full Text Available Tamoxifen is widely used for endocrine treatment and breast cancer prevention. It acts as both an estrogen antagonist in breast tissue and an estrogen agonist in the female lower genital tract. Tamoxifen causes severe gynecologic side effects, such as endometrial cancer. This review focuses on the effects of prolonged tamoxifen treatment on the human female genital tract and considers its tumorigenicity in the gynecologic organs through clinical data analysis. Tamoxifen is associated with an increased incidence of benign endometrial lesions such as polyps and hyperplasia and a two- to four-fold increased risk of endometrial cancer in postmenopausal patients. Moreover, the incidence of functional ovarian cysts is significantly high in premenopausal tamoxifen users. To prevent tamoxifen from having severe side effects in gynecologic organs, frequent gynecological examination should be performed for both premenopausal and postmenopausal patients with breast cancer who are treated with this drug.

  10. Bilateral Macular Edema in a Patient Treated with Tamoxifen: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Paraskevas Zafeiropoulos

    2014-12-01

    Full Text Available We present a case of a 41-year-old female patient with progressive bilateral visual loss. On examination, her best corrected visual acuity (BCVA in her right eye was 3/10 and her BCVA in her left eye was 2/10. Fundus and optical coherence tomography examination revealed severe bilateral macular edema. She had been diagnosed with breast cancer 6 years ago and was receiving tamoxifen at a dosage of 20 mg/day ever since. Tamoxifen therapy was discontinued, and the patient received 250 mg of acetazolamide three times a day for a period of 1 month. Both foveae regained their normal contour within 2 months, and her vision was restored to 10/10 BCVA 3 months later. To our knowledge, this is the first case reported where bilateral intraretinal macular edema is the only retinal manifestation in a patient on oral tamoxifen.

  11. 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...

  12. Bilateral macular edema in a patient treated with tamoxifen: a case report and review of the literature.

    Science.gov (United States)

    Zafeiropoulos, Paraskevas; Nanos, Panagiotis; Tsigkoulis, Evangelos; Stefaniotou, Maria

    2014-01-01

    We present a case of a 41-year-old female patient with progressive bilateral visual loss. On examination, her best corrected visual acuity (BCVA) in her right eye was 3/10 and her BCVA in her left eye was 2/10. Fundus and optical coherence tomography examination revealed severe bilateral macular edema. She had been diagnosed with breast cancer 6 years ago and was receiving tamoxifen at a dosage of 20 mg/day ever since. Tamoxifen therapy was discontinued, and the patient received 250 mg of acetazolamide three times a day for a period of 1 month. Both foveae regained their normal contour within 2 months, and her vision was restored to 10/10 BCVA 3 months later. To our knowledge, this is the first case reported where bilateral intraretinal macular edema is the only retinal manifestation in a patient on oral tamoxifen.

  13. [Effect of the estrogen antagonist tamoxifen in the treatment of advanced mastocarcinoma (author's transl)].

    Science.gov (United States)

    Szepesi, T; Kärcher, K H

    1977-12-01

    Today the endocrin therapy of the advanced mastocarcinoma is in common use. Besides the already known therapy by estrogens, androgens, gestagens, and steroids, Tamoxifen, and estrogen antagonist, is a very promising therapeutic drug. In the presented study, Tamoxifen was submitted to a critical clinical control during a period of one year from 1st October 1975 until 1st October 1976. After a three months' treatment, a rate of 41% of objective remissions could be obtained. The criteria of success were estimated according to the scheme of Karnofsky. The average remission time is 5,5 months. By a determination of the estrogen receptors it would be possible to realize a therapeutic selection and to achieve a higher remission rate. The authors made an interesting observation, i.e. a probably immuno-stimulating effect which, however, still has to be submitted to further examinations. The side effects are described in detail and the indications are established. Its is astonishing that the subjective ameliorations, i.e. cessation of pains in case of generalized formation of metastases in the bones are much more frequent than the objective remissions. We came to the conclusion that the treatment by Tamoxifen is a valuable alternative in the therapy of the mastocarcinoma, above all in the postmenopausal period if the disease is advanced and incurable.

  14. TAMOXIFEN RETINOPATHY DURING TREATMENT OF AN INOPERABLE DESMOID TUMOR.

    Science.gov (United States)

    Furst, Meredith; Somogyi, Marie B; Wong, Robert W; Araujo, Dejka; Harper, Clio A

    2017-12-08

    To evaluate the clinical significance and rarity of tamoxifen retinopathy after a long-term tamoxifen treatment for an inoperable desmoid tumor. Case report. Tamoxifen retinopathy is a condition rarely observed in clinical practice. Although tamoxifen is typically a treatment for breast cancer patients, we present a 68-year-old woman taking tamoxifen for an inoperable desmoid tumor, an equally rare condition. She presented with bilaterally deteriorating vision over the course of a year. Fundoscopic examination revealed parafoveal deposits bilaterally. Spectral domain optical coherence tomography exhibited hyperreflective deposits in all layers of the retina. She had a cumulative treatment dose of 292 g of tamoxifen, and the medication was subsequently stopped. Her vision remained stable 3 months after the cessation of tamoxifen. The development of tamoxifen retinopathy in the treatment of a desmoid tumor makes this case a rare entity, and this is the first reported case of these two concomitant conditions to our knowledge. With the use of long-term tamoxifen as a primary treatment, we recommend screening at regular intervals by an ophthalmologist as an integral part of treatment.

  15. 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.

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

    International Nuclear Information System (INIS)

    Sun, Xueying; Jiang, Ruohan; Przepiorski, Aneta; Reddy, Shiva; Palmano, Kate P; Krissansen, Geoffrey W

    2012-01-01

    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. 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. Tamoxifen weakly (IC 50 ~ 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 < 0.001), respectively, compared to untreated controls. The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies. Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia. It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-γ, and intestinal cells expressing IL-18 and IFN-γ. It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues. B, T and Natural killer (NK) cells containing high levels of Lf were identified in 4T1 tumors, suggesting they had migrated from the intestine. Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors. The results indicate that Fe-Lf is a potent

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

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Xueying [Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1005 (New Zealand); Department of General Surgery, The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 (China); Jiang, Ruohan; Przepiorski, Aneta; Reddy, Shiva [Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1005 (New Zealand); Palmano, Kate P [Fonterra Research Centre, Palmerston North, 4442 (New Zealand); Krissansen, Geoffrey W [Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1005 (New Zealand)

    2012-12-11

    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. 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. Tamoxifen weakly (IC{sub 50} ~ 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 < 0.001), respectively, compared to untreated controls. The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies. Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia. It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-γ, and intestinal cells expressing IL-18 and IFN-γ. It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues. B, T and Natural killer (NK) cells containing high levels of Lf were identified in 4T1 tumors, suggesting they had migrated from the intestine. Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors. The results indicate that Fe-Lf is a

  18. 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

  19. 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

    International Nuclear Information System (INIS)

    Noh, Woo Chul; Ham, Yong Ho

    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

  20. The distribution pattern of ERα expression, ESR1 genetic variation and expression of growth factor receptors: association with breast cancer prognosis in Russian patients treated with adjuvant tamoxifen.

    Science.gov (United States)

    Babyshkina, Nataliya; Vtorushin, Sergey; Zavyalova, Marina; Patalyak, Stanislav; Dronova, Tatyana; Litviakov, Nikolay; Slonimskaya, Elena; Kzhyshkowska, Julia; Cherdyntseva, Nadejda; Choynzonov, Evgeny

    2017-08-01

    Identification of additional biomarkers associated with ER genomic and nongenomic pathways could be very useful to distinguish patients who will benefit from tamoxifen treatment. The aim of this study was to analyze the prognostic significance of the distribution pattern of ERα expression, ESR1 gene single-nucleotide polymorphisms and expression levels of growth factor receptors in Russian hormone receptor-positive breast cancer patients treated with adjuvant tamoxifen. Formalin-fixed paraffin-embedded tumor tissue samples from 97 patients were examined for the distribution pattern of ERα expression, as well as for EGFR and TGF-βR1 expression by immunohistochemistry. Genotypes for ESR1 +30T>C (rs2077647) and ESR1 2014G>A (rs2228480) were analyzed using a TaqMan assay. Progression-free survival (PFS) was used as an endpoint for the survival analyses. We found that patients with the heterogeneous distribution of ERα expression had poor prognosis on tamoxifen treatment (P = 0.021). We identified a high EGFR expression in patients who developed distant metastasis or recurrence during tamoxifen treatment (a tamoxifen-resistant group-TR) in contrast to the distant metastasis-free patients (a tamoxifen-sensitive group-TS) (80.0 vs. 41.9 %, respectively, P = 0.009). Carriers of the ESR12014A mutant allele were more prevalent among the TR patients compared to the TS patients (26.3 vs. 8.0 %, respectively, P = 0.009). EGFR expression and the distribution pattern of ERα expression were associated with the response to tamoxifen by both univariate and multivariate logistic regression analyses. The presence of these markers either alone or in combination was correlated with the worse PFS for all patients. Analysis of the distribution pattern of ERα expression and the EGFR status in tumor tissue may be valuable for patient selection for tamoxifen adjuvant therapy.

  1. 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

  2. The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): study protocol for a randomized controlled trial and progress

    International Nuclear Information System (INIS)

    Kim, Hyun-Ah; Ahn, Sei Hyun; Nam, Seok Jin; Park, Seho; Ro, Jungsil

    2016-01-01

    Ovarian function suppression (OFS) has been shown to be effective as adjuvant endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. However, it is currently unclear if addition of OFS to standard tamoxifen therapy after completion of adjuvant chemotherapy results in a survival benefit. In 2008, the Korean Breast Cancer Society Study Group initiated the ASTRRA randomized phase III trial to evaluate the efficacy of OFS in addition to standard tamoxifen treatment in hormone receptor-positive breast cancer patients who remain or regain premenopausal status after chemotherapy. Premenopausal women with estrogen receptor-positive breast cancer treated with definitive surgery were enrolled after completion of neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed at the time of enrollment and every 6 months for 2 years by follicular-stimulating hormone levels and bleeding history. If ovarian function was confirmed as premenopausal status, the patient was randomized to receive 2 years of goserelin plus 5 years of tamoxifen treatment or 5 years of tamoxifen alone. The primary end point will be the comparison of the 5-year disease-free survival rates between the OFS and tamoxifen alone groups. Patient recruitment was finished on March 2014 with the inclusion of a total of 1483 patients. The interim analysis will be performed at the time of the observation of the 187th event. This study will provide evidence of the benefit of OFS plus tamoxifen compared with tamoxifen only in premenopausal patients with estrogen receptor-positive breast cancer treated with chemotherapy

  3. An open, randomised, multicentre, phase 3 trial comparing the efficacy of two tamoxifen schedules in preventing gynaecomastia induced by bicalutamide monotherapy in prostate cancer patients.

    Science.gov (United States)

    Bedognetti, Davide; Rubagotti, Alessandra; Conti, Giario; Francesca, Francesco; De Cobelli, Ottavio; Canclini, Luca; Gallucci, Michele; Aragona, Francesco; Di Tonno, Pasquale; Cortellini, Pietro; Martorana, Giuseppe; Lapini, Alberto; Boccardo, Francesco

    2010-02-01

    Bicalutamide monotherapy is a valuable option for prostate cancer (PCa) patients who wish to avoid the consequences of androgen deprivation; however, this treatment induces gynaecomastia and mastalgia in most patients. Tamoxifen is safe and effective in preventing breast events induced by bicalutamide monotherapy without affecting antitumor activity, but possible interference between bicalutamide and tamoxifen remains a matter of concern. To reduce the exposure to tamoxifen, we considered the putative advantages of weekly administration. To compare the efficacy of two different schedules of tamoxifen in preventing breast events. Toxicity, prostate-specific antigen behaviour, and sexual-functioning scores were also evaluated. This was a noninferiority trial. From December 2003 to February 2006, 80 patients with localised/locally advanced or biochemically recurrent PCa who were also candidates for bicalutamide single therapy were randomised to receive two different schedules of tamoxifen: daily (n=41) and weekly (n=39). Median follow-up was 24.2 mo. Daily bicalutamide (150 mg) plus daily tamoxifen 20mg continuously (daily group) or the same but with tamoxifen at 20mg weekly after the first 8 wk of daily treatment (weekly group). Three patients in the weekly group and one in the daily group were discontinued for adverse events. For gynaecomastia, we used ultrasonography. For mastalgia and sexual functioning, we used questionnaires. Gynaecomastia developed in 31.7% of patients in the daily group and in 74.4% of patients in the weekly group (p<0.0001), and it was more severe in patients who switched to weekly tamoxifen (p=0.001). Mastalgia occurred in 12.2% and 46.1% of patients, respectively (p=0.001). There were no major differences among treatment schedules relative to sexual functioning scores and incidence and severity of adverse events. No differences between groups in PSA behaviour and disease progression have been detected so far. This study demonstrated that

  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. ATLAS: Adjuvant Tamoxifen Longer Against Shorter

    Science.gov (United States)

    1998-09-01

    largely tunaffected by other these 30 000 women during about 10 years of follow-up patient characteristics or treatments. were 21% (SD 3), 29% (SD 2...for both types of mosted to stop part of the eduon y epatient . most of them did stop, part of the reduction in the The right side of figure 4...patient characteristics (e.g. high/ low-risk, ER+/ER-, pre/post-menopausal) recorded at entry. Other trials of tamoxifen duration The Atlas collaboration

  6. Tamoxifen induces apoptotic neutrophil efferocytosis in horses.

    Science.gov (United States)

    Olave, C; Morales, N; Uberti, B; Henriquez, C; Sarmiento, J; Ortloff, A; Folch, H; Moran, G

    2018-03-01

    Macrophages and neutrophils are important cellular components in the process of acute inflammation and its subsequent resolution, and evidence increasingly suggests that they play important functions during the resolution of chronic, adaptive inflammatory processes. Exacerbated neutrophil activity can be harmful to surrounding tissues; this is important in a range of diseases, including allergic asthma and chronic obstructive pulmonary disease in humans, and equine asthma (also known as recurrent airway obstruction (RAO). Tamoxifen (TX) is a non-steroidal estrogen receptor modulator with effects on cell growth and survival. Previous studies showed that TX treatment in horses with induced acute pulmonary inflammation promoted early apoptosis of blood and BALF neutrophils, reduction of BALF neutrophils, and improvement in animals' clinical status. The aim of this study was to describe if TX induces in vitro efferocytosis of neutrophils by alveolar macrophages. Efferocytosis assay, myeloperoxidase (MPO) detection and translocation phosphatidylserine (PS) were performed on neutrophils isolated from peripheral blood samples from five healthy horses. In in vitro samples from heathy horses, TX treatment increases the phenomenon of efferocytosis of peripheral neutrophils by alveolar macrophages. Similar increases in supernatant MPO concentration and PS translocation were observed in TX-treated neutrophils, compared to control cells. In conclusion, these results confirm that tamoxifen has a direct effect on equine peripheral blood neutrophils, through stimulation of the engulfment of apoptotic neutrophils by alveolar macrophages.

  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. Tamoxifen treatment of bleeding irregularities associated with Norplant use.

    Science.gov (United States)

    Abdel-Aleem, Hany; Shaaban, Omar M; Amin, Ahmed F; Abdel-Aleem, Aly M

    2005-12-01

    To evaluate the possible role of tamoxifen (selective estrogen receptor modulators, SERM) in treating bleeding irregularities associated with Norplant contraceptive use. Randomized clinical trial including 100 Norplant users complaining of vaginal bleeding irregularities. The trial was conducted in the Family Planning Clinic of Assiut University Hospital. Women were assigned at random to receive tamoxifen tablets (10 mg) twice daily for 10 days or similar placebo. Women were followed-up for 3 months. The end points were percentage of women who stopped bleeding during treatment, bleeding/spotting days during the period of follow-up, effect of treatment on their lifestyle, and side effects and discontinuation of contraception. There was good compliance with treatment. At the end of treatment, a significantly higher percentage of tamoxifen users stopped bleeding in comparison to the control group (88% vs. 68%, respectively; p=.016). Women who used tamoxifen had significantly less bleeding and/or spotting days than women who used placebo, during the first and second months. During the third month, there were no significant differences between the two groups. Women who used tamoxifen reported improvement in performing household activities, religious duties and in sexual life, during the first 2 months. In the third month, there were no differences between the two groups. There were no significant differences between tamoxifen and placebo groups in reporting side effects. In the group who used tamoxifen, two women discontinued Norplant use because of bleeding vs. nine women in the placebo group. Tamoxifen use at a dose of 10 mg twice daily orally, for 10 days, has a beneficial effect on vaginal bleeding associated with Norplant use. In addition, the bleeding pattern was better in women who used tamoxifen for the following 2 months after treatment. However, these results have to be confirmed in a larger trial before advocating this line of treatment.

  9. Black cohosh (Cimicifuga racemosa) in tamoxifen-treated breast cancer patients with climacteric complaints - a prospective observational study.

    Science.gov (United States)

    Rostock, Matthias; Fischer, Julia; Mumm, Andreas; Stammwitz, Ute; Saller, Reinhard; Bartsch, Hans Helge

    2011-10-01

    The antihormonal therapy of breast cancer patients with the antiestrogen tamoxifen often induces or aggravates menopausal complaints. As estrogen substitution is contraindicated, herbal alternatives, e.g. extracts of black cohosh are often used. A prospective observational study was carried out in 50 breast cancer patients with tamoxifen treatment. All patients had had surgery, most of them had undergone radiation therapy (87%) and approximately 50% had received chemotherapy. Every patient was treated with an isopropanolic extract of black cohosh (1-4 tablets, 2.5 mg) for 6 months. Patients recorded their complaints before therapy and after 1, 3, and 6 months of therapy using the menopause rating scale (MRS II). The reduction of the total MRS II score under black cohosh treatment from 17.6 to 13.6 was statistically significant. Hot flashes, sweating, sleep problems, and anxiety improved, whereas urogenital and musculoskeletal complaints did not change. In all, 22 patients reported adverse events, none of which were linked with the study medication; 90% reported the tolerability of the black cohosh extract as very good or good. Black cohosh extract seems to be a reasonable treatment approach in tamoxifen treated breast cancer patients with predominantly psychovegetative symptoms.

  10. Thrombosis of digital arteries associated with tamoxifen use: case report.

    Science.gov (United States)

    Hutchison, Richard L; Rayan, Ghazi M

    2012-02-01

    Arterial thrombosis in the upper extremity occurs often at the wrist. We report a unique case of thrombosis that involved multiple digital arteries, without radial or ulnar artery involvement, which developed only after using tamoxifen despite chronic occupational blunt percussive hand use. Revascularization was achieved after thrombectomy. Multiple digital arterial thromboses may complicate the use of tamoxifen. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  11. Tamoxifen for women at high risk of breast cancer

    OpenAIRE

    Nazarali, Safia A; Narod, Steven A

    2014-01-01

    Safia A Nazarali, Steven A Narod Women's College Research Institute, Women's College Hospital, and The University of Toronto, Toronto, Ontario, Canada Abstract: Tamoxifen has been used as a treatment for women who have been diagnosed with breast cancer for roughly four decades and has been approved as chemoprevention for over ten years. Although tamoxifen has been proven to be beneficial in preventing breast cancer in high-risk women, its use has not been widely embraced. To ...

  12. Tamoxifen from Failed Contraceptive Pill to Best-Selling Breast Cancer Medicine: A Case-Study in Pharmaceutical Innovation

    Directory of Open Access Journals (Sweden)

    Viviane M. Quirke

    2017-09-01

    Full Text Available Today, tamoxifen is one of the world's best-selling hormonal breast cancer drugs. However, it was not always so. Compound ICI 46,474 (as it was first known was synthesized in 1962 within a project to develop a contraceptive pill in the pharmaceutical laboratories of ICI (now part of AstraZeneca. Although designed to act as an anti-estrogen, the compound stimulated, rather than suppressed ovulation in women. This, and the fact that it could not be patented in the USA, its largest potential market, meant that ICI nearly stopped the project. It was saved partly because the team's leader, Arthur Walpole, threatened to resign, and pressed on with another project: to develop tamoxifen as a treatment for breast cancer. Even then, its market appeared small, because at first it was mainly used as a palliative treatment for advanced breast cancer. An important turning point in tamoxifen's journey from orphan drug to best-selling medicine occurred in the 1980s, when clinical trials showed that it was also useful as an adjuvant to surgery and chemotherapy in the early stages of the disease. Later, trials demonstrated that it could prevent its occurrence or re-occurrence in women at high risk of breast cancer. Thus, it became the first preventive for any cancer, helping to establish the broader principles of chemoprevention, and extending the market for tamoxifen and similar drugs further still. Using tamoxifen as a case study, this paper discusses the limits of the rational approach to drug design, the role of human actors, and the series of feedback loops between bench and bedside that underpins pharmaceutical innovation. The paper also highlights the complex evaluation and management of risk that are involved in all therapies, but more especially perhaps in life-threatening and emotion-laden diseases like cancer.

  13. Discrepancy between ultrasonography and hysteroscopy and histology of endometrium in postmenopausal breast cancer patients using tamoxifen

    NARCIS (Netherlands)

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

    Background. The increased risk of endometrial carcinoma following the use of tamoxifen has stimulated studies on endometrial diagnostic screening methods. In tamoxifen users the endometrial thickening observed with transvaginal ultrasonography (TVU) frequently cannot be confirmed by hysteroscopy or

  14. Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells

    NARCIS (Netherlands)

    Meijer, Danielle; van Agthoven, Ton; Bosma, Peter T.; Nooter, Kees; Dorssers, Lambert C. J.

    2006-01-01

    Antiestrogens, such as tamoxifen, are widely used for endocrine treatment of estrogen receptor-positive breast cancer. However, as breast cancer progresses, development of tamoxifen resistance is inevitable. The mechanisms underlying this resistance are not well understood. To identify genes

  15. Adjuvant tamoxifen influences the lipid profile in breast cancer patients.

    Science.gov (United States)

    Lin, Che; Chen, Li-Sheng; Kuo, Shou-Jen; Chen, Dar-Ren

    2014-02-01

    Currently there is a debate regarding whether tamoxifen used in breast cancer has an impact on lipid profiles. The aim of this study was to determine whether tamoxifen has an impact on the serum lipid profile in Taiwanese women. Data of 109 patients were collected from the routine clinical follow-up for women with hormone receptor-positive breast cancer who were treated between July 2005 and March 2008. These patients were divided into 2 subgroups, based on their tumor grade and lymph node status. Subgroup 1 patients had tumor grade I/II and a negative lymph node status. Those patients with tumor grade III or a positive lymph node status were defined as subgroup 2. In the 109 patients, the mean serum total cholesterol (TC) levels after tamoxifen treatment, as well as the serum low-density lipoprotein cholesterol (LDL-C) levels, were lower than the baseline levels, with statistically significant differences. Treatment with tamoxifen lowered the serum TC and LDL-C levels in both subgroups. The results indicate that tamoxifen has an impact on the serum lipid profile of breast cancer patients in Taiwan. Physicians should follow up the lipid profile in these patients.

  16. 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.

  17. 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.

  18. 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.

  19. The Possible Therapeutic Role of Polyphenyl Constituents in Turmeric and Tamoxifen on Hepatocellular Carcinoma Chemically Induced in Rats

    International Nuclear Information System (INIS)

    Abdelgawad, M.R.

    2017-01-01

    Tamoxifen is a drug wildly used for the adjuvant therapy in the treatment of women with estrogen receptor-positive breast tumors and has a low incidence of serious side-effects. Feeding turmeric ( Curcuma longa L .) to rats has no apparent side effects; reduced the types of inflammation that can cause liver cell damage, blockage and scarring. Turmeric delay the damage caused by progressive inflammatory liver disease. This study was carried out to study the possible therapeutic effect of polyphenyl constituents in turmeric and tamoxifen on hepatocarcinogenesis in rats chemically induced by diethylnitrosamine (DEN). Thirty five male rats were injected with DEN in a single dose i.p. (200mg/kg), 7 rats were sacrificed after ~6 months for histopathological examination for HCC nodules in different lobes and lobules, many nodules were observed by naked eye with a diameter of about ~2-3mm. The remaining 28 hepatoma (HCC) bearing rats chemically induced were randomized divided into 4 groups (each of 7rats): hepatoma bearing rats receiving the control diet; hepatoma bearing rats (supplemented with 4g/kg (wt/wt) turmeric (~200 μg curcumin /rat/day/4weeks; hepatoma bearing rats treated with 50mg/kg (wt/wt) tamoxifen dissolved in 0.1 ml dimethylsulfoxide and diluted with normal saline and drinking water; hepatoma bearing rats treated with 50mg/kg (wt/wt) tamoxifen in 0.1 ml dimethylsulfoxide and diluted with normal saline and drinking water and supplemented with 4g/ kg (wt/wt) turmeric(~200 μg curcumin /rat/day/4weeks; besides, 7 male rats serves as control group. By the end of the experiment at 4 weeks, rats in each group were sacrificed for examination.

  20. Estrogen receptor, Progesterone receptor, HER2 status and Ki67 index and responsiveness to adjuvant tamoxifen in postmenopausal high-risk breast cancer patients enrolled in the DBCG 77C trial

    DEFF Research Database (Denmark)

    Knoop, Ann; Lænkholm, Anne Vibeke; Jensen, M. B.

    2014-01-01

    BCRR and BCM in postmenopausal patients with ER positive breast cancers. The relative benefit from tamoxifen was not significantly different in luminal A and B subtypes. Funding: The Danish Breast Cancer Cooperative Group (DBCG) prepared the original protocol (DBCG 77C) and was the sponsor of the study......Background: The DBCG 77C trial compared one year of tamoxifen in postmenopausal, steroid-receptor unknown, high-risk breast cancer patients to no adjuvant systemic therapy. After a potential follow-up of 30 years we report overall efficacy of the study and results according to subtypes subsequently...... assessed by immunohistochemistry and fluorescent in situ hybridisation (FISH). Methods: Between 1977 and 1982, 1716 postmenopausal patients with tumours larger than 5 cm or positive axillary nodes were randomly assigned to no systemic therapy or tamoxifen 30 mg daily for one year. Archival tumour tissue...

  1. Adenosarcoma of the uterus following tamoxifen treatment for breast cancer

    NARCIS (Netherlands)

    Mourits, MJE; Hollema, H; Willemse, PHB; De Vries, EGE; Aalders, JG; Van der Zee, AGJ

    1998-01-01

    A 71-year-old patient developed an uterine adenosarcoma two months after two years of tamoxifen adjuvant treatment for early breast cancer. After curettage for postmenopausal bleeding, the patient underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic

  2. 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

    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:

  3. Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer

    International Nuclear Information System (INIS)

    Hennig, Ewa E.; Piatkowska, Magdalena; Karczmarski, Jakub; Goryca, Krzysztof; Brewczynska, Elzbieta; Jazwiec, Radoslaw; Kluska, Anna; Omiotek, Robert; Paziewska, Agnieszka; Dadlez, Michal; Ostrowski, Jerzy

    2015-01-01

    Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy. Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r 2 = 0.23; p < 10 −16 ) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10 −16 ) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10 −43 ). The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard

  4. Feature of amenorrhea in postoperative tamoxifen users with breast cancer.

    Science.gov (United States)

    Kim, Hoon; Han, Wonshik; Ku, Seung Yup; Suh, Chang Suk; Kim, Seok Hyun; Choi, Young Min

    2017-03-01

    Tamoxifen has been used to prevent the recurrence of breast cancer. However, tamoxifen-users frequently experience amenorrhea and it can be confused from that caused by other hormonal abnormalities. In amenorrheic patients without breast cancer, clinicians usually measure the sex hormone levels that are known to be associated with ovarian or menstrual function. This study aimed to investigate the feature of female sex hormones in premenopausal breast cancer patients undergoing tamoxifen treatment. The medical records of fifty-nine premenopausal breast cancer patients who underwent tamoxifen treatment were reviewed retrospectively. The study population consisted of amenorrheic patients (n=36) and patients with menstruation (n=23). Serum hormone levels were measured either specifically between cycle days 2 and 5 in menstruating patients or at any time in amenorrheic participants. Serum levels of lutenizing hormone and estradiol were not statistically different according to the presence of menstruation. Serum follicle stimulating hormone level was significantly higher in amenorrheic patients (8.1±5.7 mIU/mL) than those in menstruating subjects (5.1±2.2 mIU/mL) (p=0.01). Serum concentration of thyroid stimulating hormone was lower in patients with amenorrhea (1.5±0.9 vs. 2.3±2.2 μIU/mL, p=0.04), although the prevalence of hypo- or hyperthyroidism was not different according to the pattern of menstruation. Menstruation status and hormone levels can be influenced by tamoxifen use in reproductive age breast cancer patients. Physicians should be attentive to the alteration of pituitary hormone levels in addition to sex steroid hormones in this population. Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology

  5. Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review

    Directory of Open Access Journals (Sweden)

    Kunath Frank

    2012-08-01

    Full Text Available Abstract Background Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients. Methods We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs. Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320; http://www.crd.york.ac.uk/PROSPERO. Results Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22 or breast pain (RR 0.06, 95% CI 0.02 to 0.17 at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58 and breast pain (RR 0.25, 95% CI 0.10 to 0.64 when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65 and breast pain (RR 0.20, 95% CI 0.06 to 0.65 when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P > 0.05. Conclusions The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear

  6. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.

    Science.gov (United States)

    Dominick, Sally; Hickey, Martha; Chin, Jason; Su, H Irene

    2015-12-09

    Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. To determine the effectiveness and safety of levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Specialised Register (MDSG), Cochrane Breast Cancer Group Specialised Register (CBCG), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Abstracts of Reviews of Effects (DARE), The Cochrane Library, clinicaltrials.gov, The World Health Organisation International Trials Registry, ProQuest Dissertations & Theses, MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science, OpenGrey, LILACS, PubMed, and Google. The final search was performed in October 2015. Randomised controlled trials of women with breast cancer on adjuvant tamoxifen that compared endometrial surveillance alone (control condition) versus the LNG-IUS with endometrial surveillance (experimental condition) on the incidence of endometrial pathology. Study selection, risk of bias assessment and data extraction were performed independently by two review authors. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer) diagnosed at hysteroscopy or

  7. A Role for Estrogen Receptor Phosphorylation in the Resistance to Tamoxifen

    International Nuclear Information System (INIS)

    De Leeuw, R.; Neefjes, J.; Michalides, R.

    2011-01-01

    About two thirds of all human breast cancer cases are estrogen receptor positive. The drug of first choice for these patients is tamoxifen. However, about half of the recurrences after removal of the primary tumor are or become resistant to this drug. While many mechanisms have been identified for tamoxifen resistance in the lab, at present only a few have been translated to the clinic. This paper highlights the role in tamoxifen resistance of phosphorylation by different kinases on different sites of the estrogen receptor. We will discuss the molecular pathways and kinases that are involved in phosphorylation of ERa and how these affect tamoxifen resistance. Finally, we will elaborate on the clinical translation of these observations and the possibility to predict tamoxifen responses in patient tumor samples before treatment onset. The findings made originally on the bench may translate into a better and personalized treatment of breast cancer patients using an old and safe anticancer drug: tamoxifen

  8. 131I labeling of tamoxifen and biodistribution studies in rats

    International Nuclear Information System (INIS)

    Biber Muftuler, F.Z.; Unak, P.; Teksoz, S.; Acar, C.; Yolcular, S.; Yuerekli, Y.

    2008-01-01

    Tamoxifen [TAM ([Z]-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-N,N-dimethylethanamine)] has been used as an antiestrogen drug for treatment and prevention of human breast cancer. Tamoxifen was labeled with 131 I using iodogen as an oxidizing agent. Mass spectroscopy of the cold standard showed that the labeling occurs in ortho position to the phenyl ether position of TAM as expected. Quality control, radiochemical yield and stability were established using the radioelectrophoresis method. The radiolabeled compound maintained its stability throughout working period of 24 h. Scintigraphic imaging was performed and tissue distribution was determined in Albino Wistar rats. According to biodistribution and imaging experiments the radiolabeled compound presented estrogen receptor (ER) specificity and it was uptaken by endometrium as well as breast tissue

  9. Radiolytic oxidation of tamoxifen using the free radicals .OH and (or) HO2

    International Nuclear Information System (INIS)

    Leguene, C.; Clavere, P.; Jore, D.; Gardes-Albert, M.

    2001-01-01

    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, . OH and (or) HO 2 . free radicals that are produced by water radiolysis. Aqueous solutions of tamoxifen of concentrations ranging between 10 -5 and 2.5 x 10 -5 M have been irradiated (γ 137 Cs) in aerated acidic medium (H 3 PO 4 10 -3 M or HCOOH 10 -1 M). The results show that tamoxifen reacts quantitatively with . OH free radicals but does not react with HO 2 . free radicals under our experimental conditions. (author)

  10. Mammographic density changes following discontinuation of tamoxifen in premenopausal women with oestrogen receptor-positive breast cancer.

    Science.gov (United States)

    Kim, Won Hwa; Cho, Nariya; Kim, Young-Seon; Yi, Ann

    2018-04-06

    To evaluate the changes in mammographic density after tamoxifen discontinuation in premenopausal women with oestrogen receptor-positive breast cancers and the underlying factors METHODS: A total of 213 consecutive premenopausal women with breast cancer who received tamoxifen treatment after curative surgery and underwent three mammograms (baseline, after tamoxifen treatment, after tamoxifen discontinuation) were included. Changes in mammographic density after tamoxifen discontinuation were assessed qualitatively (decrease, no change, or increase) by two readers and measured quantitatively by semi-automated software. The association between % density change and clinicopathological factors was evaluated using univariate and multivariate regression analyses. After tamoxifen discontinuation, a mammographic density increase was observed in 31.9% (68/213, reader 1) to 22.1% (47/213, reader 2) by qualitative assessment, with a mean density increase of 1.8% by quantitative assessment compared to density before tamoxifen discontinuation. In multivariate analysis, younger age (≤ 39 years) and greater % density decline after tamoxifen treatment (≥ 17.0%) were independent factors associated with density change after tamoxifen discontinuation (p density change with a mean density increase of 1.8%, which was associated with younger age and greater density change after tamoxifen treatment. • Increased mammographic density after tamoxifen discontinuation can occur in premenopausal women. • Mean density increase after tamoxifen discontinuation was 1.8%. • Density increase is associated with age and density decrease after tamoxifen.

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

    International Nuclear Information System (INIS)

    Hong, Wei; Chen, Linfeng; Li, Juan; Yao, Zhi

    2010-01-01

    Estrogen receptor alpha (ERα), a ligand controlled transcription factor, plays an important role in breast cancer growth and endocrine therapy. Tamoxifen (TAM) antagonizes ERα activity and has been applied in breast cancer treatment. TAM-bound ERα associates with nuclear receptor-corepressors. Mitogen-activated protein kinase (MAPK) has been elucidated to result in cross-talk between growth factor and ERα mediated signaling. We show that activated MAPK represses interaction of TAM-bound ERα with silencing mediator for retinoid and thyroid hormone receptors (SMRT) and inhibits the recruitment of SMRT by ERα to certain estrogen target genes. Blockade of MAPK signaling cascade with MEK inhibitor U0126 promotes the interaction and subsequently inhibits ERα activity via enhanced recruitment of SMRT, leading to reduced expression of ERα 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 ERα, suggesting corepressor mediates inhibition of ERα 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.

  12. 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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

    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. 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

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

    Science.gov (United States)

    de Graan, Anne-Joy M; Teunissen, Sebastiaan F; de Vos, Filip Y F L; Loos, Walter J; van Schaik, Ron H N; de Jongh, Felix E; de Vos, Aad I; van Alphen, Robbert J; van der Holt, Bronno; Verweij, Jaap; Seynaeve, Caroline; Beijnen, Jos H; Mathijssen, Ron H J

    2011-08-20

    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 value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. A strong and highly significant correlation (r = -0.72; P dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P dextromethorphan exposure. Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.

  16. Antiarrhythmic effect of tamoxifen on the vulnerability induced by hyperthyroidism to heart ischemia/reperfusion damage.

    Science.gov (United States)

    Pavón, Natalia; Hernández-Esquivel, Luz; Buelna-Chontal, Mabel; Chávez, Edmundo

    2014-09-01

    Hyperthyroidism, known to have deleterious effects on heart function, and is associated with an enhanced metabolic state, implying an increased production of reactive oxygen species. Tamoxifen is a selective antagonist of estrogen receptors. These receptors make the hyperthyroid heart more susceptible to ischemia/reperfusion. Tamoxifen is also well-known as an antioxidant. The aim of the present study was to explore the possible protective effect of tamoxifen on heart function in hyperthyroid rats. Rats were injected daily with 3,5,3'-triiodothyronine at 2mg/kg body weight during 5 days to induce hyperthyroidism. One group was treated with 10mg/kg tamoxifen and another was not. The protective effect of the drug on heart rhythm was analyzed after 5 min of coronary occlusion followed by 5 min reperfusion. In hyperthyroid rats not treated with tamoxifen, ECG tracings showed post-reperfusion arrhythmias, and heart mitochondria isolated from the ventricular free wall lost the ability to accumulate and retain matrix Ca(2+) and to form a high electric gradient. Both of these adverse effects were avoided with tamoxifen treatment. Hyperthyroidism-induced oxidative stress caused inhibition of cis-aconitase and disruption of mitochondrial DNA, effects which were also avoided by tamoxifen treatment. The current results support the idea that tamoxifen inhibits the hypersensitivity of hyperthyroid rat myocardium to reperfusion damage, probably because its antioxidant activity inhibits the mitochondrial permeability transition. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Dried blood spots voor het bepalen van de serumconcentratie van tamoxifen en zijn actieve metaboliet endoxifen

    NARCIS (Netherlands)

    Jager, Nynke G L; Rosing, Hilde; Schellens, Jan H M; Beijnen, Jos H.; Linn, Sabine C.

    2016-01-01

    OBJECTIVE To establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and endoxifen in order to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. The antiestrogenic effect of tamoxifen is

  18. 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...

  19. 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.

  20. Production and Investigation of Controlled Drug Release Properties of Tamoxifen Loaded Alginate-Gum Arabic Microbeads

    Directory of Open Access Journals (Sweden)

    Rukiye Yavaşer

    2016-08-01

    Full Text Available The entrapment of tamoxifen onto alginate-gum arabic beads and the production of controlled drug release was investigated in this study. The polymeric system that would provide the controlled release of tamoxifen was formed using alginate and gum arabic. In the first phase of the study, the optimization of the alginate-gum arabic beads production was conducted; then the study continued with drug entrapment experiments. Tamoxifen entrapment yield was found to be approximately 90% of initial tamoxifen concentration. In vitro drug release experiments were performed in simulated gastric juice and intestinal fluid where the tamoxifen release was 20% and 53% of the initial drug present, respectively. As a result of this study, it is expected that a valuable contribution to the field of controlled drug release system production is realized.

  1. 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...

  2. CB1 and CB2 Receptors are Novel Molecular Targets for Tamoxifen and 4OH-Tamoxifen

    OpenAIRE

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

    2013-01-01

    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 t...

  3. GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells.

    Science.gov (United States)

    Vaziri-Gohar, Ali; Houston, Kevin D

    2016-02-15

    Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant therapy for estrogen receptor-α (ERα)-positive breast cancer patients. To determine if extracellular factors contribute to the modulation of IGF-1 signaling after tamoxifen treatment, MCF-7 cells were treated with IGF-1 in conditioned medium (CM) obtained from 4-OHT-treated MCF-7 cells and the accumulation of phospho-Akt (S473) was measured. CM inhibited IGF-1-dependent cell signaling and suggesting the involvement of extracellular factors (ie. IGFBPs). A significant increase in IGFBP-1 mRNA and extracellular IGFBP-1 protein was observed in 4-OHT-treated MCF-7 cells. Knockdown experiments demonstrated that both GPER1 and CREB mediate IGFBP-1 induction. Furthermore, experiments showed that 4-OHT-dependent IGFBP-1 transcription is downstream of GPER1-activation in breast cancer cells. Additionally, neutralization and knockdown experiments demonstrated a role for IGFBP-1 in the observed inhibition of IGF-1 signaling. These results suggested that 4-OHT inhibits IGF-1 signaling via GPER1 and CREB mediated extracellular IGFBP-1 accumulation in breast cancer cells. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  4. 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.

  5. Novel Carbonyl Analogs of Tamoxifen: Design, Synthesis, and Biological Evaluation

    Directory of Open Access Journals (Sweden)

    Konstantinos M. Kasiotis

    2017-09-01

    Full Text Available Aim of this work was to provide tamoxifen analogs with enhanced estrogen receptor (ER binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known ER inhibitor ICI182,780. Theoretical calculations and molecular modeling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation.

  6. 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. Copyright © 2012. Published by Elsevier B.V.

  7. Novel Carbonyl Analogues of Tamoxifen: Design, Synthesis, and Biological Evaluation

    Science.gov (United States)

    Kasiotis, Konstantinos M.; Lambrinidis, George; Fokialakis, Nikolas; Tzanetou, Evangelia N.; Mikros, Emmanuel; Haroutounian, Serkos A.

    2017-09-01

    Aim of this work was to provide tamoxifen analogues with enhanced estrogen receptor binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known estrogen receptor inhibitor ICI182,780. Theoretical calculations and molecular modelling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation.

  8. Tamoxifen added to radiotherapy and surgery for the treatment of ductal carcinoma in situ of the breast: A meta-analysis of 2 randomized trials

    International Nuclear Information System (INIS)

    Petrelli, Fausto; Barni, Sandro

    2011-01-01

    Background: Surgical excision with adequate margins is the treatment of choice for ductal, in situ carcinoma of the breast (DCIS). The addition of radiotherapy (RT) halved local in situ and invasive recurrence. The purpose of our meta-analysis is to evaluate the reduction in recurrence (in situ or invasive) with the addition of tamoxifen (T), in particular in patients with DCIS treated with surgery + RT. Patients and methods: The eligible studies (NSABP-B24 and UK ANZ DCIS trials) included prospective, randomized, controlled trials in which the addition of T had been compared with surgery + RT without T in women with DCIS of the breast. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated for both in situ and invasive recurrence (local and controlateral). Results: Tamoxifen does not reduce breast cancer-specific or overall mortality when added to loco-regional therapy for DCIS of the breast (surgery plus or minus RT). Tamoxifen reduces overall breast cancer recurrence by 29% in all patients and by 33% in those treated with both surgery and RT. Only ipsilateral invasive (RR 0.61 [95% CI 0.41, 0.92]; p = 0.02) and controlateral in situ relapses (RR 0.40 [95% CI 0.16, 0.96]; p = 0.04) are significantly lowered when T is added to RT. Tamoxifen seems to exert a local synergistic effect with RT. Both young and older women ( 50 years) achieve some benefit from the addition of T (RR 0.6 and 0.74, respectively). Conclusion: The addition of T to surgery and RT for DCIS of the breast reduces the risk of local invasive and controlateral in situ relapses, but not the survival. The benefit is independent of age. In conclusion, surgery associated with RT and T is the treatment of choice for patients with (estrogen-receptor positive) DCIS of the breast.

  9. 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

  10. Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology Group (COG) phase II study.

    Science.gov (United States)

    Skapek, Stephen X; Anderson, James R; Hill, D Ashley; Henry, David; Spunt, Sheri L; Meyer, William; Kao, Simon; Hoffer, Fredric A; Grier, Holcombe E; Hawkins, Douglas S; Raney, R Beverly

    2013-07-01

    Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group. Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT. Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates. Copyright © 2012 Wiley Periodicals, Inc.

  11. Safety and Efficacy of High-Dose Tamoxifen and Sulindac for Desmoid Tumor in Children: Results of a Children’s Oncology Group (COG) Phase II Study

    Science.gov (United States)

    Skapek, Stephen X.; Anderson, James R.; Hill, D. Ashley; Henry, David; Spunt, Sheri L.; Meyer, William; Kao, Simon; Hoffer, Fredric A.; Grier, Holcombe E.; Hawkins, Douglas S.; Raney, R. Beverly

    2015-01-01

    Background Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children’s Oncology Group. Procedures Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. Results Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10–18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23–0.48) and 96%, respectively. All three deaths were due to progressive DT. Conclusions Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates. PMID:23281268

  12. Synergistic effects of retinoic acid and tamoxifen on human breast cancer cells: Proteomic characterization

    International Nuclear Information System (INIS)

    Wang Ying; He Qingyu; Chen Hongming; Chiu Jenfu

    2007-01-01

    The anti-estrogen tamoxifen and vitamin A-related compound, all-trans retinoic acid (RA), in combination act synergistically to inhibit the growth of MCF-7 human breast cancer cells. In the present study, we applied two-dimensional gel electrophoresis based proteomic approach to globally analyze this synergistic effect of RA and tamoxifen. Proteomic study revealed that multiple clusters of proteins were involved in RA and tamoxifen-induced apoptosis in MCF-7 breast cancer cells, including post-transcriptional and splicing factors, proteins related to cellular proliferation or differentiation, and proteins related to energy production and internal degradation systems. The negative growth factor-transforming growth factor β (TGFβ) was secreted by RA and/or tamoxifen treatment and was studies as a potential mediator of the synergistic effects of RA and tamoxifen in apoptosis. By comparing protein alterations in treatments of RA and tamoxifen alone or in combination to those of TGFβ treatment, or co-treatment with TGFβ inhibitor SB 431542, proteomic results showed that a number of proteins were involved in TGFβ signaling pathway. These results provide valuable insights into the mechanisms of RA and tamoxifen-induced TGFβ signaling pathway in breast cancer cells

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

    International Nuclear Information System (INIS)

    Teunissen, S.F.; Rosing, H.; Schinkel, A.H.; Schellens, J.H.M.; Beijnen, J.H.

    2010-01-01

    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 -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.

  14. Tamoxifen-Containing Eye Drops Successfully Trigger Cre-Mediated Recombination in the Entire Eye.

    Science.gov (United States)

    Schlecht, Anja; Leimbeck, Sarah V; Tamm, Ernst R; Braunger, Barbara M

    2016-01-01

    Embryonic lethality in mice with targeted gene deletion is a major issue that can be circumvented by using Cre-loxP-based animal models. Various inducible Cre systems are available, e.g. such that are activated following tamoxifen treatment, and allow deletion of a specific target gene at any desired time point during the life span of the animal. In this study, we describe the efficiency of topical tamoxifen administration by eye drops using a Cre- reporter mouse strain (R26R). We report that tamoxifen-responsive CAGGCre-ER (TM) mice show a robust Cre- mediated recombination throughout the entire eye.

  15. Uptake of tamoxifen in consecutive premenopausal women under surveillance in a high-risk breast cancer clinic.

    Science.gov (United States)

    Donnelly, L S; Evans, D G; Wiseman, J; Fox, J; Greenhalgh, R; Affen, J; Juraskova, I; Stavrinos, P; Dawe, S; Cuzick, J; Howell, A

    2014-04-02

    Randomised trials of tamoxifen versus placebo indicate that tamoxifen reduces breast cancer risk by approximately 33%, yet uptake is low. Approximately 10% of women in our clinic entered the IBIS-I prevention trial. We assess the uptake of tamoxifen in a consecutive series of premenopausal women not in a trial and explore the reasons for uptake through interviews. All eligible women between 33 and 46 years at ≥17% lifetime risk of breast cancer and undergoing annual mammography in our service were invited to take a 5-year course of tamoxifen. Reasons for accepting (n=15) or declining (n=15) were explored using semi-structured interviews. Of 1279 eligible women, 136 (10.6%) decided to take tamoxifen. Women >40 years (74 out of 553 (13.4%)) and those at higher non-BRCA-associated risk were more likely to accept tamoxifen (129 out of 1109 (11.6%)). Interviews highlighted four themes surrounding decision making: perceived impact of side effects, the impact of others' experience on beliefs about tamoxifen, tamoxifen as a 'cancer drug', and daily reminder of cancer risk. Tamoxifen uptake was similar to previously ascertained uptake in a randomised controlled trial (IBIS-I). Concerns were similar in women who did or did not accept tamoxifen. Decision making appeared to be embedded in the experience of significant others.

  16. Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer.

    Science.gov (United States)

    Mathew, Aju; Davidson, Nancy E

    2015-11-01

    Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5-10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS + tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS + AI compared with OFS + tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Spectral domain optical coherence tomography findings in tamoxifen retinopathy--a case report.

    Science.gov (United States)

    Nair, Sandhya Narayanan; Anantharaman, Giridhar; Gopalakrishnan, Mahesh; Vyas, Jyothiprakash

    2013-01-01

    To report spectral domain optical coherence tomography findings in a case of typical tamoxifen retinopathy. In this observational case report, a patient with tamoxifen retinopathy was imaged with spectral domain optical coherence tomography and fundus auto fluorescence. Spectral domain optical coherence tomography showed numerous hyperreflective spots within the retina, mainly in the inner retinal layers in both the eyes. The external limiting membrane, the Inner Segment-Outer Segment junction, and the photoreceptors were not discernable at the fovea in the right eye. In the left eye, there was foveal atrophy with total loss of photoreceptors. The autofluorescent images showed macular hypofluorescence with foveal hyperfluorescence. Spectral domain optical coherence tomography demonstrated abnormalities in the outer retinal layers in tamoxifen retinopathy. There were also characteristic alterations in the autofluorescence pattern at the macula in tamoxifen retinopathy.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. Tamoxifen with and without radiation after partial mastectomy in patients with involved nodes

    Energy Technology Data Exchange (ETDEWEB)

    Cooke, Andrew L; Perera, Francisco; Fisher, Barbara; Opeitum, Abiola; Yu, Norman

    1995-02-15

    Purpose: To determine the effect of tamoxifen on local control after partial mastectomy with and without adjuvant breast irradiation. Methods and Materials: A retrospective study of 97 node positive patients identified from the records of the London Regional Cancer Center included 44 patients who received tamoxifen and breast irradiation (40 or 50 Gy plus booster dose) after partial mastectomy, and 53 patients who received tamoxifen only after partial mastectomy. Base line characteristics of the two groups were similar. Results: At 39 months actuarial follow-up there was a breast tumor recurrence (BTR) in 5% vs. 21% of patients when radiation was omitted (p = 0.0388), but there was no difference in the cause-specific mortality of the two treatment groups. Cox Regression analysis (on only 10 BTR) showed age and adjuvant radiation as significant predictors of BTR. In patients not receiving radiation, no BTR was seen in 22 patients {>=}70 years of age at diagnosis vs. 8 BTR in 31 patients <70 years (p = 0.0130). All BTR occurred while patients were receiving tamoxifen. Conclusion: Tamoxifen alone with omission of radiation after partial mastectomy provides inferior breast tumor control in node positive patients. This is especially true for patients under 70 years of age. Patients aged 70 years or older at the time of diagnosis of breast cancer who receive tamoxifen have a low rate of breast tumor recurrence when radiation is omitted. These patients represent a group for whom radiation might not be necessary.

  4. 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

    Science.gov (United States)

    Wu, Chien-Tung; Lai, Jung-Nien; Tsai, Yueh-Ting

    2014-01-01

    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. PMID:25485843

  5. 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

  6. 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

    and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors......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 gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

  7. Endocrinology and hormone therapy in breast cancer: Endocrine therapy in premenopausal women

    International Nuclear Information System (INIS)

    Pritchard, Kathleen

    2005-01-01

    Endocrine therapy remains important in premenopausal women with hormone receptor positive breast cancer. Ovarian ablation, used alone, is effective in delaying recurrence and increasing survival in such women. When added to chemotherapy, it is less clear that it is effective perhaps because of the endocrine ablative effect of chemotherapy. Trials comparing ovarian ablation with or without tamoxifen to CMF-type chemotherapy suggest that the endocrine therapy is equivalent to or better than this chemotherapy in women whose tumors have estrogen and/or progesterone receptor. Tamoxifen is also effective in preventing recurrence and prolonging survival in the adjuvant setting in premenopausal women. While most of the available data deals with tamoxifen given alone, it appears to have a similar beneficial effect when added to chemotherapy in the premenopausal adjuvant setting. Adjuvant aromatase inhibitors should not be used in premenopausal women

  8. Apoptotic efficiency of aqueous extracts of turmeric, garlic and their active compounds in combination with Tamoxifen in lung and oral cancers: A comparative study

    Directory of Open Access Journals (Sweden)

    Satish Kumar Vemuri

    2018-06-01

    Full Text Available Anticancer treatment against oral and lung cancers has caught the eye of oncologist and researchers worldwide as most common cause deaths in India and worldwide is due to these cancers and most of the treatment strategies employed are not showing any effectiveness against neoplastic ability of the cancers. One of the reasons for cancer deaths could be because of poor prognosis and associated therapies. The existing cancer agents are being re-evaluated and development of new mechanisms of treatment being explored continuously, but it’s inadequate in offering treatment. Therefore, endeavors for new anticancer agents with high efficacy and considerable side effects still going on. The literature reviews shows numerous medicinal plants exhibiting anti-proliferative, pro-apoptotic, anti-metastatic and anti-angiogenic properties and these effects were reported by conducting both in vitro experiments and animal studies. Use of natural phytochemical compounds in cancer chemoprevention is an emerging strategy to forestall the cancer progression or cure cancer.In the present study we have attempted to evaluate the efficacy of Curcumin longa and Allium sativum aqueous extracts individually and in combination with its active compounds (Curcumin and Quercetin and also with Tamoxifen hydrochloride. Our results suggest that aqueous extracts of Curcumin longa and Allium sativum were effective in inducing apoptosis and cell death in two immortal cell lines i.e. A549 and SCC-9 (Adeno carcinoma of lung, squamous cell carcinoma of tongue, but there was no apoptosis or cell senescence in normal cell line (HEK 293. There was significant increase in apoptosis and cell senescence in combination therapy. Hence a combination of natural extracts along with Tamoxifen can be considered an alternate in cancer treatments but this requires more research. Keywords: Curcumin longa, Allium sativum, Tamoxifen hydrochloride, A549, SCC-9, HEK 293 cell lines

  9. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.

    Science.gov (United States)

    Regan, Meredith M; Neven, Patrick; Giobbie-Hurder, Anita; Goldhirsch, Aron; Ejlertsen, Bent; Mauriac, Louis; Forbes, John F; Smith, Ian; Láng, István; Wardley, Andrew; Rabaglio, Manuela; Price, Karen N; Gelber, Richard D; Coates, Alan S; Thürlimann, Beat

    2011-11-01

    Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years

  10. Survival benefit of tamoxifen and aromatase inhibitor in male and female breast cancer.

    Science.gov (United States)

    Eggemann, Holm; Altmann, Udo; Costa, Serban-Dan; Ignatov, Atanas

    2018-02-01

    Our goal was to compare the survival advantage of tamoxifen (TAM) and aromatase inhibitor (AI) in female (FBC) and male breast cancer (MBC). We performed a retrospective study of 2785 FBC and 257 MBC patients treated with hormonal therapy. The median follow-up was 106 months (range 3-151 months) and 42 months (range 2-115 months) for FBC and MBC, respectively. The patients were divided into two groups according to the hormonal therapy used: TAM-treated and AI-treated. MBC was characterized by older age, advanced tumor stage, and higher rate of lymph node metastases, in comparison with FBC. Matching analysis was performed using six prognostic criteria: patient age, tumor stage, tumor grade, lymph node status, human epidermal growth factor receptor (HER2) status, and administration of chemotherapy. The female and male patients were matched 2:1. In this analysis, 316 women and 158 men treated with TAM, and 60 women and 30 men treated with AI, were included. The overall survival (OS) was estimated by the Kaplan-Meier method and was compared between FBC and MBC. TAM-treated FBC and MBC patients had similar 5-year OS, 85.1 and 89.2%, respectively (p = 0.972). Notably, FBC patients treated with AI had significantly greater 5-year OS (85.0%) in comparison with AI-treated MBC patients (5-year OS of 73.3%; p = 0.028). The OS of TAM-treated patients with MBC was similar to the OS of TAM-treated FBC patients, whereas AI treatment is associated with poorer survival of MBC patients.

  11. 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.

  12. Tamoxifen-loaded polymeric micelles: preparation, physico-chemical characterization and in vitro evaluation studies.

    Science.gov (United States)

    Cavallaro, Gennara; Maniscalco, Laura; Licciardi, Mariano; Giammona, Gaetano

    2004-11-20

    Several samples of polymeric micelles, formed by amphiphilic derivatives of PHEA, obtained by grafting into polymeric backbone of PEGs and/or hexadecylamine groups (PHEA-PEG-C(16) and PHEA-C(16)) and containing different amount of Tamoxifen, were prepared. All Tamoxifen-loaded polymeric micelles showed to increase drug water solubility. TEM studies provided evidence of the formation of supramolecular core/shell architectures containing drug, in the nanoscopic range and with spherical shape. Samples with different amount of encapsulated Tamoxifen were subjected to in vitro cytotoxic studies in order to evaluate the effect of Tamoxifen micellization on cell growth inhibition. All samples of Tamoxifen-loaded polymeric micelles showed a significantly higher antiproliferative activity in comparison with free drug, probably attributable to fluidification of cellular membranes, caused by amphiphilic copolymers, that allows a higher penetration of the drug into tumoral cells. To gain preliminary information about the potential use of prepared micelles as Tamoxifen drug delivery systems, studies evaluating drug release ability of micelle systems in media mimicking biological fluids (buffer solutions at pH 7.4 and 5.5) and in human plasma were carried out. These studies, performed evaluating the amount of Tamoxifen that remains in solution as a function of time, showed that at pH 7.4, as well as in plasma, PHEA-C(16) polymeric micelles were able to release lower drug amounts than PHEA-PEG(5000)-C(16) ones, while at pH 5.5, the behavior difference between two kind of micelles was less pronounced.

  13. 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

  14. Memory enhancement by Tamoxifen on amyloidosis mouse model.

    Science.gov (United States)

    Pandey, Deepika; Banerjee, Sugato; Basu, Mahua; Mishra, Nibha

    2016-03-01

    Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) used in the treatment of breast cancer. Earlier studies show its neuroprotection via regulating apoptosis, microglial functions, and synaptic plasticity. TMX also showed memory enhancement in ovariectomized mice, and protection from amyloid induced damage in hippocampal cell line. These reports encouraged us to explore the role of TMX in relevance to Alzheimer's disease (AD). We report here, the effect of TMX treatment a) on memory, and b) levels of neurotransmitters (acetylcholine (ACh) and dopamine (DA)) in breeding-retired-female mice injected with beta amyloid1-42 (Aβ1-42). Mice were treated with TMX (10mg/kg, i.p.) for 15 days. In Morris water maze test, the TMX treated mice escape latency decreased during training trials. They also spent longer time in the platform quadrant on probe trial, compared to controls. In Passive avoidance test, TMX treated mice avoided stepping on the shock chamber. This suggests that TMX protects memory from Aβ induced toxicity. In frontal cortex, ACh was moderately increased, with TMX treatment. In striatum, dopamine was significantly increased, 3,4-dihydroxyphenylacetic acid (DOPAC) level and DOPAC/DA ratio was decreased post TMX treatment. Therefore, TMX enhances spatial and contextual memory by reducing dopamine metabolism and increasing ACh level in Aβ1-42 injected-breeding-retired-female mice. Copyright © 2015. Published by Elsevier Inc.

  15. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer.

    Science.gov (United States)

    Osipo, Clodia; Gajdos, Csaba; Liu, Hong; Chen, Bin; Jordan, V Craig

    2003-11-05

    Long-term tamoxifen treatment of breast cancer can result in tamoxifen-stimulated breast cancer, in which estrogen inhibits tumor growth after tamoxifen withdrawal. We investigated the molecular mechanism(s) of estradiol-induced tumor regression by using an in vivo model of tamoxifen-stimulated human breast cancer. Growth of parental estradiol-stimulated MCF-7E2 and long-term tamoxifen-stimulated MCF-7TAMLT xenografts in athymic mice was measured during treatment with vehicle, estradiol, estradiol plus tamoxifen, tamoxifen alone, estradiol plus fulvestrant, or fulvestrant alone. Apoptosis was detected by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Protein expression was assessed by western blot analysis. mRNA expression was assessed by real-time reverse transcription-polymerase chain reaction. All statistical tests were two-sided. MCF-7E2 tumor growth was stimulated by estradiol (cross-sectional area at week 13 = 1.06 cm2, 95% confidence interval [CI] = 0.82 to 1.30 cm2; Pestradiol-induced regression to 0.18 cm2 (95% CI = 0.15 to 0.21 cm2; P<.001), and tamoxifen or estradiol plus fulvestrant enhanced tumor growth to 1.00 cm2 (95% CI = 0.88 to 1.22 cm2). Estradiol increased the number of apoptotic cells in tumors by 23% (95% CI = 20% to 26%; P<.001) compared with all other treatments, decreased estrogen receptor alpha(ERalpha) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2/neu mRNA and protein and nuclear factor kappaB (NF-kappaB) protein but did not affect Fas ligand protein expression compared with control. Paradoxically, fulvestrant reversed this effect and stimulated MCF-7TAMLT tumor growth apparently through ERalpha-mediated regulation of Fas, HER2/neu, and NF-kappaB. Physiologic levels of estradiol induced regression of tamoxifen-stimulated breast cancer tumors, apparently by inducing the death receptor Fas and suppressing the antiapoptotic

  16. 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.

  17. 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.

  18. Smart coumarin-tagged imprinted polymers for the rapid detection of tamoxifen.

    Science.gov (United States)

    Ray, Judith V; Mirata, Fosca; Pérollier, Celine; Arotcarena, Michel; Bayoudh, Sami; Resmini, Marina

    2016-03-01

    A signalling molecularly imprinted polymer was synthesised for easy detection of tamoxifen and its metabolites. 6-Vinylcoumarin-4-carboxylic acid (VCC) was synthesised from 4-bromophenol to give a fluorescent monomer, designed to switch off upon binding of tamoxifen. Clomiphene, a chlorinated analogue, was used as the template for the imprinting, and its ability to quench the coumarin fluorescence when used in a 1:1 ratio was demonstrated. Tamoxifen and 4-hydroxytamoxifen were also shown to quench coumarin fluorescence. Imprinted and non-imprinted polymers were synthesised using VCC, methacrylic acid as a backbone monomer and ethylene glycol dimethacrylate as cross-linker, and were ground and sieved to particle sizes ranging between 45 and 25 μm. Rebinding experiments demonstrate that the imprinted polymer shows very strong affinity for both clomiphene and tamoxifen, while the non-imprinted polymer shows negligible rebinding. The fluorescence of the imprinted polymer is quenched by clomiphene, tamoxifen and 4-hydroxytamoxifen. The switch off in fluorescence of the imprinted polymer under these conditions could also be detected under a UV lamp with the naked eye, making this matrix suitable for applications when coupled with a sample preparation system.

  19. Tamoxifen treatment for pubertal gynecomastia in two siblings with partial androgen insensitivity syndrome.

    Science.gov (United States)

    Saito, Reiko; Yamamoto, Yukiyo; Goto, Motohide; Araki, Shunsuke; Kubo, Kazuyasu; Kawagoe, Rinko; Kawada, Yasusada; Kusuhara, Koichi; Igarashi, Maki; Fukami, Maki

    2014-01-01

    Although tamoxifen has been shown to be fairly safe and effective for idiopathic pubertal gynecomastia, it remains unknown whether it is also beneficial for gynecomastia associated with endocrine disorders. Here, we report the effect of tamoxifen on pubertal gynecomastia in 2 siblings with partial androgen insensitivity syndrome (PAIS). Cases 1 and 2 presented with persistent pubertal gynecomastia at 13 and 16 years of age, respectively. Physical examinations revealed breast of Tanner stage 3 and normal male-type external genitalia in both cases. Clinical features such as female-type pubic hair and borderline small testis indicated mildly impaired masculinization. Molecular analysis identified a previously reported p.Arg789Ser mutation in the androgen receptor gene (AR) in the 2 cases. Two months of oral administration of tamoxifen ameliorated gynecomastia to Tanner stage 2 with no adverse events. Additional treatment with testosterone enanthate showed negligible effects on body hair and penile length. Hormone values of the 2 cases during tamoxifen treatment remained similar to those in previously reported untreated patients with PAIS. The results indicate that tamoxifen was effective in treating pubertal gynecomastia in these 2 patients with PAIS and may be considered as a therapeutic option in this situation pending further studies.

  20. Estradiol affects liver mitochondrial function in ovariectomized and tamoxifen-treated ovariectomized female rats

    International Nuclear Information System (INIS)

    Moreira, Paula I.; Custodio, Jose B.A.; Nunes, Elsa; Moreno, Antonio; Seica, Raquel; Oliveira, Catarina R.; Santos, Maria S.

    2007-01-01

    Given the tremendous importance of mitochondria to basic cellular functions as well as the critical role of mitochondrial impairment in a vast number of disorders, a compelling question is whether 17β-estradiol (E2) modulates mitochondrial function. To answer this question we exposed isolated liver mitochondria to E2. Three groups of rat females were used: control, ovariectomized and ovariectomized treated with tamoxifen. Tamoxifen has antiestrogenic effects in the breast tissue and is the standard endocrine treatment for women with breast cancer. However, under certain circumstances and in certain tissues, tamoxifen can also exert estrogenic agonist properties. We observed that at basal conditions, ovariectomy and tamoxifen treatment do not induce any statistical alteration in oxidative phosphorylation system and respiratory chain parameters. Furthermore, tamoxifen treatment increases the capacity of mitochondria to accumulate Ca 2+ delaying the opening of the permeability transition pore. The presence of 25 μM E2 impairs respiration and oxidative phosphorylation system these effects being similar in all groups of animals studied. Curiously, E2 protects against lipid peroxidation and increases the production of H 2 O 2 in energized mitochondria of control females. Our results indicate that E2 has in general deleterious effects that lead to mitochondrial impairment. Since mitochondrial dysfunction is a triggering event of cell degeneration and death, the use of exogenous E2 must be carefully considered

  1. Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

    Directory of Open Access Journals (Sweden)

    Afif Rieth Nery-Aguiar

    2016-02-01

    Full Text Available OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20 and group II (tamoxifen, n=20, receiving 0.5 ml of propylene glycol and 250 µg of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student’s t tests (p<0.05. RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001. CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression.

  2. The effect of tamoxifen on pubertal bone development in adolescents with pubertal gynecomastia.

    Science.gov (United States)

    Akgül, Sinem; Derman, Orhan; Kanbur, Nuray

    2016-01-01

    During puberty, estrogen has a biphasic effect on epiphyses; at low levels, it leads to an increase in height and bone mass, whereas at high levels, it leads to closure of the epiphysis. Tamoxifen is a selective estrogen receptor modulator that has been used in the treatment of pubertal gynecomastia. Although it has not been approved for this indication, studies have shown it to be both successful and safe. In males, the peak of pubertal bone development occurs during Tanner stage 3-4, which is also when pubertal gynecomastia reaches its highest prevalence. Thus tamoxifen treatment could potentially effect pubertal bone development. The aim of this study was to assess the effects of tamoxifen on bone mineral density (BMD) and skeletal maturation when used for pubertal gynecomastia. We evaluated 20 boys with pubertal gynecomastia receiving tamoxifen for at least 4 months. BMD was measured with dual-energy X-ray absorptiometry. Z-score and absolute BMD (g/cm(2)) was determined at baseline and 2 months after completing tamoxifen treatment. Bone age and height was evaluated before treatment and again one year later. Using absolute BMD (g/cm(2)), the mean difference from baseline was significant between the two groups both at spine (p=0.002) and femur (p=0.001), but not with the Z-score. This result was attributed to the expected increase during puberty according to sex and age. No significant effect on skeletal maturation was found (p=1.112). We conclude that when pubertal bone development is concerned, tamoxifen is safe for the treatment of pubertal gynecomastia as neither bone mineralization nor growth potential was affected.

  3. Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis

    International Nuclear Information System (INIS)

    Pogribny, Igor P.; Bagnyukova, Tetyana V.; Tryndyak, Volodymyr P.; Muskhelishvili, Levan; Rodriguez-Juarez, Rocio; Kovalchuk, Olga; Han Tao; Fuscoe, James C.; Ross, Sharon A.; Beland, Frederick A.

    2007-01-01

    Tamoxifen is a widely used anti-estrogenic drug for chemotherapy and, more recently, for the chemoprevention of breast cancer. Despite the indisputable benefits of tamoxifen in preventing the occurrence and re-occurrence of breast cancer, the use of tamoxifen has been shown to induce non-alcoholic steatohepatitis, which is a life-threatening fatty liver disease with a risk of progression to cirrhosis and hepatocellular carcinoma. In recent years, the high-throughput microarray technology for large-scale analysis of gene expression has become a powerful tool for increasing the understanding of the molecular mechanisms of carcinogenesis and for identifying new biomarkers with diagnostic and predictive values. In the present study, we used the high-throughput microarray technology to determine the gene expression profiles in the liver during early stages of tamoxifen-induced rat hepatocarcinogenesis. Female Fisher 344 rats were fed a 420 ppm tamoxifen containing diet for 12 or 24 weeks, and gene expression profiles were determined in liver of control and tamoxifen-exposed rats. The results indicate that early stages of tamoxifen-induced liver carcinogenesis are characterized by alterations in several major cellular pathways, specifically those involved in the tamoxifen metabolism, lipid metabolism, cell cycle signaling, and apoptosis/cell proliferation control. One of the most prominent changes during early stages of tamoxifen-induced hepatocarcinogenesis is dysregulation of signaling pathways in cell cycle progression from the G 1 to S phase, evidenced by the progressive and sustained increase in expression of the Pdgfc, Calb3, Ets1, and Ccnd1 genes accompanied by the elevated level of the PI3K, p-PI3K, Akt1/2, Akt3, and cyclin B, D1, and D3 proteins. The early appearance of these alterations suggests their importance in the mechanism of neoplastic cell transformation induced by tamoxifen

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    International Nuclear Information System (INIS)

    Hatkevich, Talia; Ramos, Joseph; Santos-Sanchez, Idalys; Patel, Yashomati M.

    2014-01-01

    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

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

    Czech Academy of Sciences Publication Activity Database

    Valný, Martin; Honsa, Pavel; Kirdajová, Denisa; Kameník, Zdeněk; Anděrová, Miroslava

    2016-01-01

    Roč. 10, ost (2016), s. 243 ISSN 1662-5102 R&D Projects: GA ČR(CZ) GA16-10214S; GA ČR(CZ) GA15-02760S Institutional support: RVO:68378041 ; RVO:61388971 Keywords : tamoxifen * brain metabolism * fate-mapping Subject RIV: FH - Neurology; EE - Microbiology, Virology (MBU-M) Impact factor: 4.555, year: 2016

  7. AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells

    International Nuclear Information System (INIS)

    Zhao Wenhui; Zhang Qingyuan; Kang Xinmei; Jin Shi; Lou Changjie

    2009-01-01

    Acquired resistance to tamoxifen has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this condition has not been completely elucidated. In this study, a tamoxifen-resistant (Tam-R) MCF-7 breast cancer cell line was developed to mimic the occurrence of acquired tamoxifen resistance as seen in clinical practice. Increased expression levels of HER1, HER2 and the estrogen receptor (ER)-AIB1 complex were found in tamoxifen-resistant cells. EGF stimulation and gefitinib inhibition experiments further demonstrated that HER1/HER2 signaling and AIB1 were involved in the proliferation of cells that had acquired Tam resistance. However, when AIB1 was silenced with AIB1-siRNA in Tam-R cells, the cell growth stimulated by the HER1/HER2 signaling pathway was significantly reduced, and the cells were again found to be inhibited by tamoxifen. These results suggest that the AIB1 protein could be a limiting factor in the HER1/HER2-mediated hormone-independent growth of Tam-R cells. Thus, AIB1 may be a new therapeutic target, and the removal of AIB1 may decrease the crosstalk between ER and the HER1/HER2 pathway, resulting in the restoration of tamoxifen sensitivity in tamoxifen-resistant cells.

  8. Lack of evidence from HPLC 32P-post-labelling for tamoxifen-DNA adducts in the human endometrium.

    Science.gov (United States)

    Carmichael, P L; Sardar, S; Crooks, N; Neven, P; Van Hoof, I; Ugwumadu, A; Bourne, T; Tomas, E; Hellberg, P; Hewer, A J; Phillips, D H

    1999-02-01

    Tamoxifen is associated with an increased incidence of endometrial cancer in women. It is also a potent carcinogen in rat liver and forms covalent DNA adducts in this tissue. A previous study exploring DNA adducts in human endometria, utilizing thin layer chromatography 32P-postlabelling, found no evidence for adducts in tamoxifen-treated women [Carmichael,P.L., Ugwumadu,A.H.N., Neven,P., Hewer,A.J., Poon,G.K. and Phillips,D.H. (1996) Cancer Res., 56, 1475-1479]. However, subsequent work utilizing HPLC 32P-post-labelling [Hemminki,K., Ranjaniemi,H., Lindahl,B. and Moberger,B. (1996) Cancer Res., 56, 4374-4377] suggested that very low levels could be detected. We have sought to investigate this question further by reproducing the HPLC methodology at two centres, and analysing endometrial DNA from 20 patients treated with 20 mg/day tamoxifen for between 22 and 65 months. Liver DNA isolated from tamoxifen-treated rats was used as a positive control. We found no convincing evidence for tamoxifen-derived DNA adducts in human endometrium. HPLC elution profiles of post-labelled DNA from tamoxifen-treated women were indistinguishable from those obtained with DNA from 14 untreated women and from six women taking toremifene, an analogue of tamoxifen.

  9. Polypoid endometriosis mimicking invasive cancer in an obese, postmenopausal tamoxifen user

    Directory of Open Access Journals (Sweden)

    William T. Jaegle

    2017-11-01

    Précis: Endometriosis is a benign estrogen dependent condition rarely problematic in a postmenopausal patient. Tamoxifen use in the setting of an obese patient may contribute to a proliferation of pre-existing endometriosis which resembles an aggressive late-stage gynecological malignancy.

  10. Use of dried blood spots for the determination of serum concentrations of tamoxifen and endoxifen

    NARCIS (Netherlands)

    Jager, N G L; Rosing, H; Schellens, J H M; Beijnen, J H; Linn, S C

    The anti-estrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite (Z)-endoxifen, and a minimum therapeutic threshold for (Z)-endoxifen in serum has been proposed. The objective of this research was to establish the relationship between dried blood spot (DBS) and serum

  11. 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.

  12. 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)

  13. Brain Function, Structure, and Neurochemistry After Tamoxifen/Chemotherapy Assessed by Neuropsychologic Testing and H Magnetic Resonance Spectroscopy

    National Research Council Canada - National Science Library

    Ernst, Thomas

    2000-01-01

    ...). On magnetic resonance spectroscopy (1H MRS), women who received tamoxifen (average 4.4 years) had no statistically significant differences in brain metabolite ratios compared to the negative control group...

  14. Tamoxifen induces regression of estradiol-induced mammary cancer in ACI.COP-Ept2 rat model

    OpenAIRE

    Ruhlen, Rachel L.; Willbrand, Dana M.; Besch-Williford, Cynthia L.; Ma, Lixin; Shull, James D.; Sauter, Edward R.

    2008-01-01

    The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5–7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonan...

  15. The Effect of Tamoxifen Administration and γ-Irradiation on Thyroid Hormones Levels in Rats Bearing Mammary Tumours

    International Nuclear Information System (INIS)

    Abdelgawad, M.R.

    2013-01-01

    Breast Cancer is the most common malignancy among women in most developed and developing regions of the world, in female, tamoxifen acting as an oestrogen antagonist on the breast. Thyroid hormones can stimulate the proliferation in vitro of certain tumor cell lines. The aim of the present study is to evaluate the effect of tamoxifen and/ or irradiation treatment on thyroid hormones in rats' mammary tumours. Forty-two female Sprague-Dawely rats randomly divided into seven groups' proliferation (6 rats each). Control group, normal rats supplemented with tamoxifen for 3 weeks, normal rats exposed to a single dose 3Gy γ-rays, rats treated with Dimethylbenz (a) anthracene (DMBA) dissolved in corn oil (30ppm) sc and followed for 6 months until breast cancer occurrence, breast cancer bearing rats supplemented with tamoxifen for 3 weeks twice a day, breast cancer bearing rats exposed to a single dose 3Gy γ-rays, breast cancer bearing rats exposed to a single dose 3Gy γ-rays and supplemented with tamoxifen for 3 weeks twice a day. At the end of the experiment, mammary tumours and control rats were sacrificed after 3 weeks from different treatments and serum thyroid hormones and estradiol (E2) levels were assayed using commercial kits. Results show T4 and E2 levels not triiodothyronine (T3) were altered in different experimental groups. It could be concluded that γ-irradiation promote the expression of neoplastic potential by affecting both E2 and thyroid hormones and tamoxifen may alter the thyroid hormones. Tamoxifen administration and γ-irradiation may have worth effects on thyroxin (T4) and E2 levels. It is recommended to further studies towards the bystander effect of γ-rays exposure and tamoxifen treatment on the tissue culture and molecular biology scale.

  16. Worry and risk perception of breast cancer in a prevention trial of low dose tamoxifen in midlife postmenopausal hormone users.

    Science.gov (United States)

    Rondanina, Gabriella; Puntoni, Matteo; Guerrieri-Gonzaga, Aliana; Marra, Domenico; Bonanni, Bernardo; DeCensi, Andrea

    2017-08-01

    There is increasing interest in combining postmenopausal hormone therapy (HT) and SERMs in midlife women. We previously showed that refusal to participate in a prevention trial of low dose tamoxifen in HT users was associated with higher worry about breast cancer. Given this counterintuitive finding, we studied which factors influenced worry and risk perception of breast cancer. We assessed the relationships of breast cancer worry and risk perception with age, age at menopause, Gail risk, education, adherence to mammographic screening, BMI, smoking, physical activity, alcohol use, anxiety and depression in 457 midlife HT users who were eligible to participate in the trial. Women with menopause 52 years (OR = 5.0, 95% CI, 1.2-21.1). Worry was also associated with high absolute risk perception and former smoking. Factors associated with higher risk perception were age>60 years, at-risk life style, worry about breast cancer and depression. The inverse association between early menopause and worry about breast cancer is in contrast with the known protective effect of early menopause on breast cancer risk and seems to reflect a feeling of aging and disease vulnerability. Our findings indicate that worry about cancer has an affective construct which is independent of breast cancer biology but is engaged in health decision making. Increasing breast cancer risk awareness in subjects high in worry without a plan of emotional coping may therefore be counterproductive because of avoidant attitudes. Copyright © 2017. Published by Elsevier Ltd.

  17. Up-regulation of HOXB cluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells.

    Science.gov (United States)

    Yang, Seoyeon; Lee, Ji-Yeon; Hur, Ho; Oh, Ji Hoon; Kim, Myoung Hee

    2018-05-28

    Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.

  18. Optimal systemic therapy for premenopausal women with hormone receptor-positive breast cancer.

    Science.gov (United States)

    Jankowitz, Rachel C; McGuire, Kandace P; Davidson, Nancy E

    2013-08-01

    Although systemic therapy is one of the cornerstones of therapy for premenopausal women with early stage breast cancer, there remain many unknowns regarding its optimal use. By accident of clinical trial design, much clinical investigation in premenopausal women has focused on chemotherapy. More recently the value of endocrine therapy (tamoxifen and ovarian suppression/ablation via surgery, LHRH agonists, or chemotherapy-induced menopause) has become apparent, and some form of endocrine therapy is viewed as standard for virtually all premenopausal women with early stage invasive breast cancer that expresses estrogen and/or progesterone receptor. Critical open questions include type and duration of endocrine therapy and the development of prognostic/predictive markers to help identify patients who are likely to benefit from chemotherapy in addition to endocrine therapy. For some years, five years of tamoxifen has been viewed as the standard endocrine therapy for premenopausal hormone-responsive breast cancer, although the ATLAS trial suggests that an additional five years of tamoxifen can be considered. The MA17 trial also suggests that an additional five years of an aromatase inhibitor can be considered for women who become postmenopausal during tamoxifen therapy. Information about the value of ovarian suppression continues to emerge, most recently with the demonstration of excellent outcome with goserelin plus tamoxifen in the ABCSG12 trial. The SOFT and TEXT trials, whose accrual is now complete, should help to define optimal endocrine therapy. In addition, use of the 21-gene recurrence score assay may help to delineate the additional value of chemotherapy for patients with node-negative breast cancer, and its utility in the setting of women with 1-3 positive lymph nodes is under study in the RxPONDER trial. Nonetheless, the need for other predictive biomarkers to select appropriate therapy remains real. Finally, attention to long term benefits and side effects

  19. Effects of 13- cis-retinoic acid on the tamoxifen induced uterine histological changes in the rabbit

    International Nuclear Information System (INIS)

    Hamid, S.; Minhas, L.A.; Khan, M.Y.

    2013-01-01

    Objective: To study the effects of 13-cis-retinoic acid on the tamoxifen induced uterine histological changes in the rabbit. Study Design: Experimental - randomized controlled trial. Place and Duration of study: The study was conducted for 4 months at the department of Anatomy, Army Medical College and National Institute of Health in 2007. Material and Methods: The animals were randomly divided into three groups, a control group A, and two experimental groups B and C, consisting of thirty rabbits each. The experimental groups were treated with tamoxifen only and tamoxifen plus retinoic acid, respectively. The animals were sacrificed after three months. The uteri were then processed for paraffin embedding. Sections were then assessed for the luminal epithelial height, endometrial area and percentage of mitotic figures. Results: The results obtained were suggestive of uterine proliferation by tamoxifen. The adjuvant administration of 13-cis-retinoic acid produced a statistically significant (p = 0.002) inhibitory effect on the tamoxifen induced increase in the area of endometrium, whereas no significant suppressive effect of this drug has been observed on the other parameters when compared with Group B. Conclusion: 13-cis Retinoic acid has not shown a significant role in the reversal of tamoxifen induced changes in the uterine tissue after a short term administration of three months. (author)

  20. 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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

    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 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 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

  2. 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.

  3. 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

    R cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin‐binding protein myristoylated alanine‐rich C‐kinase substrate (MARCKS) were increased two‐ and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in Tam......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 (Tam...... was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell–cell and cell matrix‐initiated signalling. Consistent with known roles for Ras/MAPK and PI3‐kinase signalling in tamoxifen resistance, tyrosine‐phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in Tam...

  4. Study of Sperm Parameters and Sperm Fertility in Mice were Exposed to Tamoxifen during Embryonic Development

    Directory of Open Access Journals (Sweden)

    J Soleimanirad

    2017-05-01

    Full Text Available Introduction: Tamoxifen is steroidal drug, which mainly treats breast cancer and also used to stimulate ovulation. The purpose of the present study was the evaluation of sperm parameters and fertility of mice whose mothers had received tamoxifen during pregnancy. Methods: In this study, 30 female and 15 male mice of NMRI were selected for mating. After mating female mice were randomly divided into two groups, the first group (control and second group (experimental. All of which contained 15 mice. From the day 13th day of pregnancy, experimental group has received tamoxifen with the dosage of 5 mg/kg for 7 days. After childbirth of the mated mice, male infants were selected. After reaching the age of puberty (6-8Weeks, adult mice were sacrificed by the cervical dislocation. After take sperm, sperm parameters (count, normality and motility, and sperm fertility was performed. In this study SPSS software and statistical t-test was used (p <0.001. Results: Studies showed that sperm parameters and sperm fertilization were significantly different. The number of sperm in the control group was 83.50±28.20 million, and in the experimental group was 60±14.14 million. There was a decrease in average sperm count in the experimental group compared with the control group (p <0.001. Our findings from in vitro fertilization culture media showed that embryos formation and oocyte disruption between control and experimental groups significantly different (p <0.001. Conclusion: The results showed that tamoxifen exposure during development can cause histological changes in the seminiferous tubules, which can lead to infertility.

  5. The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

    International Nuclear Information System (INIS)

    Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

    2013-01-01

    Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

  6. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. The biochemical effects of nano tamoxifen and some bioactive components in experimental breast cancer.

    Science.gov (United States)

    Ezzat, Afaf; Abdelhamid, Abdou Osman; El Awady, Mostafa K; Abd El Azeem, Amal S; Mohammed, Dina Mostafa

    2017-11-01

    The effect of nano tamoxifen and some bioactive components such as yeast, isoflavone, and silymarin on the level of resistance and prevention of breast cancer progression in experimental animals is the target of this study. Thirty female Sprague-Dawley rats received a single medication dosage of 7,12-dimethylbenz[a]anthracene (DMBA) intragastrically. After fourteen days of DMBA admission, the procedure protocol started out. Finally, all the experimental results evaluated, tabulated and statistically analyzed. The results demonstrated a highly significant elevation in the 8-OHdG level in group 1 (nano yeast) and 3 (nano silymarin) while the results demonstrated a highly significant reduction in group 2 (nano tamoxifen). The apoptosis results demonstrated a significant elevation in group 3 (nano silymarin) where appeared significant reduction in group 4 (nano isoflavone). ErbB-2 results demonstrated a significant elevation in group 2 (nano tamoxifen) and a significant reduction in each of group 3 (nano silymarin) and 4 (nano isoflavone). The lipid peroxide level demonstrated an extremely significant reduction in group 4 (nano isoflavone). And a significant reduction of total antioxidant was observed in group 3 (nano silymarin) in comparison to injected animals control. This may be considered a new vision and strategy to resist breast cancer disease or prevent progression. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability.

    Science.gov (United States)

    Jacobsson, S O; Rongård, E; Stridh, M; Tiger, G; Fowler, C J

    2000-12-15

    In the present study, the effects of the combination of tamoxifen ((Z)-2[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylamine citrate) and three cannabinoids (Delta(9)-tetrahydrocannabinol [Delta(9)-THC], cannabidiol, and anandamide [AEA]) upon the viability of C6 rat glioma cells was assessed at different incubation times and using different culturing concentrations of foetal bovine serum (FBS). Consistent with previous data for human glioblastoma cells, the tamoxifen sensitivity of the cells was increased as the FBS content of the culture medium was reduced from 10 to 0.4 and 0%. The cells expressed protein kinase C alpha and calmodulin (the concentration of which did not change significantly as the FBS concentration was reduced), but did not express estrogen receptors. Delta(9)-THC and cannabidiol, but not AEA, produced a modest reduction in cell viability after 6 days of incubation in serum-free medium, whereas no effects were seen in 10% FBS-containing medium. There was no observed synergy between the effects of tamoxifen and the cannabinoids upon cell viability.

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

    Directory of Open Access Journals (Sweden)

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

    Directory of Open Access Journals (Sweden)

    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

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

    International Nuclear Information System (INIS)

    Hiscox, Stephen; Gee, Julia; Baruha, Bedanta; Smith, Chris; Bellerby, Rebecca; Goddard, Lindy; Jordan, Nicola; Poghosyan, Zaruhi; Nicholson, Robert I; Barrett-Lee, Peter

    2012-01-01

    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. 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. 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 and EGFR and induction of cell migration

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

    International Nuclear Information System (INIS)

    Ribeiro, Mariana P.C.; Nunes-Correia, Isabel; Santos, Armanda E.; Custódio, José B.A.

    2014-01-01

    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

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

    International Nuclear Information System (INIS)

    Moi, Line L Haugan; Flågeng, Marianne Hauglid; Gjerde, Jennifer; Madsen, Andre; Røst, Therese Halvorsen; Gudbrandsen, Oddrun Anita; Lien, Ernst A; Mellgren, Gunnar

    2012-01-01

    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. 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. 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 < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). The expression of SRCs and HER-2 and -3 is stimulated

  16. A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen.

    Science.gov (United States)

    Johansson, Harriet; Gandini, Sara; Serrano, Davide; Gjerde, Jennifer; Lattanzi, Monia; Macis, Debora; Guerrieri-Gonzaga, Aliana; Aristarco, Valentina; Mellgren, Gunnar; Lien, Ernst; DeCensi, Andrea; Bonanni, Bernardo

    2016-08-01

    Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted.

  17. Establishment of a tamoxifen-inducible Cre-driver mouse strain for widespread and temporal genetic modification in adult mice.

    Science.gov (United States)

    Ichise, Hirotake; Hori, Akiko; Shiozawa, Seiji; Kondo, Saki; Kanegae, Yumi; Saito, Izumu; Ichise, Taeko; Yoshida, Nobuaki

    2016-07-29

    Temporal genetic modification of mice using the ligand-inducible Cre/loxP system is an important technique that allows the bypass of embryonic lethal phenotypes and access to adult phenotypes. In this study, we generated a tamoxifen-inducible Cre-driver mouse strain for the purpose of widespread and temporal Cre recombination. The new line, named CM32, expresses the GFPneo-fusion gene in a wide variety of tissues before FLP recombination and tamoxifen-inducible Cre after FLP recombination. Using FLP-recombined CM32 mice (CM32Δ mice) and Cre reporter mouse lines, we evaluated the efficiency of Cre recombination with and without tamoxifen administration to adult mice, and found tamoxifen-dependent induction of Cre recombination in a variety of adult tissues. In addition, we demonstrated that conditional activation of an oncogene could be achieved in adults using CM32Δ mice. CM32Δ;T26 mice, which harbored a Cre recombination-driven, SV40 large T antigen-expressing transgene, were viable and fertile. No overt phenotype was found in the mice up to 3 months after birth. Although they displayed pineoblastomas (pinealoblastomas) and/or thymic enlargement due to background Cre recombination by 6 months after birth, they developed epidermal hyperplasia when administered tamoxifen. Collectively, our results suggest that the CM32Δ transgenic mouse line can be applied to the assessment of adult phenotypes in mice with loxP-flanked transgenes.

  18. The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor positive early stage breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fowble, B; Fein, D A; Hanlon, A L; Eisenberg, B L; Hoffman, J P; Sigurdson, E R; Daly, M B; Goldstein, L J

    1995-07-01

    Purpose: In the NSABP B14 trial evaluating tamoxifen (tam) in axillary node negative, estrogen receptor positive tumors fewer breast recurrences were observed in patients treated with conservative surgery and radiation who received tam compared to the observation arm. An additional series, however, has suggested that tam adversely impacts on the cosmetic result. To further address these issues we compared the outcome of estrogen receptor positive tumors treated with conservative surgery and radiation with or without tam. Materials and Methods: From 1982 to 1991, 491 women with estrogen receptor positive stage I-II breast cancer underwent excisional biopsy, axillary dissection and radiation. The median age of the patient population was 60 years (range 39-85). The median followup was 5.3 years (range .1-12.8). 69% had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49%. The final margin of resection was negative in 64%, unknown in 18%, and close or positive in 19%. None of the patients received adjuvant chemotherapy. 154 patients received tam and 337 received no adjuvant therapy. Patients who received tam were more often axillary node positive (44% tam vs 5% no tam) and less often had unknown margins (9% tam vs 22% no tam). There were no significant differences for the 2 groups for median age, primary tumor size, histology, race, or use of reexcision. Results: The 5 yr act rate of breast recurrence was 4% for the tam patients compared to 7% for patients not receiving tam (p=.21). At 8 yrs, the breast recurrence rates were 4% for the tam patients compared to 11% for the no tam patients (p=.05). However, at 9 years the rates were 17% tam vs 14% no tam (p=.21). The benefit from tam in terms of a decreased 5 year actuarial breast recurrence rate was most evident for patients who did not have a reexcision (3% tam vs 10% no tam, p=.15), had unknown margins (7% tam vs 13% no tam, p=.37) or close margins (0% tam vs 11% no tam, p=.34

  19. The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor positive early stage breast cancer

    International Nuclear Information System (INIS)

    Fowble, B.; Fein, D.A.; Hanlon, A.L.; Eisenberg, B.L.; Hoffman, J.P.; Sigurdson, E.R.; Daly, M.B.; Goldstein, L.J.

    1995-01-01

    Purpose: In the NSABP B14 trial evaluating tamoxifen (tam) in axillary node negative, estrogen receptor positive tumors fewer breast recurrences were observed in patients treated with conservative surgery and radiation who received tam compared to the observation arm. An additional series, however, has suggested that tam adversely impacts on the cosmetic result. To further address these issues we compared the outcome of estrogen receptor positive tumors treated with conservative surgery and radiation with or without tam. Materials and Methods: From 1982 to 1991, 491 women with estrogen receptor positive stage I-II breast cancer underwent excisional biopsy, axillary dissection and radiation. The median age of the patient population was 60 years (range 39-85). The median followup was 5.3 years (range .1-12.8). 69% had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49%. The final margin of resection was negative in 64%, unknown in 18%, and close or positive in 19%. None of the patients received adjuvant chemotherapy. 154 patients received tam and 337 received no adjuvant therapy. Patients who received tam were more often axillary node positive (44% tam vs 5% no tam) and less often had unknown margins (9% tam vs 22% no tam). There were no significant differences for the 2 groups for median age, primary tumor size, histology, race, or use of reexcision. Results: The 5 yr act rate of breast recurrence was 4% for the tam patients compared to 7% for patients not receiving tam (p=.21). At 8 yrs, the breast recurrence rates were 4% for the tam patients compared to 11% for the no tam patients (p=.05). However, at 9 years the rates were 17% tam vs 14% no tam (p=.21). The benefit from tam in terms of a decreased 5 year actuarial breast recurrence rate was most evident for patients who did not have a reexcision (3% tam vs 10% no tam, p=.15), had unknown margins (7% tam vs 13% no tam, p=.37) or close margins (0% tam vs 11% no tam, p=.34

  20. Tamoxifen for one year versus two years versus 6 months of Tamoxifen and 6 months of megestrol acetate: A randomized comparison in postmenopausal patients with high-risk breast cancer (DBCG 89C)

    DEFF Research Database (Denmark)

    Andersen, Jørn; Kamby, C.; Ejlertsen, B.

    2008-01-01

    From January 1, 1990 to December 31, 1994, DBCG conducted a randomised trial in 1 615 postmenopausal women with operable, high-risk, receptor-positive or -unknown breast cancer. The patients were after surgery randomised to Tamoxifen for 1 year (TAM1), Tamoxifen for 2 years (TAM 2) or Tamoxifen...... for 6 months followed by megestrol acetate for 6 months (TAM/MA). When the preplanned sample size of 1 500 patients was reached it was decided to continue randomisation to TAM1 or TAM2 and the study was finally closed December 31, 1996. With a median follow-up of more than 10 years...... in hazard ratios for DFS or OS among the three arms. Sideeffects were rare but more common in the TAM2 and TAM/MA arms Udgivelsesdato: 2008...

  1. Minimal impact of adjuvant exemestane or tamoxifen treatment on mammographic breast density in postmenopausal breast cancer patients: A Dutch TEAM trial analysis

    NARCIS (Netherlands)

    J.G.H. van Nes; L.V. Beex (Louk); C.M. Seynaeve (Caroline); H. Putter (Hein); A. Sramek (Alexandr); S. Lardenoije (Susanne); M.D.-D.E. Carpentier (Marjolijn Duijm-D.E.); I. Van Rongen (Inge); J.W.R. Nortier (Johan W. R.); H.M. Zonderland (Harmine); C.J.H. van de Velde (Cornelis)

    2015-01-01

    textabstractBackground. Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane

  2. Tamoxifen effects on subjective and psychosexual well-being, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy

    NARCIS (Netherlands)

    Mourits, MJ; Bockermann, [No Value; de Vries, EG; van der Zee, AG; ten Hoor, KA; van der Graaf, WT; Sluiter, WJ; Willemse, PH

    2002-01-01

    To evaluate the impact of tamoxifen on subjective and psychosexual well-being in breast cancer patients in relation to type of prior chemotherapy and menopausal status. Longitudinal interview study in breast cancer patients during and after adjuvant tamoxifen use. Menopausal status was defined by

  3. Effects of tamoxifen on neuronal morphology, connectivity and biochemistry of hypothalamic ventromedial neurons: Impact on the modulators of sexual behavior.

    Science.gov (United States)

    Sá, Susana I; Teixeira, Natércia; Fonseca, Bruno M

    2018-01-01

    Tamoxifen (TAM) is a selective estrogen receptor modulator, widely used in the treatment and prevention of estrogen-dependent breast cancer. Although with great clinical results, women on TAM therapy still report several side effects, such as sexual dysfunction, which impairs quality of life. The anatomo-functional substrates of the human sexual behavior are still unknown; however, these same substrates are very well characterized in the rodent female sexual behavior, which has advantage of being a very simple reflexive response, dependent on the activation of estrogen receptors (ERs) in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl). In fact, in the female rodent, the sexual behavior is triggered by increasing circulation levels of estradiol that changes the nucleus neurochemistry and modulates its intricate neuronal network. Therefore, we considered of notice the examination of the possible neurochemical alterations and the synaptic plasticity impairment in VMNvl neurons of estradiol-primed female rats treated with TAM that may be in the basis of this neurological disorder. Accordingly, we used stereological and biochemical methods to study the action of TAM in axospinous and axodendritic synaptic plasticity and on ER expression. The administration of TAM changed the VMNvl neurochemistry by reducing ERα mRNA and increasing ERβ mRNA expression. Furthermore, present results show that TAM induced neuronal atrophy and reduced synaptic connectivity, favoring electrical inactivity. These data suggest that these cellular and molecular changes may be a possible neuronal mechanism of TAM action in the disruption of the VMNvl network, leading to the development of behavioral disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

    International Nuclear Information System (INIS)

    Patel, Shilpen; DiBiase, Steven; Meisenberg, Barry; Flannery, Todd; Patel, Ashish; Dhople, Anil; Cheston, Sally; Amin, Pradip

    2012-01-01

    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 2 divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m 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 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 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 2 . Conclusions: The MTD of tamoxifen was 100 mg/m 2 when given concurrently with temozolomide 75 mg/m 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.

  5. 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.

  6. 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.

  7. The effects of soy and tamoxifen on apoptosis in the hippocampus and dentate gyrus in a pentylenetetrazole-induced seizure model of ovariectomized rats.

    Science.gov (United States)

    Ebrahimzadeh-Bideskan, Ali Reza; Mansouri, Somaieh; Ataei, Mariam Lale; Jahanshahi, Mehrdad; Hosseini, Mahmoud

    2018-03-01

    The effects of tamoxifen and soy on apoptosis of the hippocampus and dentate gyrus of ovariectomized rats after repeated seizures were investigated. Female rats were divided into: (1) Control, (2) Sham, (3) Sham-Tamoxifen (Sham-T), (4) Ovariectomized (OVX), (5) OVX-Tamoxifen (OVX-T), (6)OVX-Soy(OVX-S) and (7) OVX-S-T. The animals in the OVX-S, OVX-T and OVX-S-T groups received soy extract (60 mg/kg; i.p.), tamoxifen (10 mg/kg) or both for 2 weeks before induction of seizures. The animals in these groups additionally received the mentioned treatments before each injection of pentylenetetrazole (PTZ; 40 mg/kg) for 6 days. The animals in the Sham and OVX groups received a vehicle of tamoxifen and soy. A significant decrease in the seizure score and TUNEL-positive neurons was seen in the OVX group compared to the Sham (P < 0.001). The animals in both the OVX-T and OVX-S groups had a significantly higher seizure score as well as number of TUNEL-positive neurons compared to the OVX group (P < 0.01-P < 0.001). Co-treatment of the OVX rats by the extract and tamoxifen decreased the seizure score and number of TUNEL-positive neurons compared to OVX-S (P < 0.001). Treatment of the OVX rats by either soy or tamoxifen increased the seizure score as well as the number of TUNEL-positive neurons in the hippocampal formation. Co-administration of tamoxifen and soy extract inhibited the effects of the soy extract and tamoxifen when they were administered alone. It might be suggested that both soy and tamoxifen have agonistic effects on estrogen receptors by changing the seizure severity.

  8. Gene expression changes induced by estrogen and selective estrogen receptor modulators in primary-cultured human endometrial cells: signals that distinguish the human carcinogen tamoxifen

    International Nuclear Information System (INIS)

    Pole, Jessica C.M.; Gold, Leslie I.; Orton, Terry; Huby, Russell; Carmichael, Paul L.

    2005-01-01

    Tamoxifen has long been the endocrine treatment of choice for women with breast cancer and is now employed for prophylactic use in women at high risk from breast cancer. Other selective estrogen receptor modulators (SERMs), such as raloxifene, mimic some of tamoxifen's beneficial effects and, like tamoxifen, exhibit a complex mixture of organ-specific estrogen agonist and antagonistic properties. However, accompanying the positive effects of tamoxifen has been the emergence of evidence for an increased risk of endometrial cancer associated with its use. A more complete understanding of the mechanism(s) of SERM carcinogenicity and endometrial effects is therefore required. We have sought to compare and characterise the transcript profile of tamoxifen, raloxifene and the agonist estradiol in human endometrial cells. Using primary cultures of human endometria, to best emulate the in vivo responses in a manageable in vitro system, we have shown 230 significant changes in gene expression for epithelial cultures and 83 in stromal cultures, either specific to 17β-estradiol, tamoxifen or raloxifene, or changed across more than one of the treatments. Considering the transcriptome as a whole, the endometrial responses to raloxifene or tamoxifen were more similar than either drug was to 17β-estradiol. Treatment of endometrial cultures with tamoxifen resulted in the largest number of gene changes relative to control cultures and a high proportion of genes associated with regulation of gene transcription, cell-cycle control and signal transduction. Tamoxifen-specific changes that might point towards mechanisms for its proliferative response in the endometrium included changes in retinoblastoma and c-myc binding proteins, the APCL, dihydrofolate reductase (DHFR) and E2F1 genes and other transcription factors. Tamoxifen was also found to give rise to the highest number of gene expression changes common to those that characterise malignant endometria. It is anticipated that this

  9. Tamoxifen and the Rafoxifene analog LY117018: their effects on arachidonic acid release from cells in culture and on prostaglandin I2 production by rat liver cells

    International Nuclear Information System (INIS)

    Levine, Lawrence

    2004-01-01

    Tamoxifen is being used successfully to treat breast cancer. However, tamoxifen also increases the risk of developing endometrial cancer in postmenopausal women. Raloxifene also decreases breast cancer in women at high risk and may have a lower risk at developing cancer of the uterus. Tamoxifen has been shown to stimulate arachidonic acid release from rat liver cells. I have postulated that arachidonic acid release from cells may be associated with cancer chemoprevention. Rat liver, rat glial, human colon carcinoma and human breast carcinoma cells were labelled with [ 3 H] arachidonic acid. The release of the radiolabel from these cells during incubation with tamoxifen and the raloxifene analog LY117018 was measured. The prostaglandin I 2 produced during incubation of the rat liver cells with μM concentrations of tamoxifen and the raloxifene analog was quantitatively estimated. Tamoxifen is about 5 times more effective than LY117018 at releasing arachidonic acid from all the cells tested. In rat liver cells only tamoxifen stimulates basal prostaglandin I 2 production and that induced by lactacystin and 12-O-tetradecanoyl-phorbol-13-acetate. LY117018, however, blocks the tamoxifen stimulated prostaglandin production. The stimulated prostaglandin I 2 production is rapid and not affected either by preincubation of the cells with actinomycin or by incubation with the estrogen antagonist ICI-182,780. Tamoxifen and the raloxifene analog, LY117018, may prevent estrogen-independent as well as estrogen-dependent breast cancer by stimulating phospholipase activity and initiating arachidonic acid release. The release of arachidonic acid and/or molecular reactions that accompany that release may initiate pathways that prevent tumor growth. Oxygenation of the intracellularly released arachidonic acid and its metabolic products may mediate some of the pharmacological actions of tamoxifen and raloxifene

  10. A tamoxifen inducible knock-in allele for investigation of E2A function

    Directory of Open Access Journals (Sweden)

    Kondo Motonari

    2009-10-01

    Full Text Available Abstract Background E-proteins are transcription factors important for the development of a variety of cell types, including neural, muscle and lymphocytes of the immune system. E2A, the best characterized E-protein family member in mammals, has been shown to have stage specific roles in cell differentiation, lineage commitment, proliferation, and survival. However, due to the complexity of E2A function, it is often difficult to separate these roles using conventional genetic approaches. Here, we have developed a new genetic model for reversible control of E2A protein activity at physiological levels. This system was created by inserting a tamoxifen-responsive region of the estrogen receptor (ER at the carboxyl end of the tcfe2a gene to generate E2AER fusion proteins. We have characterized and analyzed the efficiency and kinetics of this inducible E2AER system in the context of B cell development. Results B cell development has been shown previously to be blocked at an early stage in E2A deficient animals. Our E2AER/ER mice demonstrated this predicted block in B cell development, and E2AER DNA binding activity was not detected in the absence of ligand. In vitro studies verified rapid induction of E2AER DNA binding activity upon tamoxifen treatment. While tamoxifen treatment of E2AER/ER mice showed inefficient rescue of B cell development in live animals, direct exposure of bone marrow cells to tamoxifen in an ex vivo culture was sufficient to rescue and support early B cell development from the pre-proB cell stage. Conclusion The E2AER system provides inducible and reversible regulation of E2A function at the protein level. Many previous studies have utilized over-expression systems to induce E2A function, which are complicated by the toxicity often resulting from high levels of E2A. The E2AER model instead restores E2A activity at an endogenous level and in addition, allows for tight regulation of the timing of induction. These features make

  11. Effect of chronic administration of Tamoxifen on fertility in male bonnet monkeys (Macaca radiata).

    Science.gov (United States)

    Rao, A J; Ramachandra, S G; Ramesh, V; Krishnamurthy, H N; Jayaraman, S; Gopalakrishnan, K; Juneja, H S

    1998-01-01

    Administration of Tamoxifen via the Alzet pump at a rate of 50 micrograms hr-1 for 90 days in the adult male bonnet monkeys Macaca radiata had no effect on the serum testosterone concentration determined at 10 AM and 10 PM as well as total sperm count determined at 15-day intervals over a period of 260 days. However, a significant reduction in sperm motility was observed beyond 90 days up until the 225th day. Breeding studies conducted from day 90 to 260 revealed that these males were infertile.

  12. Cre recombinase expression or topical tamoxifen treatment do not affect retinal structure and function, neuronal vulnerability or glial reactivity in the mouse eye.

    Science.gov (United States)

    Boneva, S K; Groß, T R; Schlecht, A; Schmitt, S I; Sippl, C; Jägle, H; Volz, C; Neueder, A; Tamm, E R; Braunger, B M

    2016-06-14

    Mice with a constitutive or tamoxifen-induced Cre recombinase (Cre) expression are frequently used research tools to allow the conditional deletion of target genes via the Cre-loxP system. Here we analyzed for the first time in a comprehensive and comparative way, whether retinal Cre expression or topical tamoxifen treatment itself would cause structural or functional changes, including changes in the expression profiles of molecular markers, glial reactivity and photoreceptor vulnerability. To this end, we characterized the transgenic α-Cre, Lmop-Cre and the tamoxifen-inducible CAGG-CreER™ mouse lines, all having robust Cre expression in the neuronal retina. In addition, we characterized the effects of topical tamoxifen treatment itself in wildtype mice. We performed morphometric analyses, immunohistochemical staining, in vivo ERG and angiography analyses and realtime RT-PCR analyses. Furthermore, the influence of Cre recombinase or topical tamoxifen exposure on neuronal vulnerability was studied by using light damage as a model for photoreceptor degeneration. Taken together, neither the expression of Cre, nor topical tamoxifen treatment caused detectable changes in retinal structure and function, the expression profiles of investigated molecular markers, glial reactivity and photoreceptor vulnerability. We conclude that the Cre-loxP system and its induction through tamoxifen is a safe and reliable method to delete desired target genes in the neural retina. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Development of biodegradable polymer based tamoxifen citrate loaded nanoparticles and effect of some manufacturing process parameters on them: a physicochemical and in-vitro evaluation

    Directory of Open Access Journals (Sweden)

    Basudev Sahana

    2010-08-01

    Full Text Available Basudev Sahana, Kousik Santra, Sumit Basu, Biswajit MukherjeeDepartment of Pharmaceutical Technology, Jadavpur University, Kolkata, IndiaAbstract: The aim of the present study was to develop nanoparticles of tamoxifen citrate, a non-steroidal antiestrogenic drug used for the treatment of breast cancer. Biodegradable poly (D, L- lactide-co-glycolide-85:15 (PLGA was used to develop nanoparticles of tamoxifen citrate by multiple emulsification (w/o/w and solvent evaporation technique. Drug-polymer ratio, polyvinyl alcohol concentrations, and homogenizing speeds were varied at different stages of preparation to optimize the desired size and release profile of drug. The characterization of particle morphology and shape was performed by field emission scanning electron microscope (FE-SEM and particle size distribution patterns were studied by direct light scattering method using zeta sizer. In vitro drug release study showed that release profile of tamoxifen from biodegradable nanoparticles varied due to the change in speed of centrifugation for separation. Drug loading efficiency varied from 18.60% to 71.98%. The FE-SEM study showed that biodegradable nanoparticles were smooth and spherical in shape. The stability studies of tamoxifen citrate in the experimental nanoparticles showed the structural integrity of tamoxifen citrate in PLGA nanoparticles up to 60°C in the tested temperatures. Nanoparticles containing tamoxifen citrate could be useful for the controlled delivery of the drug for a prolonged period.Keywords: biodegradable, nanoparticles, PLGA, stability, tamoxifen citrate

  14. Endocrine effects of adjuvant letrozole + triptorelin compared with tamoxifen + triptorelin in premenopausal patients with early breast cancer.

    Science.gov (United States)

    Rossi, Emanuela; Morabito, Alessandro; De Maio, Ermelinda; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; Piccirillo, Maria Carmela; D'Aiuto, Giuseppe; D'Aiuto, Massimiliano; Rinaldo, Massimo; Botti, Gerardo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

    2008-01-10

    To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin +/- zoledronate. Serum 17-beta-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Delta4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Median age was 44 years for both groups of patients. Letrozole + triptorelin (+/- zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

  15. Implication of protein tyrosine phosphatase 1B in MCF-7 cell proliferation and resistance to 4-OH tamoxifen

    International Nuclear Information System (INIS)

    Blanquart, Christophe; Karouri, Salah-Eddine; Issad, Tarik

    2009-01-01

    The protein tyrosine phosphatase 1B (PTP1B) and the T-cell protein tyrosine phosphatase (TC-PTP) were initially thought to be mainly anti-oncogenic. However, overexpression of PTP1B and TC-PTP has been observed in human tumors, and recent studies have demonstrated that PTP1B contributes to the appearance of breast tumors by modulating ERK pathway. In the present work, we observed that decreasing the expression of TC-PTP or PTP1B in MCF-7 cells using siRNA reduced cell proliferation without affecting cell death. This reduction in proliferation was associated with decreased ERK phosphorylation. Moreover, selection of tamoxifen-resistant MCF-7 cells, by long-term culture in presence of 4-OH tamoxifen, resulted in cells that display overexpression of PTP1B and TC-PTP, and concomitant increase in ERK and STAT3 phosphorylation. siRNA experiments showed that PTP1B, but not TC-PTP, is necessary for resistance to 4-OH tamoxifen. Therefore, our work indicates that PTP1B could be a relevant therapeutic target for treatment of tamoxifen-resistant breast cancers.

  16. Tamoxifen enhances erlotinib-induced cytotoxicity through down-regulating AKT-mediated thymidine phosphorylase expression in human non-small-cell lung cancer cells.

    Science.gov (United States)

    Ko, Jen-Chung; Chiu, Hsien-Chun; Syu, Jhan-Jhang; Jian, Yi-Jun; Chen, Chien-Yu; Jian, Yun-Ting; Huang, Yi-Jhen; Wo, Ting-Yu; Lin, Yun-Wei

    2014-03-01

    Tamoxifen is a triphenylethylene nonsteroidal estrogen receptor (ER) antagonist used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer. However, the molecular mechanism of tamoxifen-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Thymidine phosphorylase (TP) is an enzyme of the pyrimidine salvage pathway which is upregulated in cancers. In this study, tamoxifen treatment inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with tamoxifen decreased TP mRNA and protein levels through AKT inactivation. Furthermore, expression of constitutively active AKT (AKT-CA) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen-treated NSCLC cells. In contrast, combination treatment with PI3K inhibitors (LY294002 or wortmannin) and tamoxifen further decreased the TP expression and cell viability of NSCLC cells. Knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and cell growth inhibition of tamoxifen. Erlotinib (Tarceva, OSI-774), an orally available small molecular inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for clinical treatment of NSCLC. Compared to a single agent alone, tamoxifen combined with erlotinib resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced activation of phospho-AKT and phospho-ERK1/2, and reduced TP protein levels. These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and erlotinib for the treatment of NSCLC. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. The Working Memory and Dorsolateral Prefrontal-Hippocampal Functional Connectivity Changes in Long-Term Survival Breast Cancer Patients Treated with Tamoxifen

    Science.gov (United States)

    Chen, Xingui; Tao, Longxiang; Li, Jingjing; Wu, Jiaonan; Zhu, Chunyan; Yu, Fengqiong; Zhang, Lei; Zhang, Jingjie; Qiu, Bensheng; Yu, Yongqiang; He, Xiaoxuan

    2017-01-01

    Abstract Background: Tamoxifen is the most widely used drug for treating patients with estrogen receptor-sensitive breast cancer. There is evidence that breast cancer patients treated with tamoxifen exhibit cognitive dysfunction. However, the underlying neural mechanism remains unclear. The present study aimed to investigate the neural mechanisms underlying working memory deficits in combination with functional connectivity changes in premenopausal women with breast cancer who received long-term tamoxifen treatment. Methods: A total of 31 premenopausal women with breast cancer who received tamoxifen and 32 matched healthy control participants were included. The participants completed n-back tasks and underwent resting-state functional magnetic resonance imaging, which measure working memory performance and brain functional connectivity, respectively. A seed-based functional connectivity analysis within the whole brain was conducted, for which the dorsolateral prefrontal cortex was chosen as the seed region. Results: Our results indicated that the tamoxifen group had significant deficits in working memory and general executive function performance and significantly lower functional connectivity of the right dorsolateral prefrontal cortex with the right hippocampus compared with the healthy controls. There were no significant changes in functional connectivity in the left dorsolateral prefrontal cortex within the whole brain between the tamoxifen group and healthy controls. Moreover, significant correlations were found in the tamoxifen group between the functional connectivity strength of the dorsolateral prefrontal cortex with the right hippocampus and decreased working memory performance. Conclusion: This study demonstrates that the prefrontal cortex and hippocampus may be affected by tamoxifen treatment, supporting an antagonistic role of tamoxifen in the long-term treatment of breast cancer patients. PMID:28177081

  18. Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial.

    Science.gov (United States)

    Rossi, Emanuela; Morabito, Alessandro; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; De Maio, Ermelinda; Di Maio, Massimo; Piccirillo, Maria Carmela; De Feo, Gianfranco; D'Aiuto, Giuseppe; Botti, Gerardo; Chiodini, Paolo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

    2009-07-01

    PURPOSE We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. PATIENTS AND METHODS Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. CONCLUSION Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

  19. Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics.

    Science.gov (United States)

    Sotgia, Federica; Fiorillo, Marco; Lisanti, Michael P

    2017-09-15

    Here, we used a data-mining and informatics approach to discover new biomarkers of resistance to hormonal therapy in breast cancer. More specifically, we investigated whether nuclear-encoded genes associated with mitochondrial biogenesis can be used to predict tumor recurrence, distant metastasis and treatment failure in high-risk breast cancer patients. Overall, this strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large and clinically relevant patient populations, with >15 years of follow-up data. For this purpose, we employed a group of 145 ER(+) luminal A breast cancer patients, with lymph-node (LN) metastasis at diagnosis, that were treated with tamoxifen, but not any chemotherapy agents. Using this approach, we identified >60 new individual mitochondrial biomarkers that predicted treatment failure and tumor recurrence, with hazard-ratios (HR) of up to 4.17 ( p =2.2e-07). These include mitochondrial chaperones (HSPD1, HSPA9), membrane proteins (VDAC2, TOMM70A) and anti-oxidants (SOD2), as well as 18 different mitochondrial ribosomal proteins (MRPs) and >20 distinct components of the OXPHOS complexes. In addition, we combined 4 mitochondrial proteins (HSPD1, UQCRB, MRPL15, COX17), to generate a compact mitochondrial gene signature, associated with a HR of 5.34 ( p =1e-09). This signature also successfully predicted distant metastasis and was effective in larger groups of ER(+) ( N =2,447), basal ( N =540) and HER2(+) ( N =193) breast cancers. It was also effective in all breast cancers ( N =3,180), if considered together as a single group. Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target for overcoming tumor recurrence, distant metastasis and treatment failure in patients with breast cancer. In summary, we identified individual mitochondrial biomarkers and 2 compact mitochondrial gene signatures that can be used to predict

  20. Optimizing tamoxifen-inducible Cre/loxp system to reduce tamoxifen effect on bone turnover in long bones of young mice.

    Science.gov (United States)

    Zhong, Zhendong A; Sun, Weihua; Chen, Haiyan; Zhang, Hongliang; Lay, Yu-An E; Lane, Nancy E; Yao, Wei

    2015-12-01

    For tamoxifen-dependent Cre recombinase, also known as CreER recombinase, tamoxifen (TAM) is used to activate the Cre to generate time- and tissue-specific mouse mutants. TAM is a potent CreER system inducer; however, TAM is also an active selective estrogen receptor modulator (SERM) that can influence bone homeostasis. The purpose of this study was to optimize the TAM dose for Cre recombinase activation while minimizing the effects of TAM on bone turnover in young growing mice. To evaluate the effects of TAM on bone turnover and bone mass, 1-month-old wild-type male and female mice were intraperitoneally injected with TAM at 0, 1, 10 or 100mg/kg/day for four consecutive days, or 100, 300 mg/kg/day for one day. The distal femurs were analyzed one month after the last TAM injection by microCT, mechanical test, and surface-based bone histomorphometry. Similar doses of TAM were used in Col1 (2.3 kb)-CreERT2; mT/mG reporter male mice to evaluate the dose-dependent efficacy of Cre-ER activation in bone tissue. A TAM dose of 100 mg/kg × 4 days significantly increased trabecular bone volume/total volume (BV/TV) of the distal femur, femur length, bone strength, and serum bone turnover markers compared to the 0mg control group. In contrast, TAM doses ≤ 10 mg/kg did not significantly change any of these parameters compared to the 0mg group, although a higher bone strength was observed in the 10mg group. Surface-based histomorphometry revealed that the 100mg/kg dose of TAM dose significantly increased trabecular bone formation and decreased periosteal bone formation at 1-week post-TAM treatment. Using the reporter mouse model Col1-CreERT2; mT/mG, we found that 10mg/kg TAM induced Col1-CreERT2 activity in bone at a comparable level to the 100mg/kg dose. TAM treatment at 100mg/kg/day × 4 days significantly affects bone homeostasis, resulting in an anabolic bone effect on trabecular bone in 1-month-old male mice. However, a lower dose of TAM at 10 mg/kg/day × 4 days can

  1. Uptake of breast cancer preventive therapy in the UK: results from a multicentre prospective survey and qualitative interviews.

    Science.gov (United States)

    Hackett, Julia; Thorneloe, Rachael; Side, Lucy; Wolf, Michael; Horne, Rob; Cuzick, Jack; Smith, Samuel G

    2018-04-24

    Uptake of preventive therapy for women at increased breast cancer risk in England is unknown following the introduction of UK clinical guidelines in 2013. Preventive therapy could create socioeconomic inequalities in cancer incidence if it is more readily accepted by particular socio-demographic groups. In this multicentre study, we investigated uptake of tamoxifen and evaluated socio-demographic and clinical factors associated with initiation. We explored women's experiences of treatment decision-making using qualitative interview data. Between September 2015 and December 2016, women (n = 732) attending an appointment at one of 20 centres in England to discuss breast cancer risk were approached to complete a survey containing socio-demographic details and nulliparity. Of the baseline survey respondents (n = 408/732, 55.7% response rate), self-reported uptake of tamoxifen at 3-month follow-up was reported in 258 (63.2%). Sixteen women participated in semi-structured interviews. One in seven (38/258 = 14.7%) women initiated tamoxifen. Women who had children were more likely to report use of tamoxifen than those without children (OR = 5.26; 95%CI: 1.13-24.49, p = 0.035). Interview data suggested that women weigh up risks and benefits of tamoxifen within the context of familial commitments, with exposure to significant other's beliefs and experiences of cancer and medication a basis for their decision. Uptake of tamoxifen is low in clinical practice. There were no socio-demographic differences in uptake, suggesting that the introduction of breast cancer preventive therapy is unlikely to create socioeconomic inequalities in cancer incidence. Women's decision-making was influenced by familial priorities, particularly having children.

  2. The anticancer drug tamoxifen is active against Trypanosoma cruzi in vitro but ineffective in the treatment of the acute phase of Chagas disease in mice

    Directory of Open Access Journals (Sweden)

    Danilo Ciccone Miguel

    2010-11-01

    Full Text Available The activity of the antineoplastic drug tamoxifen was evaluated against Trypanosoma cruzi. In vitro activity was determined against epimastigote, trypomastigote and amastigote forms of CL14, Y and Y benznidazole resistant T. cruzi strains. Regardless of the strain used, the drug was active against all life-cycle stages of the parasite with a half maximal effective concentration ranging from 0.7-17.9 µM. Two experimental models of acute Chagas disease were used to evaluate the in vivo efficacy of treatment with tamoxifen. No differences in parasitemia and mortality were observed between control mock-treated and tamoxifen-treated mice.

  3. Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study.

    Science.gov (United States)

    Beer, Beate; Schubert, Birthe; Oberguggenberger, Anne; Meraner, Verena; Hubalek, Michael; Oberacher, Herbert

    2010-10-01

    There is substantial evidence that circulating estrogens promote the proliferation of breast cancer. Consequently, adjuvant hormonal treatment strategies targeting estrogen action have been established. Such hormonal therapies include selective estrogen receptor modulators, such as tamoxifen, which interfere at the estrogen receptors directly, or non-steroidal aromatase inhibitors, such as anastrozole and letrozole, which inhibit estrogen synthesis through blocking the aromatase, a key enzyme of estrogen production. Despite considerable therapeutic success, in several cases, the use of these drugs is limited by side effects that have been described to significantly impair the adherence of patients to endocrine treatment. However, objective data concerning patient adherence and its clinical relevance are limited. One promising approach to check patient-reported adherence is drug monitoring in human plasma. Therefore, a liquid chromatography-tandem mass spectrometry method to determine the plasma concentrations of tamoxifen, anastrozole, and letrozole has been developed and fully validated according to guidelines for clinical and forensic toxicology. The validation criteria evaluated were selectivity, linearity, accuracy and precision, limit of quantification, recovery and matrix effects, sample stability, and carryover. The six-point calibration curves showed linearity over the range of concentrations from 25 to 500 ng/ml for tamoxifen, 5 to 200 ng/ml for anastrozole, and 10 to 300 ng/ml for letrozole. The intra- and inter-day precision and accuracies were always better than 15%. The validated procedure was successfully applied to a clinical study (Patient-Reported Outcomes in Breast Cancer Patients undergoing Endocrine Therapy, PRO-BETh). A major aim of PRO-BETh study is the comprehensive evaluation of adherence to treatment in pre- and post-menopausal women with breast cancer. Plasma samples of 310 breast cancer patients undergoing anti-estrogen therapy were

  4. Comparing guidelines for adjuvant endocrine therapy in postmenopausal women with breast cancer: a coming of age.

    Science.gov (United States)

    Verma, Sunil; Jackisch, Christian

    2011-02-01

    Following surgery for early breast cancer, the standard of care for postmenopausal women is adjuvant therapy with any combination of radiation therapy, endocrine therapy, chemotherapy and/or targeted therapy. Clinicians rely on many tools, including guidelines, to make these treatment decisions. Such guidelines include the St Gallen consensus statement, the American Society of Clinical Oncology guidelines and the National Comprehensive Cancer Network guidelines, as well as various regional and national guidelines. Recommendations may vary, because different methods and criteria were used to assess the strength of supporting data. This article provides an overview of global guidelines for the adjuvant treatment of breast cancer and points out the major differences. Ongoing changes are highlighted, particularly those regarding the adjuvant endocrine treatment of postmenopausal women with breast cancer. While previous guidelines recommended tamoxifen alone, all major guidelines now recommend using third-generation aromatase inhibitors either in sequence with tamoxifen or as upfront treatment.

  5. 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.

  6. Tamoxifen attenuates development of lithium-induced nephrogenic diabetes insipidus in rats

    DEFF Research Database (Denmark)

    Tingskov, Stine Julie; Hu, Shan; Frøkiær, Jorgen

    2018-01-01

    of aquaporin-2 (AQP2), which are essential for water reabsorption of tubular fluid in the collecting duct. Sex hormones have previously been shown to affect the regulation of AQP2, so we tested whether tamoxifen (TAM), a selective estrogen receptor modulator, would attenuate lithium-induced alterations...... on renal water homeostasis. Rats were treated for 14 days with lithium and TAM treatment was initiated one week after onset of lithium administration. Lithium treatment resulted in severe polyuria and reduced AQP2 expression, which was ameliorated by TAM. Consistent with this, TAM attenuated downregulation...... of AQP2 and increased phosphorylation of the cAMP responsive element binding protein (CREB), which induced AQP2 expression, in freshly isolated inner medullary collecting duct suspension prepared from lithium-treated rats. In conclusion, TAM attenuated dose-dependently polyuria, impaired urine...

  7. The evaluation of in vitro effect of daunorubicin and tamoxifen in ehrlich ascites tumour (EAT) cells

    International Nuclear Information System (INIS)

    Topcul, M.; Topcul, F.; Oezalpan, A.

    2001-01-01

    In the most countries, breast cancer is still the most important cancer among women. It is known that Ehrlich Ascites Tumour is experimental breast cancer model in animal. The cells used in the study are hyper diploid line of Ehrlich Ascites Tumour (EAT) cells, initially provided to us from Institute of Pathology, Koln University. In the present study, an hyper diploid line which is estrogen receptor positive was used. An anthracycline-derived antibiotic, Daunorubicin (DNR, Cerubidine) is one of the clinically used anticancer drugs. DNR has been used alone or in combination with other cytotoxic agents against a variety of animal and human tumours. In vitro cell culture studies show that DNR enters the cell nuclei, inhibits nucleic acid synthesis, and arrest cell division. Tamoxifen (TAM, Nolvadex) is a semi-synthetical estrogen antagonist, used in the management of pre and post menopausal breast cancer. This drug bind to intracellular estrogen receptors, and prevents endogenous estrogens from binding to their own receptors. It is known that Ehrlich Ascites Tumour is experimental breast cancer model in animal. The cells used in the study are hyper diploid line of EAT cells initially provided to us from Institute of Pathology, Koln University. In the present study, an hyper diploid line which is Estrogen Receptor (+) was used. Estrogen Receptor levels were studied by the methods of Lippman and Huff and Raynaud et al. with minor modifications. Estrogen Receptor activity as demonstrated by dextran-coated charcoal technique is closely correlated with the clinical ability of Tamoxifen to inhibit tumour growth

  8. Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

    International Nuclear Information System (INIS)

    Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S.; Rouchka, Eric C.; Hill, Bradford G.; Klinge, Carolyn M.

    2016-01-01

    Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

  9. Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S. [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Rouchka, Eric C. [Bioinformatics and Biomedical Computing Laboratory, Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY 40292 (United States); Hill, Bradford G. [Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Klinge, Carolyn M., E-mail: carolyn.klinge@louisville.edu [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States)

    2016-09-10

    Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

  10. CYP2C19*2 and CYP2C19*17 variants and effect of tamoxifen on breast cancer recurrence

    DEFF Research Database (Denmark)

    Damkier, Per; Kjaersgaard, Anders; Barker, Kimberly A.

    2017-01-01

    *17 allele were 1.02 (CI 0.71-1.46) and 0.57 (CI 0.26-1.24), respectively. Accounting for CYP2D6 genotype status did not change these estimates. We found no evidence to support a clinically meaningful role of CYP2C19 polymorphisms and response to tamoxifen in breast cancer patients and, consequently, CYP2C19...... genotype status should not be included in clinical decisions on tamoxifen treatment....

  11. Effects of liarozole fumarate (R85246) in combination with tamoxifen on N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma and uterus in the rat model

    International Nuclear Information System (INIS)

    Goss, Paul E; Strasser-Weippl, Kathrin; Qi, Shangle; Hu, Haiqing

    2007-01-01

    Liarozole fumarate (liarozole – R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Our objective was to determine the effects of liarozole alone or in combination with tamoxifen on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in ovariectomized immature rats. (1) Tumor burden experiments: Animals bearing one or more tumors greater than 10 mm in diameter were treated for 56 consecutive days with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 100 μg/kg by subcutaneous injection, or a combination of liarozole and tamoxifen. At the end of the treatment period, total cumulative tumor volume as well as retinoic acid levels were measured. (2) Uterotrophic assay and proliferation experiments: 21-day-old ovariectomized (OVX) Sprague-Dawley rats were treated with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 1 mg/kg by subcutaneous injection, and combination of both for 4 consecutive days. At the end of the treatment period, uterine weight, epithelial lining cell height and indices of proliferation cell nuclear antigen (PCNA) were measured. The tumor burden experiments in rats bearing estrogen receptor (ER) positive mammary tumours showed that liarozole has a marked anti-tumour effect. In combination with tamoxifen, liarozole had neither an additive nor an antagonistic effect. However, liarozole markedly reduced the uterotrophic effects induced by tamoxifen. Liarozole's antitumor effects on ER positive mammary tumors and its protective effect on the uterus merit further studies to confirm its clinical value in combination with tamoxifen in ER positive postmenopausal breast cancer. Liarozole and other retinomimetics might also be suitable chemoprevention drugs in combination with tamoxifen because of their favorable toxicity profile

  12. Effect of long-term treatment with steroid hormones or tamoxifen on the progesterone receptor and androgen receptor in the endometrium of ovariectomized cynomolgus macaques

    Directory of Open Access Journals (Sweden)

    Cline J Mark

    2003-02-01

    Full Text Available Abstract The progesterone receptor (PR and androgen receptor (AR belong to the nuclear receptor superfamily. Two isoforms of PR (A and B have been identified with different functions. The expression of AR, each isoform of PR and their involvement in long-term effects on the endometrium after hormonal replacement therapy (HRT or tamoxifen (TAM treatment is not known. The aims of this study were to determine PR(A+B, PRB and AR distribution by immunohistochemistry in the macaque (Macaca fascicularis endometrium. Ovariectomized (OVX animals were orally treated continuously for 35 months with either conjugated equine estrogens (CEE; medroxyprogesterone acetate (MPA; the combination of CEE/MPA; or TAM. Treatment with CEE/MPA tended to down-regulate PR in the superficial glands, but increased it in the stroma. TAM treatment increased both the PR and PRB levels in the stroma. Overall, less than 20% of the cells were positive for the PRB isoform and less variation was observed after steroid treatment. AR was found in the stroma, mainly distributed in the basal layer of the endometrium in the OVX and steroid treated groups, but was absent in the TAM treated group. No AR was found in the glandular epithelium. The present data show that long-term hormone treatment affects the PR level, and also the ratio between PRA and PRB in the endometrium.

  13. Integrated molecular analysis of Tamoxifen-resistant invasive lobular breast cancer cells identifies MAPK and GRM/mGluR signaling as therapeutic vulnerabilities.

    Science.gov (United States)

    Stires, Hillary; Heckler, Mary M; Fu, Xiaoyong; Li, Zhao; Grasso, Catherine S; Quist, Michael J; Lewis, Joseph A; Klimach, Uwe; Zwart, Alan; Mahajan, Akanksha; Győrffy, Balázs; Cavalli, Luciane R; Riggins, Rebecca B

    2018-08-15

    Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests that estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but the mechanistic drivers of this are undefined. In the current work, we comprehensively characterize the SUM44/LCCTam ILC cell model system through integrated analysis of gene expression, copy number, and mutation, with the goal of identifying actionable alterations relevant to clinical ILC that can be co-targeted along with ER to improve treatment outcomes. We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Motivators and barriers of tamoxifen use as risk-reducing medication amongst women at increased breast cancer risk: a systematic literature review.

    Science.gov (United States)

    Meiser, B; Wong, W K T; Peate, M; Julian-Reynier, C; Kirk, J; Mitchell, G

    2017-01-01

    Selective estrogen receptor modulators, such as tamoxifen, reduce breast cancer risk by up to 50% in women at increased risk for breast cancer. Despite tamoxifen's well-established efficacy, many studies show that most women are not taking up tamoxifen. This systematic literature review aimed to identify the motivators and barriers to tamoxifen use 's amongst high-risk women. Using MEDLINE, PsycINFO, and Embase plus reviewing reference lists of relevant articles published between 1995 and 2016, 31 studies (published in 35 articles) were identified, which addressed high-risk women's decisions about risk-reducing medication to prevent breast cancer and were peer-reviewed primary clinical studies. A range of factors were identified as motivators of, and barriers to, tamoxifen uptake including: perceived risk, breast-cancer-related anxiety, health professional recommendation, perceived drug effectiveness, concerns about side-effects, knowledge and access to information about side-effects, beliefs about the role of risk-reducing medication, provision of a biomarker, preference for other forms of breast cancer risk reduction, previous treatment experience, concerns about randomization in clinical trial protocols and finally altruism. Results indicate that the decision for high-risk women regarding tamoxifen use or non-use as a risk-reducing medication is not straightforward. Support of women making this decision is essential and needs to encompass the full range of factors, both informational and psychological.

  15. 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.

  16. Tamoxifen induces regression of estradiol-induced mammary cancer in the ACI.COP-Ept2 rat model.

    Science.gov (United States)

    Ruhlen, Rachel L; Willbrand, Dana M; Besch-Williford, Cynthia L; Ma, Lixin; Shull, James D; Sauter, Edward R

    2009-10-01

    The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5-7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonance imaging, by 89%. Tumors expressed estrogen receptors (ER), progesterone receptor (PR), and Erbb2. ERalpha and PR were overexpressed in tumor compared to adjacent non-tumor mammary gland. Thus, this model is highly relevant to hormone responsive human breast cancers.

  17. Direct and Systemic Administration of a CNS-Permeant Tamoxifen Analog Reduces Amphetamine-Induced Dopamine Release and Reinforcing Effects.

    Science.gov (United States)

    Carpenter, Colleen; Zestos, Alexander G; Altshuler, Rachel; Sorenson, Roderick J; Guptaroy, Bipasha; Showalter, Hollis D; Kennedy, Robert T; Jutkiewicz, Emily; Gnegy, Margaret E

    2017-09-01

    Amphetamines (AMPHs) are globally abused. With no effective treatment for AMPH addiction to date, there is urgent need for the identification of druggable targets that mediate the reinforcing action of this stimulant class. AMPH-stimulated dopamine efflux is modulated by protein kinase C (PKC) activation. Inhibition of PKC reduces AMPH-stimulated dopamine efflux and locomotor activity. The only known CNS-permeant PKC inhibitor is the selective estrogen receptor modulator tamoxifen. In this study, we demonstrate that a tamoxifen analog, 6c, which more potently inhibits PKC than tamoxifen but lacks affinity for the estrogen receptor, reduces AMPH-stimulated increases in extracellular dopamine and reinforcement-related behavior. In rat striatal synaptosomes, 6c was almost fivefold more potent at inhibiting AMPH-stimulated dopamine efflux than [ 3 H]dopamine uptake through the dopamine transporter (DAT). The compound did not compete with [ 3 H]WIN 35,428 binding or affect surface DAT levels. Using microdialysis, direct accumbal administration of 1 μM 6c reduced dopamine overflow in freely moving rats. Using LC-MS, we demonstrate that 6c is CNS-permeant. Systemic treatment of rats with 6 mg/kg 6c either simultaneously or 18 h prior to systemic AMPH administration reduced both AMPH-stimulated dopamine overflow and AMPH-induced locomotor effects. Finally, 18 h pretreatment of rats with 6 mg/kg 6c s.c. reduces AMPH-self administration but not food self-administration. These results demonstrate the utility of tamoxifen analogs in reducing AMPH effects on dopamine and reinforcement-related behaviors and suggest a new avenue of development for therapeutics to reduce AMPH abuse.

  18. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.

    Science.gov (United States)

    Paik, Soonmyung; Shak, Steven; Tang, Gong; Kim, Chungyeul; Baker, Joffre; Cronin, Maureen; Baehner, Frederick L; Walker, Michael G; Watson, Drew; Park, Taesung; Hiller, William; Fisher, Edwin R; Wickerham, D Lawrence; Bryant, John; Wolmark, Norman

    2004-12-30

    The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor-positive tumors is poorly defined by clinical and histopathological measures. We tested whether the results of a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of 21 prospectively selected genes in paraffin-embedded tumor tissue would correlate with the likelihood of distant recurrence in patients with node-negative, tamoxifen-treated breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trial B-14. The levels of expression of 16 cancer-related genes and 5 reference genes were used in a prospectively defined algorithm to calculate a recurrence score and to determine a risk group (low, intermediate, or high) for each patient. Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks. The proportions of patients categorized as having a low, intermediate, or high risk by the RT-PCR assay were 51, 22, and 27 percent, respectively. The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-risk, intermediate-risk, and high-risk groups were 6.8 percent (95 percent confidence interval, 4.0 to 9.6), 14.3 percent (95 percent confidence interval, 8.3 to 20.3), and 30.5 percent (95 percent confidence interval, 23.6 to 37.4). The rate in the low-risk group was significantly lower than that in the high-risk group (P<0.001). In a multivariate Cox model, the recurrence score provided significant predictive power that was independent of age and tumor size (P<0.001). The recurrence score was also predictive of overall survival (P<0.001) and could be used as a continuous function to predict distant recurrence in individual patients. The recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor-positive breast cancer. Copyright 2004 Massachusetts Medical Society.

  19. Late tamoxifen in patients previously operated for breast cancer without postoperative tamoxifen: 5-year results of a single institution randomised study

    International Nuclear Information System (INIS)

    Veronesi, Andrea; Miolo, GianMaria; Magri, Maria D; Crivellari, Diana; Scalone, Simona; Bidoli, Ettore; Lombardi, Davide

    2010-01-01

    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. 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. 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. This 5-year analysis revealed significantly less metachronous ER-positive breast cancers in the TAM treated patients. No other statistically significant differences have emerged thus far

  20. 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

  1. FDG-PET in monitoring therapy of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  2. FDG-PET in monitoring therapy of breast cancer

    International Nuclear Information System (INIS)

    Biersack, H.J.; Bender, H.; Palmedo, H.

    2004-01-01

    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.)

  3. Tamoxifen is a potent antioxidant modulator for sperm quality in patients with idiopathic oligoasthenospermia.

    Science.gov (United States)

    Guo, Li; Jing, Jun; Feng, Yu-Ming; Yao, Bing

    2015-09-01

    To explore the new mechanisms of tamoxifen (TAM) in the treatment for patients with idiopathic oligoasthenospermia-antioxidation. In a prospective, randomized, controlled clinical trial, 120 cases of idiopathic oligoasthenospermia were enrolled and randomly assigned to the indomethacin group (n = 60) treated with indomethacin (25 mg, bid) and TAM group (n = 60) treated with TAM (10 mg, bid) for 3 months. Before and after treatment, we evaluated semen parameters, serum malondialdehyde (MDA) and total antioxidant capacity (TAC), seminal plasma MDA and TAC, spermatozoa intracellular reactive oxygen species (ROS), sperm succinate dehydrogenase (SDH) activity, sperm mitochondrial membrane potential (MMP), and sperm adenosine triphosphate (ATP) content. The independent t test and one-way repeated measures analysis of variance were used to compare the variables between and within two groups. In the indomethacin group, the percentage of progressive motile sperms, total motility, sperm MMP, and ATP content were increased significantly after 3-month treatment (P sperm count, sperm concentration, the percentage of progressive motile sperms, total motility, serum and seminal plasma TAC, sperm MMP, and ATP content were significantly improved or increased (P sperm count, sperm concentration, serum TAC, seminal plasma TAC, spermatozoa intracellular ROS, and sperm SDH activity. TAM treatment can significantly improve sperm quality, which is achieved through alleviating oxidative stress, improving sperm mitochondrial functionality, and subsequently increasing sperm motility.

  4. 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.

  5. 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.

  6. 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.

  7. Agonistic activity of tamoxifen, a selective estrogen-receptor modulator (SERM), on arthritic ovariectomized mice

    Science.gov (United States)

    Silva, L.A.S.; Felix, F.B.; Araujo, J.M.D.; Souza, E.V.; Camargo, E.A.; Grespan, R.

    2017-01-01

    Arthritis is positively associated with the decline of sex hormones, especially estrogen. Tamoxifen (TMX) is a selective estrogen receptor modulator, possessing agonist or antagonistic activity in different tissues. Thus, the objective of this study was to investigate the effect of TMX on the zymosan-induced arthritis model. Female Swiss normal and ovariectomized (OVX) mice were divided into groups and treated for five days with TMX (0.3, 0.9 or 2.7 mg/kg) or 17-β-estradiol (E2, 50 µg/kg). On the fifth day, arthritis was induced and 4 h later, leukocyte migration into joint cavities was evaluated. The neutrophil migration in OVX animals, but not in normal mice, treated with TMX (all tested doses) was significantly decreased compared with mice that received the vehicle (P≤0.05). Similarly, this effect was also demonstrated in the E2-treated group. Therefore, the present study demonstrates that TMX presented agonist effects in inhibiting neutrophil migration and preventing arthritis progression in OVX mice. PMID:29160416

  8. Effect of paclitaxel, epirubicin and tamoxifen on labelling index in cultured ehrlich ascites tumor cells

    International Nuclear Information System (INIS)

    Arican, G. Oe.; Oezalpan, A.

    2001-01-01

    The effect of Paclitaxel (PAC), Epirubicin (EPR) and Tamoxifen (TAM) on ''3H-thymidine labelling index (''3H-TdR LI) of Ehrlich ascites tumor cells (EAT) was investigated in cultured. In the present study, an estrogen receptor positive ER(+) hyper diploid cell lines were studied. We used optimum doses of PAC, EPR and TAM (12 mg/ml, 12 mg/ml and 2 mg/ml, respectively). Cells were treated with these doses for 0, 4, 8, 16 and 32 hours. At the end of these periods, both control and treated cells were labelled for 5 mCi/ml 3H-thymidine for 30 minutes. The results showed that inhibition of DNA synthesis in cultured EAT cells were increased in the combined treatment of two drugs when compared to the treatment of a single drug (p<0.01). In the treatment of three drugs, however, this effect reached a maximum (p<0.001). As a result, PAC+EPR+TAM treatment's had a maximum synergistic effect at 4 hours treatment

  9. Iodine-125-labelled tamoxifen is differentially cytoxic to cells containing oestrogen receptors

    International Nuclear Information System (INIS)

    Bloomer, W.D.; McLaughlin, W.H.; Weichselbaum, R.R.

    1980-01-01

    Tamoxifen, a non-steroidal anti-oestrogen competes with 17 - oestradiol for oestrogen receptor protein and is translocated to the nucleus. Carrier-free 125 I-TAM was tested for cytotoxicity in oestrogen receptor rich (human breast cancer MCF-7) and poor (V-79 Chinese hamster) cells. 125 I-TAM was differentially cytotoxic to MCF-7 cells. The D 37 values for MCF-7 and V-79 cells were 0.5 and 1.5 pCi/cell respectively. No radiotoxicity was observed with Na 125 I at doses equal to 125 I-TAM; iodide was effectively excluded from both cell lines and remained in the extracellular space. Also, nonradioactive 127 I-TAM and TAM were both non-toxic when tested at levels comparable to 125 I-TAM. It is suggested that the marked cytotoxicity in MCF-7 cells results from close approximation of 125 I with the genetic apparatus as a result of direct charging of specific nuclear receptors and/or translocation of 125 I-TAM receptor complexes from the cytoplasm to the nucleus, and that the minimal toxicity in V-79 cells reflects transmitted cytoplasmic radiation effects, limited direct nuclear charging and/or limited nuclear translocation resulting from the relative paucity of oestrogen in the cells. (U.K.)

  10. Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

    International Nuclear Information System (INIS)

    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 17β-estradiol (E 2 ) at both low (0.1 μg/kg) and high (20 μg/kg) doses confirmed its ability to increase the number of striatal 3 H-Spiperone ( 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 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

  11. Induction of microRNAome deregulation in rat liver by long-term tamoxifen exposure

    International Nuclear Information System (INIS)

    Pogribny, Igor P.; Tryndyak, Volodymyr P.; Boyko, Alex; Rodriguez-Juarez, Rocio; Beland, Frederick A.; Kovalchuk, Olga

    2007-01-01

    Micro RNAs (miRNAs) are small non-coding RNA molecules that function as negative regulators of gene expression. They play a crucial role in the regulation of genes involved in the control of development, cell proliferation, apoptosis, and stress response. Although miRNA levels are substantially altered in tumors, their role in carcinogenesis, specifically at the early pre-cancerous stages, has not been established. Here we report that exposure of Fisher 344 rats to tamoxifen, a potent hepatocarcinogen in rats, for 24 weeks leads to substantial changes in the expression of miRNA genes in the liver. We noted a significant up-regulation of known oncogenic miRNAs, such as the 17-92 cluster, miR-106a, and miR-34. Furthermore, we confirmed the corresponding changes in the expression of proteins targeted by these miRNAs, which include important cell cycle regulators, chromatin modifiers, and expression regulators implicated in carcinogenesis. All these miRNA changes correspond to previously reported alterations in full-fledged tumors, including hepatocellular carcinomas. Thus, our findings indicate that miRNA changes occur prior to tumor formation and are not merely a consequence of a transformed state

  12. Apolipoprotein D expression does not predict breast cancer recurrence among tamoxifen-treated patients

    DEFF Research Database (Denmark)

    Klebaner, Daniella; Hamilton-Dutoit, Stephen; Ahern, Thomas P

    2017-01-01

    confounding using logistic regression. RESULTS: Cytoplasmic ApoD expression was seen in 68% of ER+ tumors, in 66% of ER- tumors, and in 66% of controls across both groups. In women with ER+ tumors, the associations of cytoplasmic ApoD expression with recurrence (OR = 1.0; 95% CI = 0.7 to 1.4) and increasing...... cytoplasmic expression with recurrence (OR = 1.0; 95% CI = 0.996 to 1.003) were null, as were those for women with ER- tumors. Associations for nuclear ApoD expression and combined nuclear and cytoplasmic expression were similarly near-null. CONCLUSION: ApoD expression is likely not a predictor of recurrence......BACKGROUND: Apolipoprotein D (ApoD) has been proposed as a predictor of breast cancer recurrence among estrogen receptor-positive (ER+), tamoxifen-treated patients. METHODS: We conducted a population-based case-control study nested in a population of 11,251 women aged 35-69 years at diagnosis...

  13. The alterations of serum FGF-21 levels, metabolic and body composition in early breast cancer patients receiving adjuvant endocrine therapy.

    Science.gov (United States)

    Akyol, Murat; Alacacioglu, Ahmet; Demir, Leyla; Kucukzeybek, Yuksel; Yildiz, Yasar; Gumus, Zehra; Kara, Mete; Salman, Tarik; Varol, Umut; Taskaynatan, Halil; Oflazoglu, Utku; Bayoglu, Vedat; Tarhan, Mustafa Oktay

    2017-01-01

    In early breast cancer patients, the effects of hormonal therapy (tamoxifen and aromatase inhibitors) on plasma fibroblast growth factor 21 (FGF-21), lipid levels and body composition have not yet been investigated. Therefore, we aimed to analyze the relationship between FGF-21 and body composition as well as the effects of tamoxifen and aromatase inhibitors on plasma lipid levels, FGF-21, and body composition. A total of 72 patients were treated with either tamoxifen or aromatase inhibitors due to their menopausal status after adjuvant radiotherapy. Each patient was followed-up over a period of 1 year. Changes in body composition and serum lipid profile, glucose and FGF-21 levels were evaluated. We recorded the type of hormonal therapy, body mass index, waist-to-hip ratio, lipid profile, and FGF-21 levels both at the beginning and after 12 months. There was a statistically significant decrease in serum FGF-21 levels after 12 months of adjuvant endocrine therapy (46 ± 19.21 pg/ml vs. 30.99 ± 13.81 pg/ml, pbody water (pbody composition, glucose, lipid profile and FGF-21 were similar in tamoxifen and aromatase inhibitor groups. A positive correlation was found between basal weight, fat mass, fat-free mass and serum FGF-21 levels; however, the correlation was maintained only for the fat-free mass at the 12th month. As part of the present study, we suggest that both tamoxifen and aromatase inhibitors can reduce FGF-21 levels independently of body compositions, and these drugs can provide antihyperlipidemic, antidiabetic and cardio-protective effects. We also recommend that serum FGF-21 level can be utilized as a tumor biomarker in early-stage breast cancer and for monitoring purposes. FGF-21 levels may help physicians estimate prognosis, too. Further studies with larger populations may shed light on the role of FGF-21 in breast cancer.

  14. Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study.

    Science.gov (United States)

    Nuzzo, F; Gallo, C; Lastoria, S; Di Maio, M; Piccirillo, M C; Gravina, A; Landi, G; Rossi, E; Pacilio, C; Labonia, V; Di Rella, F; Bartiromo, A; Buonfanti, G; De Feo, G; Esposito, G; D'Aniello, R; Maiolino, P; Signoriello, S; De Maio, E; Tinessa, V; Colantuoni, G; De Laurentiis, M; D'Aiuto, M; Di Bonito, M; Botti, G; Giordano, P; Daniele, G; Morabito, A; Normanno, N; de Matteis, A; Perrone, F

    2012-08-01

    To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P<0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole+zoledronic acid versus letrozole comparison (P<0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P=0.004 and 0.47, respectively). In the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.

  15. The Possible Effect Of Tamoxifen Vs Whole Body Irradiation Treatment On Thyroid Hormones in Female Rats Bearing Mammary Tumors Chemically Induced

    International Nuclear Information System (INIS)

    Abdelgawad, M.R.

    2012-01-01

    Breast cancer is the most common malignancy among women in most developed and developing regions of the world. In women, this drug has tissuespecific effects, acting as an estrogen antagonist on the breast, and as an estrogen agonist on bone, lipid metabolism (increasing high-density lipoprotein cholesterol and decreasing low-density lipoprotein cholesterol), and the endometrium. Thyroid hormones act on almost all organs throughout the body and regulate the basal metabolism of the organism. Thyroid hormone can also stimulate the proliferation in vitro of certain tumor cell lines. The aim of the present study is to evaluate the significant value of tamoxifen and/or irradiation treatment on thyroid hormones in breast cancer bearing female rats. Forty two female Sprague-Dawely rats randomly divided into seven groups and the effect of tamoxifen and post-irradiation was studied on breast cancer chemically induced. The results shows a T 4 and estradiol levels not T 3 were altered in different experimental groups. It could be concluded that irradiation-induced changes in the composition of the mammary microenvironment promote the expression of neoplastic potential by affecting both estradiol and thyroid hormones, and tamoxifen may alter the thyroid hormones. Irradiation and tamoxifen administration may have worth effects on T 4 and estradiol levels and it is recommended to further studies towards the bystander effect of radiation and tamoxifen on the tissue culture and molecular biology scale.

  16. 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 for es...

  17. Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor-Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14.

    Science.gov (United States)

    Wolmark, Norman; Mamounas, Eleftherios P; Baehner, Frederick L; Butler, Steven M; Tang, Gong; Jamshidian, Farid; Sing, Amy P; Shak, Steven; Paik, Soonmyung

    2016-07-10

    We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1-expressing groups. RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) -positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. Median follow-up was 11.2 years for B-28 and 13.9 years for B-14. Of 1,065 B-28 patients, 36% had low ( 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS ≥ 31, respectively (log-rank P = .01). For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis. © 2016 by American Society of Clinical Oncology.

  18. Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor–Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14

    Science.gov (United States)

    Wolmark, Norman; Baehner, Frederick L.; Butler, Steven M.; Tang, Gong; Jamshidian, Farid; Sing, Amy P.; Shak, Steven; Paik, Soonmyung

    2016-01-01

    Purpose We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1–expressing groups. Patients and Methods RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) –positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. Results Median follow-up was 11.2 years for B-28 and 13.9 years for B-14. Of 1,065 B-28 patients, 36% had low ( 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS ≥ 31, respectively (log-rank P = .01). Conclusion For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis. PMID:27217450

  19. 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

    of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated......BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years...... 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...

  20. Awareness of preventive medication among women at high risk for breast cancer and their willingness to consider transdermal or oral tamoxifen: a focus group study

    International Nuclear Information System (INIS)

    Karavites, Lindsey C.; Allu, Subhashini; Khan, Seema A.; Kaiser, Karen

    2015-01-01

    Despite demonstrated efficacy, acceptance of selective estrogen receptor modulators (SERMs), such as tamoxifen, for breast cancer risk reduction remains low. Delivering SERMs via local transdermal therapy (LTT) could significantly reduce systemic effects and therefore may increase acceptance. We aim to assess women’s knowledge of breast cancer prevention medications and views on LTT of SERMs. Focus groups were conducted with healthy women identified through the comprehensive breast center of a large urban cancer institution. Group discussions covered risk perceptions, knowledge of and concerns about risk reducing medications. Participants reported their perceived risk for breast cancer (average, below/above average), preference for SERMs in a pill or gel form, risk factors, and prior physician recommendations regarding risk-reducing medicines. Participants’ breast cancer risk was estimated using tools based on the Gail Model. Trained personnel examined all qualitative results systematically; risk perceptions and preferred method of medication delivery were tallied quantitatively. Four focus groups (N = 32) were conducted. Most participants had at least a college degree (78.2 %) and were of European (50 %) or African ancestry (31 %). The majority (72 %) were at elevated risk for breast cancer; approximately half of these women perceived themselves to be at elevated risk. Few participants had prior knowledge of preventive medications. The women noted a number of concerns about LTT, including dosage, impact on day-to-day life, and side effects; nonetheless, over 90 % of the women stated they would prefer LTT to a pill. Awareness of preventive medications was low even in a highly educated sample of high-risk women. If given a choice in the route of administration, most women preferred a gel to a pill, anticipating fewer side effects. Future work should focus on demonstrating equivalent efficacy and reduced toxicity of topical over oral medications and on raising

  1. Awareness of preventive medication among women at high risk for breast cancer and their willingness to consider transdermal or oral tamoxifen: a focus group study.

    Science.gov (United States)

    Karavites, Lindsey C; Allu, Subhashini; Khan, Seema A; Kaiser, Karen

    2015-11-09

    Despite demonstrated efficacy, acceptance of selective estrogen receptor modulators (SERMs), such as tamoxifen, for breast cancer risk reduction remains low. Delivering SERMs via local transdermal therapy (LTT) could significantly reduce systemic effects and therefore may increase acceptance. We aim to assess women's knowledge of breast cancer prevention medications and views on LTT of SERMs. Focus groups were conducted with healthy women identified through the comprehensive breast center of a large urban cancer institution. Group discussions covered risk perceptions, knowledge of and concerns about risk reducing medications. Participants reported their perceived risk for breast cancer (average, below/above average), preference for SERMs in a pill or gel form, risk factors, and prior physician recommendations regarding risk-reducing medicines. Participants' breast cancer risk was estimated using tools based on the Gail Model. Trained personnel examined all qualitative results systematically; risk perceptions and preferred method of medication delivery were tallied quantitatively. Four focus groups (N = 32) were conducted. Most participants had at least a college degree (78.2 %) and were of European (50 %) or African ancestry (31 %). The majority (72 %) were at elevated risk for breast cancer; approximately half of these women perceived themselves to be at elevated risk. Few participants had prior knowledge of preventive medications. The women noted a number of concerns about LTT, including dosage, impact on day-to-day life, and side effects; nonetheless, over 90 % of the women stated they would prefer LTT to a pill. Awareness of preventive medications was low even in a highly educated sample of high-risk women. If given a choice in the route of administration, most women preferred a gel to a pill, anticipating fewer side effects. Future work should focus on demonstrating equivalent efficacy and reduced toxicity of topical over oral medications and on raising

  2. Clinical relevance of "withdrawal therapy" as a form of hormonal manipulation for breast cancer

    Directory of Open Access Journals (Sweden)

    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.

  3. Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice

    Science.gov (United States)

    Foley, John J.; Clark-Vetri, Rachel; Raffa, Robert B.

    2011-01-01

    Rationale A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect. Objectives To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay. Methods Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5-fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure. Results The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose. Conclusions These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations. PMID:21537942

  4. Cancer Care Coordinators to Improve Tamoxifen Persistence in Breast Cancer: How Heterogeneity in Baseline Prognosis Impacts on Cost-Effectiveness.

    Science.gov (United States)

    Nair, Nisha; Kvizhinadze, Giorgi; Blakely, Tony

    2016-12-01

    To assess the cost-effectiveness of a cancer care coordinator (CCC) in helping women with estrogen receptor positive (ER+) early breast cancer persist with tamoxifen for 5 years. We investigated the cost-effectiveness of a CCC across eight breast cancer subtypes, defined by progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, and local/regional spread. These subtypes range from excellent to poorer prognoses. The CCC helped in improving tamoxifen persistence by providing information, checking-in by phone, and "troubleshooting" concerns. We constructed a Markov macrosimulation model to estimate health gain (in quality-adjusted life-years or QALYs) and health system costs in New Zealand, compared with no CCC. Participants were modeled until death or till the age of 110 years. Some input parameters (e.g., the impact of a CCC on tamoxifen persistence) had sparse evidence. Therefore, we used estimates with generous uncertainty and conducted sensitivity analyses. The cost-effectiveness of a CCC for regional ER+/PR-/HER2+ breast cancer (worst prognosis) was NZ $23,400 (US $15,800) per QALY gained, compared with NZ $368,500 (US $248,800) for local ER+/PR+/HER2- breast cancer (best prognosis). Using a cost-effectiveness threshold of NZ $45,000 (US $30,400) per QALY, a CCC would be cost-effective only in the four subtypes with the worst prognoses. There is value in investigating cost-effectiveness by different subtypes within a disease. In this example of breast cancer, the poorer the prognosis, the greater the health gains from a CCC and the better the cost-effectiveness. Incorporating heterogeneity in a cost-utility analysis is important and can inform resource allocation decisions. It is also feasible to undertake in practice. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  5. 17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity.

    Science.gov (United States)

    Pajarillo, Edward; Johnson, James; Kim, Judong; Karki, Pratap; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook

    2018-03-01

    Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson's disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Graphene as a nanocarrier for tamoxifen induces apoptosis in transformed cancer cell lines of different origins.

    Science.gov (United States)

    Misra, Santosh K; Kondaiah, Paturu; Bhattacharya, Santanu; Rao, C N R

    2012-01-09

    A cationic amphiphile, cholest-5en-3β-oxyethyl pyridinium bromide (PY(+) -Chol), is able to efficiently disperse exfoliated graphene (GR) in water by the physical adsorption of PY(+) -Chol on the surface of GR to form stable, dark aqueous suspensions at room temperature. The GR-PY(+) -Chol suspension can then be used to solubilize Tamoxifen Citrate (TmC), a breast cancer drug, in water. The resulting TmC-GR-PY(+) -Chol is stable for a long time without any precipitation. Fluorescence emission and UV absorption spectra indicate the existence of noncovalent interactions between TmC, GR, and PY(+) -Chol in these suspensions. Electron microscopy shows the existence of segregated GR sheets and TmC 'ribbons' in the composite suspensions. Atomic force microscopy indicates the presence of 'extended' structures of GR-PY(+) -Chol, which grows wider in the presence of TmC. The slow time-dependent release of TmC is noticed in a reconstituted cell culture medium, a property useful as a drug carrier. TmC-GR-PY(+) -Chol selectively enhanced the cell death (apoptosis) of the transformed cancer cells compared to normal cells. This potency is found to be true for a wide range of transformed cancer cells viz. HeLa, A549, ras oncogene-transformed NIH3T3, HepG2, MDA-MB231, MCF-7, and HEK293T compared to the normal cell HEK293 in vitro. Confocal microscopy confirmed the high efficiency of TmC-GR-PY(+) -Chol in delivering the drug to the cells, compared to the suspensions devoid of GR. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial

    DEFF Research Database (Denmark)

    Metzger Filho, Otto; Giobbie-Hurder, Anita; Mallon, Elizabeth

    2015-01-01

    assigned onto the Breast International Group (BIG) 1-98 trial and who had centrally reviewed pathology data were included (N = 2,923). HER2-negative IDC and ILC were additionally classified as hormone receptor-positive with high (luminal B [LB] -like) or low (luminal A [LA] -like) proliferative activity......PURPOSE: To evaluate the relative effectiveness of letrozole compared with tamoxifen for patients with invasive ductal or lobular carcinoma. PATIENTS AND METHODS: Patients diagnosed with early-stage invasive ductal carcinoma (IDC) or classic invasive lobular carcinoma (ILC) who were randomly...

  8. Antiproliferation and apoptosis induced by tamoxifen in human bile duct carcinoma QBC939 cells via upregulated p53 expression

    International Nuclear Information System (INIS)

    Han, Peng; Kang, Jin-He; Li, Hua-Liang; Hu, Su-Xian; Lian, Hui-Hui; Qiu, Ping-Ping; Zhang, Jian; Li, Wen-Gang; Chen, Qing-Xi

    2009-01-01

    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.

  9. 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.

  10. 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 [First Hospital Attached to Fujian Medical University, Xiamen 361004 (China); Chen, Qing-Xi [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.

  11. Potent inhibition of rhabdoid tumor cells by combination of flavopiridol and 4OH-tamoxifen

    International Nuclear Information System (INIS)

    Cimica, Velasco; Smith, Melissa E; Zhang, Zhikai; Mathur, Deepti; Mani, Sridhar; Kalpana, Ganjam V

    2010-01-01

    Rhabdoid Tumors (RTs) are highly aggressive pediatric malignancies with poor prognosis. There are currently no standard or effective treatments for RTs in part because treatments are not designed to specifically target these tumors. Our previous studies indicated that targeting the cyclin/cdk pathway is a novel therapeutic strategy for RTs and that a pan-cdk inhibitor, flavopiridol, inhibits RT growth. Since the toxicities and narrow window of activity associated with flavopiridol may limit its clinical use, we tested the effect of combining flavopiridol with 4-hydroxy-Tamoxifen (4OH-Tam) in order to reduce the concentration of flavopiridol needed for inhibition of RTs. The effects of flavopiridol, 4OH-Tam, and their combination on RT cell cycle regulation and apoptosis were assessed by: i) cell survival assays, ii) FACS analysis, iii) caspase activity assays, and iv) immunoblot analysis. Furthermore, the role of p53 in flavopiridol- and 4OH-Tam-mediated induction of cell cycle arrest and apoptosis was characterized using RNA interference (siRNA) analysis. The effect of p53 on flavopiridol-mediated induction of caspases 2, 3, 8 and 9 was also determined. We found that the combination of flavopiridol and 4OH-Tam potently inhibited the growth of RT cells. Low nanomolar concentrations of flavopiridol induced G 2 arrest, which was correlated to down-modulation of cyclin B1 and up-regulation of p53. Addition of 4OH-Tam did not affect flavopiridol-mediated G 2 arrest, but enhanced caspase 3,7-mediated apoptosis induced by the drug. Abrogation of p53 by siRNA abolished flavopiridol-induced G 2 arrest, but enhanced flavopiridol- (but not 4OH-Tam-) mediated apoptosis, by enhancing caspase 2 and 3 activities. Combining flavopiridol with 4OH-Tam potently inhibited the growth of RT cells by increasing the ability of either drug alone to induce caspases 2 and 3 thereby causing apoptosis. The potency of flavopiridol was enhanced by abrogation of p53. Our results warrant further

  12. Potent inhibition of rhabdoid tumor cells by combination of flavopiridol and 4OH-tamoxifen

    Energy Technology Data Exchange (ETDEWEB)

    Cimica, Velasco; Smith, Melissa E; Zhang, Zhikai; Mathur, Deepti [Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461 (United States); Mani, Sridhar [Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461 (United States); Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461 (United States); Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461 (United States); Kalpana, Ganjam V [Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461 (United States); Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461 (United States)

    2010-11-19

    Rhabdoid Tumors (RTs) are highly aggressive pediatric malignancies with poor prognosis. There are currently no standard or effective treatments for RTs in part because treatments are not designed to specifically target these tumors. Our previous studies indicated that targeting the cyclin/cdk pathway is a novel therapeutic strategy for RTs and that a pan-cdk inhibitor, flavopiridol, inhibits RT growth. Since the toxicities and narrow window of activity associated with flavopiridol may limit its clinical use, we tested the effect of combining flavopiridol with 4-hydroxy-Tamoxifen (4OH-Tam) in order to reduce the concentration of flavopiridol needed for inhibition of RTs. The effects of flavopiridol, 4OH-Tam, and their combination on RT cell cycle regulation and apoptosis were assessed by: i) cell survival assays, ii) FACS analysis, iii) caspase activity assays, and iv) immunoblot analysis. Furthermore, the role of p53 in flavopiridol- and 4OH-Tam-mediated induction of cell cycle arrest and apoptosis was characterized using RNA interference (siRNA) analysis. The effect of p53 on flavopiridol-mediated induction of caspases 2, 3, 8 and 9 was also determined. We found that the combination of flavopiridol and 4OH-Tam potently inhibited the growth of RT cells. Low nanomolar concentrations of flavopiridol induced G{sub 2} arrest, which was correlated to down-modulation of cyclin B1 and up-regulation of p53. Addition of 4OH-Tam did not affect flavopiridol-mediated G{sub 2} arrest, but enhanced caspase 3,7-mediated apoptosis induced by the drug. Abrogation of p53 by siRNA abolished flavopiridol-induced G{sub 2} arrest, but enhanced flavopiridol- (but not 4OH-Tam-) mediated apoptosis, by enhancing caspase 2 and 3 activities. Combining flavopiridol with 4OH-Tam potently inhibited the growth of RT cells by increasing the ability of either drug alone to induce caspases 2 and 3 thereby causing apoptosis. The potency of flavopiridol was enhanced by abrogation of p53. Our results

  13. Potent inhibition of rhabdoid tumor cells by combination of flavopiridol and 4OH-tamoxifen

    Directory of Open Access Journals (Sweden)

    Mani Sridhar

    2010-11-01

    Full Text Available Abstract Background Rhabdoid Tumors (RTs are highly aggressive pediatric malignancies with poor prognosis. There are currently no standard or effective treatments for RTs in part because treatments are not designed to specifically target these tumors. Our previous studies indicated that targeting the cyclin/cdk pathway is a novel therapeutic strategy for RTs and that a pan-cdk inhibitor, flavopiridol, inhibits RT growth. Since the toxicities and narrow window of activity associated with flavopiridol may limit its clinical use, we tested the effect of combining flavopiridol with 4-hydroxy-Tamoxifen (4OH-Tam in order to reduce the concentration of flavopiridol needed for inhibition of RTs. Methods The effects of flavopiridol, 4OH-Tam, and their combination on RT cell cycle regulation and apoptosis were assessed by: i cell survival assays, ii FACS analysis, iii caspase activity assays, and iv immunoblot analysis. Furthermore, the role of p53 in flavopiridol- and 4OH-Tam-mediated induction of cell cycle arrest and apoptosis was characterized using RNA interference (siRNA analysis. The effect of p53 on flavopiridol-mediated induction of caspases 2, 3, 8 and 9 was also determined. Results We found that the combination of flavopiridol and 4OH-Tam potently inhibited the growth of RT cells. Low nanomolar concentrations of flavopiridol induced G2 arrest, which was correlated to down-modulation of cyclin B1 and up-regulation of p53. Addition of 4OH-Tam did not affect flavopiridol-mediated G2 arrest, but enhanced caspase 3,7-mediated apoptosis induced by the drug. Abrogation of p53 by siRNA abolished flavopiridol-induced G2 arrest, but enhanced flavopiridol- (but not 4OH-Tam- mediated apoptosis, by enhancing caspase 2 and 3 activities. Conclusions Combining flavopiridol with 4OH-Tam potently inhibited the growth of RT cells by increasing the ability of either drug alone to induce caspases 2 and 3 thereby causing apoptosis. The potency of flavopiridol was

  14. Tamoxifen induces the expression of maspin through estrogen receptor-alpha.

    Science.gov (United States)

    Liu, Zesheng; Shi, Heidi Y; Nawaz, Zafar; Zhang, Ming

    2004-06-08

    Maspin (mammary serine protease inhibitor) is a tumor suppressor gene that plays an important role in inhibiting tumor growth, invasion and metastasis. Maspin expression is down regulated at transcription level in primary and metastatic breast tumor cells. Previous studies on hormonal regulation of maspin prompt us to test whether an estrogen antagonist tamoxifen (TAM) can exert its anti-tumor function by up regulating maspin gene expression. For this purpose, we first tested whether maspin promoter could be activated in normal and several breast tumor cells. We then carried out a series of promoter analysis in which estrogen receptors and TAM were reconstituted in an in vitro cell culture system. Here we report our new finding that tumor suppresser gene maspin is one of the TAM target genes. TAM induces a maspin/luciferase reporter in cell culture and this induction requires the presence of (estrogen receptor alpha) ERalpha but not estrogen receptor-beta (ERbeta). Maspin promoter deletion and mutation analysis showed that the cis element(s) within a region between -90and+87 bp but not the HRE site (-272 bp) was involved in TAM induction of maspin expression. TAM bound ERalpha may directly control maspin gene expression through the interaction with cofactor (s). Analysis using several ERalpha mutants showed that the N-terminal A/B motif (AF-1) was critical for maspin basal level transcription activation. An ERalpha mutant with point mutations at DNA binding domain abolished estrogen induction of an ERE-luciferase reporter but was still active in activating maspin promoter by TAM. LBD-AF2 domain was required for ERalpha-dependent TAM induction. Deletion of LBD-AF2 or a point mutation in the ERalpha LBD-AF2 region (LBDmtL539A) completely abolished the activation of maspin promoter, suggesting that TAM induction of maspin involves the recruitment of cofactor(s) by ERalpha to the maspin promoter region. This finding indicates that one of the pathways for cancer

  15. Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials.

    Science.gov (United States)

    Cuzick, Jack; Brentnall, Adam R; Segal, Corrinne; Byers, Helen; Reuter, Caroline; Detre, Simone; Lopez-Knowles, Elena; Sestak, Ivana; Howell, Anthony; Powles, Trevor J; Newman, William G; Dowsett, Mitchell

    2017-03-01

    Purpose At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not been directly assessed previously. Materials and Methods A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were matched to 636 controls by age, trial, follow-up time, and treatment arm. Genotyping was done using the OncoArray. Conditional logistic regression and matched concordance indices (mC) were used to measure the performance of SNP88 alone and with other breast cancer risk factors assessed using the Tyrer-Cuzick (TC) model. Results SNP88 was predictive of breast cancer risk overall (interquartile range odds ratio [IQ-OR], 1.37; 95% CI, 1.14 to 1.66; mC, 0.55), but mainly for estrogen receptor-positive disease (IQ-OR, 1.44; 95% CI, 1.16 to 1.79; P for heterogeneity = .10) versus estrogen receptor-negative disease. However, the observed risk of SNP88 was only 46% (95% CI, 19% to 74%) of expected. No significant interaction was observed with treatment arm (placebo IQ-OR, 1.46; 95% CI, 1.13 to 1.87; tamoxifen IQ-OR, 1.25; 95% CI, 0.96 to 1.64; P for heterogeneity = .5). The predictive power was similar to the TC model (IQ-OR, 1.45; 95% CI, 1.21 to 1.73; mC, 0.55), but SNP88 was independent of TC (Spearman rank-order correlation, 0.012; P = .7), and when combined multiplicatively, a substantial improvement was seen (IQ-OR, 1.64; 95% CI, 1.36 to 1.97; mC, 0.60). Conclusion A polygenic risk score may be used to refine risk from the TC or similar models in women who are at an elevated risk of breast cancer and considering preventive therapy. Recalibration may be necessary for accurate risk assessment.

  16. Generation of brain tumours in mice by Cre-mediated recombination of neural progenitors in situ with the tamoxifen metabolite endoxifen.

    Science.gov (United States)

    Benedykcinska, Anna; Ferreira, Andreia; Lau, Joanne; Broni, Jessica; Richard-Loendt, Angela; Henriquez, Nico V; Brandner, Sebastian

    2016-02-01

    Targeted cell- or region-specific gene recombination is widely used in the functional analysis of genes implicated in development and disease. In the brain, targeted gene recombination has become a mainstream approach to study neurodegeneration or tumorigenesis. The use of the Cre-loxP system to study tumorigenesis in the adult central nervous system (CNS) can be limited, when the promoter (such as GFAP) is also transiently expressed during development, which can result in the recombination of progenies of different lineages. Engineering of transgenic mice expressing Cre recombinase fused to a mutant of the human oestrogen receptor (ER) allows the circumvention of transient developmental Cre expression by inducing recombination in the adult organism. The recombination of loxP sequences occurs only in the presence of tamoxifen. Systemic administration of tamoxifen can, however, exhibit toxicity and might also recombine unwanted cell populations if the promoter driving Cre expression is active at the time of tamoxifen administration. Here, we report that a single site-specific injection of an active derivative of tamoxifen successfully activates Cre recombinase and selectively recombines tumour suppressor genes in neural progenitor cells of the subventricular zone in mice, and we demonstrate its application in a model for the generation of intrinsic brain tumours. © 2016. Published by The Company of Biologists Ltd.

  17. 17 beta-estradiol and tamoxifen upregulate estrogen receptor beta expression and control podocyte signaling pathways in a model of type 2 diabetes.

    Science.gov (United States)

    Catanuto, Paola; Doublier, Sophie; Lupia, Enrico; Fornoni, Alessia; Berho, Mariana; Karl, Michael; Striker, Gary E; Xia, Xiaomei; Elliot, Sharon

    2009-06-01

    Diabetic nephropathy remains one of the most important causes of end-stage renal disease. This is particularly true for women from racial/ethnic minorities. Although administration of 17beta-estradiol to diabetic animals has been shown to reduce extracellular matrix deposition in glomeruli and mesangial cells, effects on podocytes are lacking. Given that podocyte injury has been implicated as a factor leading to the progression of proteinuria and diabetic nephropathy, we treated db/db mice, a model of type 2 diabetic glomerulosclerosis, with 17beta-estradiol or tamoxifen to determine whether these treatments reduce podocyte injury and decrease glomerulosclerosis. We found that albumin excretion, glomerular volume, and extracellular matrix accumulation were decreased in these mice compared to placebo treatment. Podocytes isolated from all treatment groups were immortalized and these cell lines were found to express the podocyte markers WT-1, nephrin, and the TRPC6 cation channel. Tamoxifen and 17beta-estradiol treatment decreased podocyte transforming growth factor-beta mRNA expression but increased that of the estrogen receptor subtype beta protein. 17beta-estradiol, but not tamoxifen, treatment decreased extracellular-regulated kinase phosphorylation. These data, combined with improved albumin excretion, reduced glomerular size, and decreased matrix accumulation, suggest that both 17beta-estradiol and tamoxifen may protect podocytes against injury and therefore ameliorate diabetic nephropathy.

  18. Generation of brain tumours in mice by Cre-mediated recombination of neural progenitors in situ with the tamoxifen metabolite endoxifen

    Directory of Open Access Journals (Sweden)

    Anna Benedykcinska

    2016-02-01

    Full Text Available Targeted cell- or region-specific gene recombination is widely used in the functional analysis of genes implicated in development and disease. In the brain, targeted gene recombination has become a mainstream approach to study neurodegeneration or tumorigenesis. The use of the Cre-loxP system to study tumorigenesis in the adult central nervous system (CNS can be limited, when the promoter (such as GFAP is also transiently expressed during development, which can result in the recombination of progenies of different lineages. Engineering of transgenic mice expressing Cre recombinase fused to a mutant of the human oestrogen receptor (ER allows the circumvention of transient developmental Cre expression by inducing recombination in the adult organism. The recombination of loxP sequences occurs only in the presence of tamoxifen. Systemic administration of tamoxifen can, however, exhibit toxicity and might also recombine unwanted cell populations if the promoter driving Cre expression is active at the time of tamoxifen administration. Here, we report that a single site-specific injection of an active derivative of tamoxifen successfully activates Cre recombinase and selectively recombines tumour suppressor genes in neural progenitor cells of the subventricular zone in mice, and we demonstrate its application in a model for the generation of intrinsic brain tumours.

  19. 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...

  20. Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1.

    Science.gov (United States)

    Zhu, Yinghua; Liu, Yujie; Zhang, Chao; Chu, Junjun; Wu, Yanqing; Li, Yudong; Liu, Jieqiong; Li, Qian; Li, Shunying; Shi, Qianfeng; Jin, Liang; Zhao, Jianli; Yin, Dong; Efroni, Sol; Su, Fengxi; Yao, Herui; Song, Erwei; Liu, Qiang

    2018-04-23

    Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.

  1. 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.

  2. 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

    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

  3. 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

    2014-05-02

    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. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. 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

  5. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    International Nuclear Information System (INIS)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori; Tsuneyama, Koichi; Endo, Shinya; Tsukui, Tohru; Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-01-01

    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

  6. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial

    DEFF Research Database (Denmark)

    Regan, M.M.; Lykkesfeldt, A.E.; Dell'Orto, P.

    2008-01-01

    Background The Breast International Group (BIG) 1-98 trial (a randomised double-blind phase III trial) has shown that letrozole significantly improves disease-free survival (DFS) compared with tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. Our aim was to establish...... whether the benefit of letrozole versus tamoxifen differs according to the ERBB2 status of tumours. Methods The BIG 1-98 trial consists of four treatment groups that compare 5 years of monotherapy with letrozole or tamoxifen, and sequential administration of one drug for 2 years followed by the other drug...... for 3 years. Our study includes data from the 4922 patients randomly assigned to the two monotherapy treatment groups (letrozole or tamoxifen for 5 years; 51 months median follow-up [range

  7. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease.

    Science.gov (United States)

    Wardell, Suzanne E; Nelson, Erik R; Chao, Christina A; McDonnell, Donald P

    2013-05-01

    There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-α pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-α conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. The high-affinity SERM bazedoxifene was shown to function as a pure ER-α antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-α that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer. ©2013 AACR.

  8. Lumpectomy Plus Tamoxifen or Anastrozole With or Without Whole Breast Irradiation in Women With Favorable Early Breast Cancer

    International Nuclear Information System (INIS)

    Poetter, Richard; Gnant, Michael; Kwasny, Werner; Tausch, Christoph; Handl-Zeller, Leonore; Pakisch, Brigitte; Taucher, Susanne; Hammer, Josef; Luschin-Ebengreuth, Gero; Schmid, Marianne; Sedlmayer, Felix; Stierer, Michael; Reiner, Georg; Kapp, Karin; Hofbauer, Friedrich; Rottenfusser, Andrea; Poestlberger, Sabine; Haider, Karin; Draxler, Wolfgang; Jakesz, Raimund

    2007-01-01

    Purpose: In women with favorable early breast cancer treated by lumpectomy plus tamoxifen or anastrazole, it remains unclear whether whole breast radiotherapy is beneficial. Methods and Material: Between January 1996 and June 2004, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) randomly assigned 869 women to receive breast radiotherapy ± boost (n 414) or not (n = 417) after breast-conserving surgery (ABCSG Study 8A). Favorable early breast cancer was specified as tumor size <3 cm, Grading 1 or 2, negative lymph nodes, positive estrogen and/or progesterone receptor status, and manageable by breast-conserving surgery. Breast radiotherapy was performed after lumpectomy with 2 tangential opposed breast fields with mean 50 Gy, plus boost in 71% of patients with mean 10 Gy, in a median of 6 weeks. The primary endpoint was local relapse-free survival; further endpoints were contralateral breast cancer, distant metastases, and disease-free and overall survival. The median follow-up was 53.8 months. Results: The mean age was 66 years. Overall, there were 21 local relapses, with 2 relapses in the radiotherapy group (5-y rate 0.4%) vs. 19 in the no-radiotherapy group (5.1%), respectively (p = 0.0001, hazard ratio 10.2). Overall relapses occurred in 30 patients, with 7 events in the radiotherapy group (5-y rate 2.1%) vs. 23 events in the no-radiotherapy group (6.1%) (p = 0.002, hazard ratio 3.5). No significant differences were found for distant metastases and overall survival. Conclusion: Breast radiotherapy ± boost in women with favorable early breast cancer after lumpectomy combined with tamoxifen/anastrazole leads to a significant reduction in local and overall relapse

  9. 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.

  10. 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.

  11. Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium

    Energy Technology Data Exchange (ETDEWEB)

    Bugel, Sean M., E-mail: Sean.Bugel@oregonstate.edu; Wehmas, Leah C., E-mail: wehmasl@onid.oregonstate.edu; La Du, Jane K., E-mail: Jane.LaDu@oregonstate.edu; Tanguay, Robert L., E-mail: Robert.Tanguay@oregonstate.edu

    2016-04-01

    The zebrafish is a powerful alternative model used to link phenotypes with molecular effects to discover drug mode of action. Using a zebrafish embryo-larval toxicity bioassay, we evaluated the effects of tamoxifen — a widely used anti-estrogen chemotherapeutic. Zebrafish exposed to ≥ 10 μM tamoxifen exhibited a unique necrotic caudal fin phenotype that was rapidly induced regardless of developmental life-stage when treatment was applied. To define tamoxifen's bioactivity resulting in this phenotype, targeted gene expression was used to evaluate 100 transcripts involved in tissue remodeling, calcium signaling, cell cycle and cell death, growth factors, angiogenesis and hypoxia. The most robustly misregulated transcripts in the tail were matrix metalloproteinases mmp9 and mmp13a, induced 127 and 1145 fold, respectively. Expression of c-fos, c-jun, and ap1s1 were also moderately elevated (3–7 fold), consistent with AP-1 activity — a transcription factor that regulates MMP expression. Immunohistochemistry confirmed high levels of induction for MMP13a in affected caudal fin skin epithelial tissue. The necrotic caudal fin phenotype was significantly attenuated or prevented by three functionally unique MMP inhibitors: EDTA (metal chelator), GM 6001 (broad MMP inhibitor), and SR 11302 (AP-1 transcription factor inhibitor), suggesting MMP-dependence. SR 11302 also inhibited induction of mmp9, mmp13a, and a putative MMP target, igfbp1a. Overall, our studies suggest that tamoxifen's effect is the result of perturbation of the MMP system in the skin leading to ectopic expression, cytotoxicity, and the necrotic caudal fin phenotype. These studies help advance our understanding of tamoxifen's non-classical mode of action and implicate a possible role for MMPs in tissues such as skin. - Highlights: • Tamoxifen rapidly induced a unique necrotic caudal fin phenotype in zebrafish. • Apoptosis co-localized temporally and spatially in the necrotic tail.

  12. 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...

  13. Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen.

    Science.gov (United States)

    Rolla, R; Vidali, M; Meola, S; Pollarolo, P; Fanello, M R; Nicolotti, C; Saggia, C; Forti, L; Agostino, F D; Rossi, V; Borra, G; Stratica, F; Alabiso, O; Bellomo, G

    2012-01-01

    The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects. 61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology. A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005). Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.

  14. [Effect of Evn-50 on cell growth and apoptosis in tamoxifen-resistance human breast cancer cell line MCF-7/TAM-R].

    Science.gov (United States)

    Hu, Hui-yong; Zhou, Jun; Wan, Fang; Dong, Li-feng; Zhang, Feng; Wang, Yi-ke; Chen, Fang-fang; Chen, Yi-ding

    2012-09-01

    To investigate the effect of Evn-50 extracted from Vitex negundo on human breast cancer cell line MCF-7 and MCF-7/TAM-R cells in vitro. MCF-7 and tamoxifen-resistant MCF-7/TAM-R cells were treated with Evn-50,tamoxifen or combination of Evn-50 and tamoxifen. Cell proliferation inhibition rates were determined by MTT assay. The apoptosis rate and the change of cell cycle were detected by PI staining flow cytometry. Protein expression of phospho-MAPK 44/42 (Thr202/Tyr204),MAPK P44/42, phospho-AKT (Ser473) and AKT were detected with Western blotting. The viability of MCF-7 cells was decreased in combination group [(28.65 ±11.43)%] and Evn-50 group [(53.02 ±15.14)%] compared with TAM group (PTAM-R in combination group [(42.11 ±14.30)%] was significantly lower than that in TAM group [(92.18 ±13.16)%] (PTAM-R cells,the expression of phosphorylation of AKT and MAPK44/42 protein was not changed in Evn-50 or TAM alone group,but significantly inhibited in the combination group at 72 h. Evn-50 can inhibit cell growth and induce apoptosis in MCF-7 and MCF-7/TAM-R cells,it can reverse tamoxifen-resistance of MCF-7/TAM-R cells.The mechanisms may be related to the down-regulation of phosphorylated ERK1/2 in MAPK signal pathway and phosphorylated AKT in AKT signal pathway.

  15. The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen improve ANP levels and decrease nuclear translocation of NF-kB in estrogen-deficient rats.

    Science.gov (United States)

    Lamas, Aline Z; Nascimento, Andrews M; Medeiros, Ana Raquel S; Caliman, Izabela F; Dalpiaz, Polyana L M; Firmes, Luciana B; Sousa, Glauciene J; Oliveira, Phablo Wendell C; Andrade, Tadeu U; Reis, Adelina M; Gouvea, Sônia A; Bissoli, Nazaré S

    2017-08-01

    The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are used for the treatment of osteoporosis and cancer, respectively, in women. The impairment of both the Atrial Natriuretic Peptide (ANP) cell signaling system and the translocation of nuclear factor-kappa B (NF-kB) to the cell nucleus are associated with detrimental cardiovascular effects and inflammation. The effects of SERMs on these parameters in the cardiac tissue of estrogen-deficient rats has not been reported. We investigated the effects of raloxifene and tamoxifen on ANP signaling, p65 NF-kB nuclear translocation, cardiac histology and contractility. Female rats were divided into five groups: control (SHAM), ovariectomized (OVX), OVX-treated 17-β-estradiol (E), OVX-treated raloxifene (RLX) and OVX-treated tamoxifen (TAM). The treatments started 21days after ovariectomy and continued for 14days. Ovariectomy reduced ANP mRNA in the left atrium (LA), decreased the content of ANP protein in the LA and in plasma, and increased the level of p65 NF-kB nuclear translocation in the left ventricle. Both 17-β-estradiol and SERMs were able to reverse these alterations, which were induced by the estrogen deficient state. The hemodynamic and cardiac structural parameters analyzed in the present work were not modified by the interventions. Our study demonstrates, for the first time, the additional benefits of raloxifene and tamoxifen in an estrogen-deficient state. These include the normalization of plasmatic and cardiac ANP levels and cardiac p65 NF-kB translocation. Therefore, these treatments promote cardiovascular protection and may contribute to the prevention of cardiac dysfunction observed long-term in postmenopausal women. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

  16. Endocrine therapy and urogenital outcomes among women with a breast cancer diagnosis

    Science.gov (United States)

    Doll, Kemi M.; Bensen, Jeannette T.; Hendrix, Laura; Anders, Carey K.; Wu, Jennifer M.; Nichols, Hazel B.

    2018-01-01

    Purpose Endocrine therapy for breast cancer can exacerbate menopausal symptoms. The association between endocrine therapy and common pelvic floor disorders including urinary incontinence has rarely been evaluated. We examined urogenital and sexual side effects among women with a breast cancer diagnosis, comparing endocrine therapy users to nonusers. Methods Urogenital and sexual symptoms were self-reported during the enrollment interview within the University of North Carolina Cancer Survivorship Cohort. Tumor characteristics and endocrine therapy use were collected from medical and prescription records. We calculated multivariable prevalence ratios (PR) and 95 % confidence intervals (CI) for the association of endocrine therapy (versus no endocrine therapy) and urinary incontinence, overall and by therapy type (tamoxifen or aromatase inhibitors). PROMIS Sexual Function and Satisfaction domain scores were compared across endocrine therapy groups. Results Among the 548 women with a breast cancer diagnosis, 49 % received endocrine therapy. Overall, 18 % of women reported urinary incontinence symptoms. We observed no association between urinary incontinence and endocrine therapy use overall (PR = 0.97; 95 % CI 0.67, 1.43), tamoxifen (PR = 1.20; 95 % CI 0.74, 1.96), or aromatase inhibitors (PR = 0.89; 95 % CI 0.55, 1.42), compared to no use. Approximately 55 % of women were sexually active. Sexual function scores did not vary according to endocrine therapy use, although urinary incontinence was associated with lower satisfaction scores (p = 0.05). Conclusions Our findings demonstrate a high prevalence of urinary incontinence after breast cancer diagnosis similar to the overall prevalence in older U.S. women, and this did not vary strongly according to use of endocrine therapy. PMID:27680018

  17. Different patterns in the risk of newly developed fatty liver and lipid changes with tamoxifen versus aromatase inhibitors in postmenopausal women with early breast cancer: A propensity score-matched cohort study.

    Science.gov (United States)

    Hong, Namki; Yoon, Han Gyul; Seo, Da Hea; Park, Seho; Kim, Seung Il; Sohn, Joo Hyuk; Rhee, Yumie

    2017-09-01

    Management of metabolic complications of long-term adjuvant endocrine therapy in early breast cancer remained an unmet need. We aimed to compare the effects of tamoxifen (TMX) and aromatase inhibitors (AIs) on the risk of fatty liver in conjunction with longitudinal changes in the serum lipid parameters. Among 1203 subjects who were taking adjuvant TMX or AI (anastrozole or letrozole) without fatty liver at baseline, those taking TMX or AI were 1:1 matched on the propensity score. The primary outcome was newly developed fatty liver detected on annual liver ultrasonography. Among 328 matched subjects (mean age 53.5 years, body mass index 22.9 kg/m 2 ), 62 cases of fatty liver in the TMX group and 41 cases in the AI group were detected in a total of 987.4 person-years. The incidence rate of fatty liver was higher in the TMX group than in the AI group (128.7 versus 81.1 per 1000 person-years, P = 0.021), particularly within the first 2 years of therapy. TMX was associated with an increased 5-year risk of newly developed fatty liver (adjusted hazard ratio 1.61, P = 0.030) compared with AI independent of obesity and cholesterol level. Subjects who developed fatty liver had higher triglycerides (TGs) and lower high-density lipoprotein cholesterol (HDL-C) level at baseline than those without, which was sustained during follow-up despite the serum cholesterol-lowering effect of TMX. TMX independently increased the 5-year risk of newly developed fatty liver compared with AI in postmenopausal women with early breast cancer. Our findings suggest the need for considering the risk of fatty liver as a different adverse event profile between AI and TMX, particularly in patients with obesity, high TGs and low HDL-C. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Tamoxifen and Aromatase Inhibitors: Cognitive Function in Occupationally Active Breast Cancer Survivors

    Science.gov (United States)

    2010-05-04

    assessments of cognitive function and sedation in patients with cancer pain admitted to a palliative care unit. Palliative Medicine, 16 (6), 513-9. 71...interventions. Palliative & Supportive Care, 5(3), 273-280. 72 Noblett, K.L., & Swain, R.A. (2003). Pretraining enhances recovery from visuospatial...Self-reported cognitive problems in women receiving adjuvant endocrine therapy for breast cancer. Eurpoean Journal of Oncology Nursing , 11(1), 6

  19. Targeted Therapy for Breast Cancer Prevention

    Science.gov (United States)

    den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

    2013-01-01

    With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

  20. A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas.

    Science.gov (United States)

    Li, Yan; He, Hai; Jia, Xinru; Lu, Wan-Liang; Lou, Jinning; Wei, Yen

    2012-05-01

    A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG(1000) and PEG(2000) chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2011-10-01

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

  2. Combined effects of goserelin and tamoxifen on estradiol level, breast density, and endometrial thickness in premenopausal and perimenopausal women with early-stage hormone receptor-positive breast cancer: a randomised controlled clinical trial.

    Science.gov (United States)

    Yang, H; Zong, X; Yu, Y; Shao, G; Zhang, L; Qian, C; Bian, Y; Xu, X; Sun, W; Meng, X; Ding, X; Chen, D; Zou, D; Xie, S; Zheng, Y; Zhang, J; He, X; Sun, C; Yu, X; Ni, J

    2013-08-06

    This study is to investigate the effects of geserelin+tamoxifen (TAM) on estradiol level, breast density (BD), endometrial thickness (ET), and blood lipids in premenopausal and perimenopausal women with hormone receptor-positive early-stage breast cancer. This study recruited 110 premenopausal and perimenopausal patients with hormone receptor-positive early-stage breast cancer between 22 June 2008 and 31 December 2009 and randomly assigned them to receive either goserelin plus TAM or TAM alone for 1.5 years. Blood levels of sex hormones and lipids and ET were determined at 0, 3, 6, 12, and 18 months. Contralateral BD was also measured at 0, 12, and 18 months. Five participants dropped out of the goserelin plus TAM group, and two participants dropped out of the TAM-alone group before initiation of endocrine therapy. The rest of patients received scheduled treatment and 3 years of median follow-up. No serious adverse effects were observed, and only two local recurrences have been observed in these patients. Estradiol level and BD were lower in the goserelin plus TAM group than in the TAM-alone group (Pwomen in the TAM-alone group exhibited endometrial thickening over the course of the study. Furthermore, no significant differences in blood lipid levels were reported between the two groups. The data from the current study demonstrated that the addition of goserelin to TAM results in downregulation of estradiol level, followed by significant reduction in BD and ET in premenopausal and perimenopausal women with hormone receptor-positive breast cancer, which may eventually lead to better outcome in these patients.

  3. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial.

    Science.gov (United States)

    Cuzick, Jack; Sestak, Ivana; Cawthorn, Simon; Hamed, Hisham; Holli, Kaija; Howell, Anthony; Forbes, John F

    2015-01-01

    Four previously published randomised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up. We report the long-term follow-up of the IBIS-I trial, in which the participants and investigators remain largely masked to treatment allocation. In the IBIS-I randomised controlled trial, premenopausal and postmenopausal women 35-70 years of age deemed to be at an increased risk of developing breast cancer were randomly assigned (1:1) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years. Patients were randomly assigned to the two treatment groups by telephone or fax according to a block randomisation schedule (permuted block sizes of six or ten). Patients and investigators were masked to treatment assignment by use of central randomisation and coded drug supply. The primary endpoint was the occurrence of breast cancer (invasive breast cancer and ductal carcinoma in situ), analysed by intention to treat. Cox proportional hazard models were used to assess breast cancer occurrence and mortality. The trial is closed to recruitment and active treatment is completed, but long-term follow-up is ongoing. This trial is registered with controlledtrials.com, number ISRCTN91879928. Between April 14, 1992, and March 30, 2001, 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were randomly allocated to the two treatment groups: 3579 to tamoxifen and 3575 to placebo. After a median follow up of 16.0 years (IQR 14.1-17.6), 601 breast cancers have been reported (251 [7.0%] in 3579 patients in the tamoxifen group vs 350 [9.8%] in 3575 women in the placebo group; hazard ratio [HR] 0.71 [95% CI 0.60-0.83], pbreast cancer was similar between years 0-10 (226 [6.3%] in 3575 women in the placebo group vs 163 [4.6%] in 3579 women in the tamoxifen group; hazard ratio [HR] 0.72 [95% CI 0

  4. Tamoxifen in combination with temozolomide induce a synergistic inhibition of PKC-pan in GBM cell lines.

    Science.gov (United States)

    Balça-Silva, Joana; Matias, Diana; do Carmo, Anália; Girão, Henrique; Moura-Neto, Vivaldo; Sarmento-Ribeiro, Ana Bela; Lopes, Maria Celeste

    2015-04-01

    Glioblastoma (GBM) is a highly proliferative, angiogenic grade IV astrocytoma that develops resistance to the alkylating agents used in chemotherapy, such as temozolomide (TMZ), which is considered the gold standard. The mean survival time for GBM patients is approximately 12 months, increasing to 14.6 months after TMZ treatment. The resistance of GBM to chemotherapy seems to be associated to genetic alterations and to the constitutive activation of several signaling pathways. Therefore, the combination of different drugs with different mechanisms of action may contribute to circumvent the chemoresistance of glioma cells. Here we describe the potential synergistic behavior of the therapeutic combination of tamoxifen (TMX), a known inhibitor of PKC, and TMZ in GBM. We used two GBM cell lines incubated in absence and presence of TMX and/or TMZ and measured cell viability, proliferation, apoptosis, cell cycle, migration ability, cytoskeletal organization and the phosphorylated amount of the p-PKC-pan. The combination of low doses of TMX with increasing doses of TMZ shows an increased antiproliferative and apoptotic effect compared to the effect with TMX alone. The combination of TMX and TMZ seems to potentiate the effect of each other. These alterations seem to be associated to a decrease in the phosphorylation status of PKC. We emphasize that TMX is an inhibitor of the p-PKC-pan and that these combination is more effective in the reduction of proliferation and in the increase of apoptosis than each drug alone, which presents a new therapeutic strategy in GBM treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Tamoxifen-elicited uterotrophy: cross-species and cross-ligand analysis of the gene expression program

    Directory of Open Access Journals (Sweden)

    Forgacs Agnes L

    2009-04-01

    Full Text Available Abstract Background Tamoxifen (TAM is a well characterized breast cancer drug and selective estrogen receptor modulator (SERM which also has been associated with a small increase in risk for uterine cancers. TAM's partial agonist activation of estrogen receptor has been characterized for specific gene promoters but not at the genomic level in vivo.Furthermore, reducing uncertainties associated with cross-species extrapolations of pharmaco- and toxicogenomic data remains a formidable challenge. Results A comparative ligand and species analysis approach was conducted to systematically assess the physiological, morphological and uterine gene expression alterations elicited across time by TAM and ethynylestradiol (EE in immature ovariectomized Sprague-Dawley rats and C57BL/6 mice. Differential gene expression was evaluated using custom cDNA microarrays, and the data was compared to identify conserved and divergent responses. 902 genes were differentially regulated in all four studies, 398 of which exhibit identical temporal expression patterns. Conclusion Comparative analysis of EE and TAM differentially expressed gene lists suggest TAM regulates no unique uterine genes that are conserved in the rat and mouse. This demonstrates that the partial agonist activities of TAM extend to molecular targets in regulating only a subset of EE-responsive genes. Ligand-conserved, species-divergent expression of carbonic anhydrase 2 was observed in the microarray data and confirmed by real time PCR. The identification of comparable temporal phenotypic responses linked to related gene expression profiles demonstrates that systematic comparative genomic assessments can elucidate important conserved and divergent mechanisms in rodent estrogen signalling during uterine proliferation.

  6. Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial.

    Science.gov (United States)

    Forbes, John F; Sestak, Ivana; Howell, Anthony; Bonanni, Bernardo; Bundred, Nigel; Levy, Christelle; von Minckwitz, Gunter; Eiermann, Wolfgang; Neven, Patrick; Stierer, Michael; Holcombe, Chris; Coleman, Robert E; Jones, Louise; Ellis, Ian; Cuzick, Jack

    2016-02-27

    Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6-8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64-1·23]). The non-inferiority of anastrozole was established (upper 95% CI

  7. The indication of endocrine therapy from the radiological view with mammary carcinoma

    International Nuclear Information System (INIS)

    Nadji-Esfahani, A.

    1982-01-01

    Important for the determining of the indication of endocrine treatment with mammary carcinoma is the pre-determination of receptors. A safe method for the choice of patients, for whom endocrine therapy would be appropriate, is not yet available. Patients who have no estrogen receptors, have as good as no chance, to be picked for endocrine therapy. The highest remission rates (around 60%) with endocrine therapy are attained when estrogen and progesterone receptors are both present, which, however, is usually only so in about one-third of the cases. Estrogen receptors are present in about 60 to 70% of the cases. With pre-menopausal women the following would be considered as endocrine procedures after switching off the ovaries: Androgens with abdominal, lung and pleura metastases; anti-estrogens (at best Tamoxifen) with abdominal and visceral metastasis; adrenalectomy with abdominal and bone metastases; and hypophyseal switching-off mostly with skeletal pains. In post-menopause estrogens are the first choice. In combination with progestogen they are indicated for abdominal and lung metastases and for carcinomatic pleura discharges. With abdominal and visceral metastasis Tamoxifen can be considered as first choice. The indications for hypophyseal switching-off, adrenalectomy and androgens are the same as for pre-menopausal women. (TRV) [de

  8. Effect of conjugated equine estrogens and tamoxifen administration on thyroid gland histomorphology of the rat Os efeitos dos estrogênios conjugados equinos e do tamoxifeno na histomorfologia da glândula tireóide de ratas

    Directory of Open Access Journals (Sweden)

    Luiz Felipe Bittencourt de Araujo

    2006-08-01

    Full Text Available OBJECTIVE: 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. METHODS: 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 µg/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. RESULTS: The thyroid follicular cell height was increased in animals treated with CEE (14.90 ± 0.20 µm, with TAM (14.90 ± 0.10 µm, and in rats with intact ovaries (15.10 ± 0.50 µm in comparison to that of the vehicle group (9.90 ± 0.20 µm (P OBJETIVO: Avaliar a ação dos estrogênios conjugados eqüinos e do tamoxifeno na histomorfologia da tireóide de ratas. MÉTODO: Estrogênios conjugados eqüinos são ministrados clinicamente como terapia estrogênica e contêm formulação complexa com muitos tipos de estrogênios que diminuem os sintomas da pós-menopausa. Trinta ratas adultas ooforectomizadas foram divididas aleatoriamente em três grupos: GI - veículo (propilenoglicol; GII - ECE 200 µg/Kg por dia; e GIII - TAM 1 mg/Kg por dia. Acrescentou-se ainda um grupo de 10 animais com os ovários intactos e tratados com veículo (GIV. Todos os animais foram tratados por gavagem durante 50 dias consecutivos, ao final foram coletadas amostras do sangue e a tireóide removida e processada para análise morfológica e imunohistoquímico para avaliar o PCNA. RESULTADOS: A maior altura das c

  9. My Lived Experiences Are More Important Than Your Probabilities: The Role of Individualized Risk Estimates for Decision Making about Participation in the Study of Tamoxifen and Raloxifene (STAR).

    Science.gov (United States)

    Holmberg, Christine; Waters, Erika A; Whitehouse, Katie; Daly, Mary; McCaskill-Stevens, Worta

    2015-11-01

    Decision-making experts emphasize that understanding and using probabilistic information are important for making informed decisions about medical treatments involving complex risk-benefit tradeoffs. Yet empirical research demonstrates that individuals may not use probabilities when making decisions. To explore decision making and the use of probabilities for decision making from the perspective of women who were risk-eligible to enroll in the Study of Tamoxifen and Raloxifene (STAR). We conducted narrative interviews with 20 women who agreed to participate in STAR and 20 women who declined. The project was based on a narrative approach. Analysis included the development of summaries of each narrative, and thematic analysis with developing a coding scheme inductively to code all transcripts to identify emerging themes. Interviewees explained and embedded their STAR decisions within experiences encountered throughout their lives. Such lived experiences included but were not limited to breast cancer family history, a personal history of breast biopsies, and experiences or assumptions about taking tamoxifen or medicines more generally. Women's explanations of their decisions about participating in a breast cancer chemoprevention trial were more complex than decision strategies that rely solely on a quantitative risk-benefit analysis of probabilities derived from populations In addition to precise risk information, clinicians and risk communicators should recognize the importance and legitimacy of lived experience in individual decision making. © The Author(s) 2015.

  10. Generation of knock-in mice that express nuclear enhanced green fluorescent protein and tamoxifen-inducible Cre recombinase in the notochord from Foxa2 and T loci.

    Science.gov (United States)

    Imuta, Yu; Kiyonari, Hiroshi; Jang, Chuan-Wei; Behringer, Richard R; Sasaki, Hiroshi

    2013-03-01

    The node and the notochord are important embryonic signaling centers that control embryonic pattern formation. Notochord progenitor cells present in the node and later in the posterior end of the notochord move anteriorly to generate the notochord. To understand the dynamics of cell movement during notochord development and the molecular mechanisms controlling this event, analyses of cell movements using time-lapse imaging and conditional manipulation of gene activities are required. To achieve this goal, we generated two knock-in mouse lines that simultaneously express nuclear enhanced green fluorescent protein (EGFP) and tamoxifen-inducible Cre, CreER(T2) , from two notochord gene loci, Foxa2 and T (Brachury). In Foxa2(nEGFP-CreERT2/+) and T(nEGFP-CreERT2/+) embryos, nuclei of the Foxa2 or T-expressing cells, which include the node, notochord, and endoderm (Foxa2) or wide range of posterior mesoderm (T), were labeled with EGFP at intensities that can be used for live imaging. Cre activity was also induced in cells expressing Foxa2 and T 1 day after tamoxifen administration. These mice are expected to be useful tools for analyzing the mechanisms of notochord development. Copyright © 2013 Wiley Periodicals, Inc.

  11. CYP2D6 gene polymorphisms in Brazilian patients with breast cancer treated with adjuvant tamoxifen and its association with disease recurrence

    Science.gov (United States)

    De Ameida Melo, Mariella; De Vasconcelos-Valença, Rodrigo José; Neto, Fidelis Manes; Borges, Rafael Soares; Costa-Silva, Danylo Rafhael; Da Conceição Barros-Oliveira, Maria; Borges, Umbelina Soares; Alencar, Airlane Pereira; Silva, Vladimir Costa; Da Silva, Benedito Borges

    2016-01-01

    At present, there is controversy regarding the efficacy of tamoxifen in breast cancer patients who are carriers of cytochrome P450 2D6 (CYP2D6) gene polymorphisms, in terms of recurrence and overall survival. Thus, the aim of the present study was to investigate the association of the CYP2D6 *4, *10 and *17 gene polymorphisms with breast cancer recurrence in a Brazilian population. The cohort comprised 40 receptor-positive breast cancer patients without recurrence and 40 with distant recurrence. A 3-ml sample of peripheral blood was collected from each patient to determine the presence of the *4, *10 and *17 single nucleotide polymorphisms of the CYP2D6 gene by quantitative polymerase chain reaction analysis. There was no statistically significant difference between the two groups regarding the polymorphism frequency (P=0.246). The results revealed that intermediate metabolizers occurred in 5% of patients without recurrence and in 15% of those with distant recurrence. Poor metabolizers occurred in only 1 patient (2.5%) per group, and there was no significant difference between the groups (P=0.789). The present study concluded that the CYP2D6 gene polymorphism in women with hormone-sensitive breast cancer treated with tamoxifen was not associated with disease recurrence. PMID:27882219

  12. Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling

    International Nuclear Information System (INIS)

    Kumar, B N Prashanth; Rajput, Shashi; Dey, Kaushik Kumar; Parekh, Aditya; Das, Subhasis; Mazumdar, Abhijit; Mandal, Mahitosh

    2013-01-01

    Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs. The effects of CXB combined with TAM were examined in two human breast cancer cell lines in culture, MCF7 and MDA-MB-231. Assays of proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, and receptor signaling were performed. Here, we elucidated how the combination of TAM and CXB at nontoxic doses exerts anti-angiogenic effects by specifically targeting VEGF/VEGFR2 autocrine signaling through ROS generation. At the molecular level, TAM-CXB suppresses VHL-mediated HIF-1α activation, responsible for expression of COX-2, MMP-2 and VEGF. Besides low VEGF levels, TAM-CXB also suppresses VEGFR2 expression, confirmed through quantifying secreted VEGF levels, luciferase and RT-PCR studies. Interestingly, we observed that TAM-CXB was effective in blocking VEGFR2 promoter induced expression and further 2 fold decrease in VEGF levels was observed in combination than TAM alone in both cell lines. Secondly, TAM-CXB regulated VEGFR2 inhibits Src expression, responsible for tumor progression and metastasis. FACS and in vivo enzymatic studies showed significant increase in the reactive oxygen species upon TAM-CXB treatment. Taken together, our experimental results indicate that this additive combination shows promising outcome in anti-metastatic and apoptotic studies. In a line, our preclinical studies evidenced that this additive

  13. An ER activity profile including ER, PR, Bcl-2 and IGF-IR may have potential as selection criterion for letrozole or tamoxifen treatment of patients with advanced breast cancer

    DEFF Research Database (Denmark)

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

    2009-01-01

    microarrays from formalin fixed paraffin embedded primary tumor material from a subgroup of patients (9.4%), who have participated in the international, randomized, phase III clinical trial PO25 comparing letrozole with tamoxifen in 907 patients with advanced breast cancer. The expression levels of ER...

  14. Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma

    International Nuclear Information System (INIS)

    Bièche, Ivan; Girault, Igor; Urbain, Estelle; Tozlu, Sengül; Lidereau, Rosette

    2004-01-01

    Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERα-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013). Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an

  15. Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation

    International Nuclear Information System (INIS)

    Moerkens, Marja; Zhang, Yinghui; Wester, Lynn; Water, Bob van de; Meerman, John HN

    2014-01-01

    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 involved. Here, we studied the estrogen and anti-estrogen sensitivity of human breast cancer MCF7 cells that have a moderate, retroviral-mediated, ectopic expression of epidermal growth factor receptor (MCF7-EGFR). Proliferation of MCF7-EGFR and parental cells was induced by 17β-estradiol (E2), epidermal growth factor (EGF) or a combination of these. Inhibition of proliferation under these conditions was investigated with 4-hydroxy-tamoxifen (TAM) or fulvestrant at 10 -12 to 10 -6 M. Cells were lysed at different time points to determine the phosphorylation status of EGFR, MAPK 1/3 , AKT and the expression of ERα. Knockdown of target genes was established using smartpool siRNAs. Transcriptomics analysis was done 6 hr after stimulation with growth factors using Affymetrix HG-U133 PM array plates. While proliferation of parental MCF7 cells could only be induced by E2, proliferation of MCF7-EGFR cells could be induced by either E2 or EGF. Treatment with TAM or fulvestrant did significantly inhibit proliferation of MCF7-EGFR cells stimulated with E2 alone. EGF treatment of E2/TAM treated cells led to a marked cell proliferation thereby overruling the anti-estrogen-mediated inhibition of cell proliferation. Under these conditions, TAM however did still inhibit ERα- mediated transcription. While siRNA-mediated knock-down of EGFR inhibited the EGF- driven proliferation under TAM/E2/EGF condition, knock down of ERα did not. The TAM resistant cell proliferation mediated by the conditional EGFR-signaling may be dependent on the PI3K/Akt pathway but not the MEK/MAPK pathway, since a MEK inhibitor (U0126), did not block the proliferation. Transcriptomic analysis under the various E2/TAM

  16. A randomized trial of tamoxifen with or without breast radiation in women over 50 years of age with T1/2 N0 disease

    International Nuclear Information System (INIS)

    Fyles, A.; Manchul, L.; McCready, D.; Merante, P.; Pintilie, M.; Trudeuau, M.; Olivotto, I.; Weir, L.

    2003-01-01

    To determine the effect of breast radiation (RT) on disease-free survival (DFS) and ipsilateral breast relapse (IBR) in women over 50 with T1 and T2 node negative breast cancer. Between December 1992 and June 2000, 769 women were randomized to RT and Tamoxifen (Tam) 20 mg daily for 5 years or Tam alone. Median age was 68 years, 639 patients had pT1 lesions and ER/PR were positive in 700 patients. Six hundred and thirty-four patients had pathologically negative nodes and 135 over age 65 were clinically node negative. Median follow-up was 5.6 years and patient and tumour characteristics were well balanced between the two arms. Overall, there were 54 relapses from breast cancer in the Tam arm and 27 in the Tam + RT arm. IBR at 5 years was 7.7% in the Tam arm compared to 0.6% in the Tam + RT group (p<0.0001). Significant factors for breast relapse and DFS at 5 years included tumour size (p=0.02 and 0.0001 respectively), hormone-receptor status (p=0.0008 and 0.0001), grade (p=0.001 and 0.003) and treatment arm (p=0.0001 and 0.004). Four-hundred and nineteen patients with low-risk features (T1, receptor-positive and grade 1/2) treated with Tam alone had a 5% risk of IBR at 5 years, increasing to 10% at 8 years. There was no difference in relapse at regional or distant sites, or in the contralateral breast. No difference was seen in the number of deaths due to breast cancer (13 and 11 for Tam + RT and Tam, respectively), nor in OS (93% at 5 years in both arms). Tamoxifen and breast RT results in a significantly lower rate of breast relapse than Tam alone in women over 50 with node-negative breast cancer. There does not appear to be a low-risk group who can be treated with Tamoxifen without breast radiation

  17. Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence

    DEFF Research Database (Denmark)

    Chirgwin, Jacquie H; Giobbie-Hurder, Anita; Coates, Alan S

    2016-01-01

    PURPOSE: To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial. METHODS: The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor......-positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards......). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age...

  18. Physico-chemical characterisation, cytotoxic activity, and biocompatibility studies of tamoxifen-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification method.

    Science.gov (United States)

    Lakkadwala, Sushant; Nguyen, Sanko; Lawrence, Joseph; Nauli, Surya M; Nesamony, Jerry

    2014-01-01

    Solid lipid nanoparticles (SLNs) can efficiently and efficaciously incorporate anti-cancer agents. To prepare and characterise tamoxifen (TAM)-loaded SLNs. Glyceryl monostearate, Tween-80, and trehalose were used in SLNs. SLNs were tested via dynamic light scattering (DLS), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Characterisation studies revealed SLNs of about 540 nm with a negative surface charge and confirmed the entrapment of TAM in the SLNs. The entrapment efficiency was estimated to be 60%. The in vitro drug release profile demonstrated a gradual increase followed by a release plateau for several days. A drug concentration-dependent increase in cytotoxic activity was observed when the SLNs were evaluated in cell cultures. Biocompatible and stable lyophilised SLNs were successfully prepared and found to possess properties that may be utilised in an anti-cancer drug delivery system.

  19. Effect of tamoxifen pre-treatment on the retention of tritiated oestradiol and 5. cap alpha. -dihydrotestosterone and on glucose metabolism in human breast carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Deshpande, N; Mitchell, I [Imperial Cancer Research Fund, London (UK). Labs.; Hughes, D

    1978-05-01

    The effect of pre-treatment with tamoxifen on glucose metabolism and retention of injected oestradiol-17B and 5..cap alpha..-dihydrotestosterone by human breast carcinomas were studied in patients undergoing mastectomy. The following effects were observed: the pretreatment reduced retention of oestradiol-17B whereas a small but statistically significant rise in 5..cap alpha..-dihydrotestosterone accumulation was observed. There was an increase in both phosphofructokinase (PFK) and glucose-6-phosphate dehydrogenase (G6PDH) activities in tumours from treated patients whereas ..cap alpha..-glycerolphosphate dehydrogenase (..cap alpha..-GPDH) activity was significantly reduced in the same tumours. The significance of these findings is discussed and it is argued that these changes in carbohydrate metabolism may not be due to the blocking of hormone receptors.

  20. Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma.

    Science.gov (United States)

    O'Day, S J; Gammon, G; Boasberg, P D; Martin, M A; Kristedja, T S; Guo, M; Stern, S; Edwards, S; Fournier, P; Weisberg, M; Cannon, M; Fawzy, N W; Johnson, T D; Essner, R; Foshag, L J; Morton, D L

    1999-09-01

    Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days. The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths. The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

  1. 25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1.

    Science.gov (United States)

    Amir, Eitan; Cecchini, Reena S; Ganz, Patricia A; Costantino, Joseph P; Beddows, Samantha; Hood, Nicola; Goodwin, Pamela J

    2012-06-01

    Observational studies suggest that host factors are associated with breast cancer risk. The influence of obesity, vitamin-D status, insulin resistance, inflammation, and elevated adipocytokines in women at high risk of breast cancer is unknown. The NSABP-P1 trial population was used for a nested case-control study. Cases were drawn from those who developed invasive breast cancer and controls selected from unaffected participants (≤4 per case) matched for age, race, 5 year Gail score, and geographic location of clinical center as a surrogate for latitude. Fasting serum banked at trial enrolment was assayed for 25-hydroxy vitamin-D (25OHD), insulin, leptin (adipocytokine), and C-reactive protein (CRP, marker of inflammation). Logistic regression was used to test for associations between study variables and the risk of invasive breast cancer. Two hundred and thirty-one cases were matched with 856 controls. Mean age was 54, and 49% were premenopausal. There were negative correlations for 25OHD with body mass index (BMI), insulin, CRP, and leptin. BMI ≥ 25 kg/m(2) was associated with higher breast cancer risk (odds ratio [OR] 1.45, p = 0.02) and tamoxifen treatment was associated with lower risk (OR = 0.44, p continuous variables, 25OHD, insulin, CRP, and leptin levels were not associated with breast cancer risk (all p > 0.34). In this high risk population, higher BMI was associated with a greater breast cancer risk. Serum levels of 25OHD, insulin, CRP, and leptin were not independent predictors of either breast cancer risk or tamoxifen benefit.

  2. The different effects of lithium and tamoxifen on memory formation and the levels of neurotrophic factors in the brain of male and female rats.

    Science.gov (United States)

    Valvassori, Samira S; Borges, Cenita P; Varela, Roger B; Bavaresco, Daniela V; Bianchini, Guilherme; Mariot, Edemilson; Arent, Camila O; Resende, Wilson R; Budni, Josiane; Quevedo, João

    2017-09-01

    Lithium (Li) is a mood-stabilizing drug used in the treatment of bipolar disorder (BD). Recently, preclinical studies have demonstrated the potential of tamoxifen (TMX) in the treatment of acute episodes of BD. However, the prolonged use of TMX for mood disorders treatment is controversial. In this study, we evaluated the effects of TMX or Li on cognitive behavior, as well as the levels of neurotrophic factors in the brain of male and female rats. Male and female Wistar rats received administrations of water (control group), TMX or Li via gavage for a period of 28days; the rats were then subjected to the open-field test (to evaluate spontaneous locomotion), and the novel object recognition and step-down inhibitory avoidance tests (to evaluate cognition). The levels of NGF, BDNF and GDNF were evaluated in the hippocampus and frontal cortex of the subject rats. No significant differences were observed in the open-field and inhibitory avoidance tests after drug administration in either the male or female rats. The administration of TMX, but not Li, decreased the recognition index of both the male and female rats in the object recognition test. The chronic administration of TMX decreased, whereas Li increased the levels of BDNF in the hippocampus of both the male and female rats. Tamoxifen decreased the levels of NGF in the hippocampus of female rats. In conclusion, it can be suggested that long-term treatments with TMX can lead to significant cognitive impairments by reducing the levels of neurotrophic factors in the brain of rats. Copyright © 2017. Published by Elsevier Inc.

  3. Cost-effectiveness of anastrozole, in comparison with tamoxifen, in the adjuvant treatment of early breast cancer in Brazil Custo-efetividade do anastrozol em comparação com tamoxifeno no tratamento adjuvante do câncer de mama precoce no Brasil

    Directory of Open Access Journals (Sweden)

    Marcelo Fonseca

    2009-01-01

    Full Text Available OBJECTIVE: Breast cancer, a leading type of cancer in many developing countries, is the most frequent non-cutaneous tumor in Brazil. Hormone therapy is the standard of care in the adjuvant treatment of early-stage, hormone-receptor-positive disease, and both tamoxifen and third-generation aromatase inhibitors are options in postmenopausal women. The comparative cost-effectiveness of different treatment strategies is of considerable interest in societies facing limited resources. METHODS: In an attempt to compare cost-effectiveness of upfront treatment with tamoxifen or anastrozole, the medical and economic results in a hypothetical cohort of 64-year-old postmenopausal women, was analyzed considering the Brazilian healthcare system in 2005, the primary perspective of the private sector, and a lifetime horizon. Data from the ATAC Trial, Markov modeling, a modified Delphi panel, and microcosting (in Brazilian R$ were used to estimate costs and effectiveness of the two upfront strategies. RESULTS: The model estimated a gain of 0.55 discounted life-years for patients receiving anastrozole, relative to those treated with tamoxifen. With an incremental cost of R$ 15,141.15, the model estimated that the cost-effectiveness of anastrozole, in relation to tamoxifen, was R$ 27,326.80. Monte Carlo simulations showed that approximately 50% of the cases fell below the threshold of R$ 29,229.00 per life-year gained, which is recommended by the World Health Organization for Brazil. CONCLUSION: It was concluded that upfront anastrozole is a cost-effective option compared with tamoxifen in the adjuvant treatment of postmenopausal women with hormone-receptor-positive early breast cancer.RESUMO OBJETIVO: O câncer de mama, o mais comum em vários países desenvolvidos, é o tumor não cutâneo mais frequente no Brasil. A terapia hormonal é o tratamento adjuvante padrão para os estágios precoces, em doença com receptor hormonal positivo, e o tamoxifeno e os

  4. HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Wen-Tsung Huang

    2017-12-01

    Full Text Available Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+ breast cancer patients. Even though dysregulations of histone deacetylases (HDACs are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan–Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

  5. Sex Therapy

    Science.gov (United States)

    Sex therapy Overview Sex therapy is a type of psychotherapy — a general term for treating mental health problems by talking with a mental health professional. Through sex therapy, you can address concerns about sexual function, ...

  6. Family Therapy

    Science.gov (United States)

    Family therapy Overview Family therapy is a type of psychological counseling (psychotherapy) that can help family members improve communication and resolve conflicts. Family therapy is usually provided by a psychologist, ...

  7. Outcomes of special histotypes of breast cancer after adjuvant endocrine therapy with letrozole or tamoxifen in the monotherapy cohort of the BIG 1-98 trial

    DEFF Research Database (Denmark)

    Munzone, E; Giobbie-Hurder, A; Gusterson, B A

    2015-01-01

    BACKGROUND: We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial. PATIENTS AND METHODS: The intention-to-treat BIG 1-98 monothera...

  8. Breast abscesses after breast conserving therapy for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fujiwara, Kazuhisa [National Kyoto Hospital (Japan)

    2001-09-01

    Breast abscess after breast conserving therapy is a rare complication and the study of this cause has not been reported. A retrospective review of 190 patients undergoing breast conserving therapy in our institution revealed 4 patients with breast abscess (mean age, 50.6 years; range, 47-57 years and median follow up 4 months; 1-11 months). Risk factors which were common to all patients were: fine needle aspiration (FNA), surgical treatment; wide excision, adjuvant therapy; oral administration of tamoxifen (TAM), radiation therapy (RT) to ipsilateral whole breast; total dose of 50 Gy and skin desquamation by RT; level I or II. Other important risk factors in 3 patients were repeated aspirations of seroma post operatively and 2 patients received chemotherapy; CAF. Cultures from one abscess grew staphylococcus aureus, one grew staphylococcus epidermidis, and two were sterile. Breast abscess may be caused by a variety of factors and it is often difficult to specify the cause. This suggests that careful observation will be necessary to determine the cause. (author)

  9. Breast abscesses after breast conserving therapy for breast cancer

    International Nuclear Information System (INIS)

    Fujiwara, Kazuhisa

    2001-01-01

    Breast abscess after breast conserving therapy is a rare complication and the study of this cause has not been reported. A retrospective review of 190 patients undergoing breast conserving therapy in our institution revealed 4 patients with breast abscess (mean age, 50.6 years; range, 47-57 years and median follow up 4 months; 1-11 months). Risk factors which were common to all patients were: fine needle aspiration (FNA), surgical treatment; wide excision, adjuvant therapy; oral administration of tamoxifen (TAM), radiation therapy (RT) to ipsilateral whole breast; total dose of 50 Gy and skin desquamation by RT; level I or II. Other important risk factors in 3 patients were repeated aspirations of seroma post operatively and 2 patients received chemotherapy; CAF. Cultures from one abscess grew staphylococcus aureus, one grew staphylococcus epidermidis, and two were sterile. Breast abscess may be caused by a variety of factors and it is often difficult to specify the cause. This suggests that careful observation will be necessary to determine the cause. (author)

  10. Familial breast cancer - targeted therapy in secondary and tertiary prevention.

    Science.gov (United States)

    Kast, Karin; Rhiem, Kerstin

    2015-02-01

    The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient's response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi.

  11. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.

    Science.gov (United States)

    Dowsett, Mitch; Cuzick, Jack; Wale, Christopher; Forbes, John; Mallon, Elizabeth A; Salter, Janine; Quinn, Emma; Dunbier, Anita; Baum, Michael; Buzdar, Aman; Howell, Anthony; Bugarini, Roberto; Baehner, Frederick L; Shak, Steven

    2010-04-10

    PURPOSE To determine whether the Recurrence Score (RS) provided independent information on risk of distant recurrence (DR) in the tamoxifen and anastrozole arms of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial. PATIENTS AND METHODS RNA was extracted from 1,372 tumor blocks from postmenopausal patients with hormone receptor-positive primary breast cancer in the monotherapy arms of ATAC. Twenty-one genes were assessed by quantitative reverse transcriptase polymerase chain reaction, and the RS was calculated. Cox proportional hazards models assessed the value of adding RS to a model with clinical variables (age, tumor size, grade, and treatment) in node-negative (N0) and node-positive (N+) women. RESULTS Reportable scores were available from 1,231 evaluable patients (N0, n = 872; N+, n = 306; and node status unknown, n = 53); 72, 74, and six DRs occurred in N0, N+, and node status unknown patients, respectively. For both N0 and N+ patients, RS was significantly associated with time to DR in multivariate analyses (P or = 31) groups were 4%, 12%, and 25%, respectively, in N0 patients and 17%, 28%, and 49%, respectively, in N+ patients. The prognostic value of RS was similar in anastrozole- and tamoxifen-treated patients. CONCLUSION This study confirmed the performance of RS in postmenopausal HR+ patients treated with tamoxifen in a large contemporary population and demonstrated that RS is an independent predictor of DR in N0 and N+ hormone receptor-positive patients treated with anastrozole, adding value to estimates with standard clinicopathologic features.

  12. 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

    BACKGROUND: Resistance to antiestrogen therapy is a major clinical challenge in the treatment of estrogen receptor α (ER)-positive breast cancer. The aim of the study was to explore the growth promoting pathways of antiestrogen resistant breast cancer cells to identify biomarkers and novel treatm...

  13. Detection of a negative correlation between prescription of Chinese herbal products containing coumestrol, genistein or daidzein and risk of subsequent endometrial cancer among tamoxifen-treated female breast cancer survivors in Taiwan between 1998 and 2008: A population-based study.

    Science.gov (United States)

    Hu, Yi-Cheng; Wu, Chien-Tung; Lai, Jung-Nien; Tsai, Yueh-Ting

    2015-07-01

    Tamoxifen users sometimes seek complementary and alternative medicine advice for treatment of a variety of illness and co-administer with phytoestrogen-containing herbs, resulting in an increasing concern of its influence in subsequent endometrial cancer risk. Our study aims to determine the prevalence of Chinese herbal products containing coumestrol, genistein, or daidzein and their association with subsequent endometrial cancer risk among tamoxifen-treated breast cancer survivors in Taiwan. We selected all patients who were newly diagnosed with invasive breast cancer and received tamoxifen treatment between January 1, 1998, and December 31, 2008, from the National Health Insurance Research Database. Among the 26,656 tamoxifen-treated breast cancer survivors, we evaluated the usage, frequency of service, and prescription of Chinese herbal products containing coumestrol, genistein, or daidzein. The logistic regression method was employed to calculate the odds ratios for utilization of those herbal products. Cox proportional hazard regression was set to calculate the hazard ratios of endometrial cancer associated with such usage. Of the patients surveyed, 36.2% (n=9652) of the tamoxifen-treated breast cancer survivors examined in the study had consumed Chinese herbal products containing coumestrol, genistein, or daidzein during the study period. Exposure to Ge Gen(Puerariae Radix) specifically was the most extensive. For it, the population consumed an average cumulative dose of above 180g. Compared to those who had never used Chinese herbal products, breast cancer survivors who had taken Chinese herbal products containing coumestrol, genistein, or daidzein concurrently with tamoxifen treatment did not have a higher hazard ratio for subsequent development of endometrial cancer. Among those tamoxifen-treated female breast cancer survivors in Taiwan, consumption of Chinese herbal products containing coumestrol, genistein, or daidzein is negatively correlated with

  14. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial: advancing the science of recruitment and breast cancer risk assessment in minority communities.

    Science.gov (United States)

    McCaskill-Stevens, Worta; Wilson, John W; Cook, Elise D; Edwards, Cora L; Gibson, Regina V; McElwain, Diane L; Figueroa-Moseley, Colmar D; Paskett, Electra D; Roberson, Noma L; Wickerham, D Lawrence; Wolmark, Norman

    2013-04-01

    One of the first chemoprevention trials conducted in the western hemisphere, the National Surgical Adjuvant Breast and Bowel Project's (NSABP) Breast Cancer Prevention Trial (BCPT), demonstrated the need to evaluate all aspects of recruitment in real time and to implement strategies to enroll racial and ethnic minority women. The purpose of this report is to review various patient recruitment efforts the NSABP developed to enhance the participation of racial and ethnic minority women in the Study of Tamoxifen and Raloxifene (STAR) trial and to describe the role that the recruitment process played in the implementation and understanding of breast cancer risk assessment in minority communities. The NSABP STAR trial was a randomized, double-blinded study comparing the use of tamoxifen 20 mg/day to raloxifene 60 mg/day, for a 5-year period, to reduce the risk of developing invasive breast cancer. Eligible postmenopausal women were required to have a 5-year predicted breast cancer risk of 1.66% based on the modified Gail Model. For the current report, eligibility and enrollment data were tabulated by race/ethnicity for women who submitted STAR risk assessment forms (RAFs). A total of 184,460 RAFs were received, 145,550 (78.9%) from white women and 38,910 (21.1%) from minority women. Of the latter group, 21,444 (11.6%) were from African Americans/blacks, 7913 (4.5%) from Hispanics/Latinas, and 9553 (5.2%) from other racial or ethnic groups. The percentages of risk-eligible women among African Americans, Hispanics/Latinas, others, and whites were 14.2%, 23.3%, 13.7%, and 57.4%, respectively. Programs targeting minority enrollment submitted large numbers of RAFs, but the eligibility rates of the women referred from those groups tended to be lower than the rates among women referred outside of those programs. The average number of completed risk assessments increased among minority women over the course of the recruitment period compared to those from whites. We have not

  15. Barriers to and facilitative processes of endocrine therapy adherence among women with breast cancer.

    Science.gov (United States)

    Bright, Emma E; Petrie, Keith J; Partridge, Ann H; Stanton, Annette L

    2016-07-01

    The treatment of chronic illness, and the prevention of disease progression and recurrence, often involve long-term adherence to prescription medications in breast cancer. Despite the survival benefit of endocrine therapies, nonadherence remains high. In this study, we examined barriers to and facilitators of endocrine therapy adherence among women with breast cancer (n = 1371). Participants currently taking tamoxifen or aromatase inhibitors were recruited from Dr. Susan Love Research Foundation's Army of Women(®) Registry. Participants responded online to open-ended and close-ended questions about thoughts, feelings, and behaviors relevant to endocrine therapy. Two weeks later, women were invited to complete a second online questionnaire regarding current endocrine therapy adherence. Approximately one-third (36 %) of participants reported the presence of factors that make endocrine therapy difficult; reporting any barrier to medication adherence was significantly associated with nonadherence (P adhere and the use of cognitive self-talk (e.g., thoughts regarding endocrine therapy efficacy) was related to higher adherence. Hierarchical linear regressions revealed a significant behavioral barrier × behavioral facilitator interaction (P behavioral barrier in the absence of a behavioral facilitator reported the lowest adherence. Findings suggest that a sizeable minority of women face barriers to taking endocrine therapy, which are associated with nonadherence.

  16. Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/Akt signaling pathway in ER-negative human gastric cancer cells.

    Science.gov (United States)

    Mao, Zonglei; Zhou, Jin; Luan, Junwei; Sheng, Weihua; Shen, Xiaochun; Dong, Xiaoqiang

    2014-03-01

    Multidrug resistance (MDR), mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem limiting successful chemotherapy of gastric cancer. Tamoxifen (TAM), a triphenylethylene nonsteroidal antiestrogen agent, shows broad-spectrum antitumor properties. Emerging studies demonstrated that TAM could significantly reduce the MDR in a variety of human cancers. Here we investigated the effects and possible underlying mechanisms of action of TAM on the reversion of MDR in ER-negative human gastric cancer cells. Our results demonstrated that in MDR phenotype SGC7901/CDDP gastric cancer cells TAM dramatically lowered the IC50 of CDDP, 5-FU and ADM, increased the intracellular Rhodamine123 accumulation and induced G0/G1 phase arrest, while G2/M phase decreased accordingly. Furthermore, at the molecular level, TAM substantially decreased the expression of P-gp, p-Akt and the Akt-regulated downstream effectors such as p-GSK-3β, p-BAD, Bcl-XL and cyclinD1 proteins without affecting the expression of t-Akt, t-GSK-3β, t-BAD proteins in SGC7901/CDDP cells. Thus, our findings demonstrate that TAM reverses P-gp-mediated gastric cancer cell MDR via inhibiting the PI3K/Akt signaling pathway. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  17. Positive and negative affect, depression, and cognitive processes in the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) Trial.

    Science.gov (United States)

    Danhauer, Suzanne C; Legault, Claudine; Bandos, Hanna; Kidwell, Kelley; Costantino, Joseph; Vaughan, Leslie; Avis, Nancy E; Rapp, Steve; Coker, Laura H; Naughton, Michelle; Naylor, Cecile; Terracciano, Antonio; Shumaker, Sally

    2013-01-01

    This study examined the relationship between positive and negative affect, depressive symptoms, and cognitive performance. The sample consisted of 1479 non-demented, postmenopausal women (mean age = 67 years) at increased risk of breast cancer enrolled in the National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene. At each annual visit, women completed a standardized neuropsychological battery and self-report measures of affect and depression. Data from three visits were used in linear mixed models for repeated measures using likelihood ratio tests. Separate analyses were performed to relate positive/negative affect and depression to each cognitive measure. Higher positive affect was associated with better letter fluency (p = .006) and category fluency (p negative affect was associated with worse global cognitive function (p negatively associated with verbal knowledge (p = .004), figural memory (p positive affect and increased verbal fluency and between depressive symptoms and decreased memory. The most novel finding shows that negative affect is related to decreased global cognition and visuospatial ability. Overall, this research in a large, longitudinal sample supports the notion that positive affect is related to increases and negative affect to decreases in performance on distinct cognitive measures.

  18. Tamoxifen-loaded nanoparticles based on a novel mixture of biodegradable polyesters: characterization and in vitro evaluation as sustained release systems.

    Science.gov (United States)

    Pérez, Elena; Benito, Marta; Teijón, César; Olmo, Rosa; Teijón, José M; Blanco, M Dolores

    2012-01-01

    Nanoparticles (NP) from mixtures of two poly(D,L-lactide-co-caprolactone) (PLC) copolymers, PLC 40/60 and PLC 86/14, with poly(D,L-lactide) (PDLLA) and PCL were prepared: PLC 40/60-PCL (25:75), PLC 86/14-PCL (75:25) and PLC 86/14-PLA (75:25). Tamoxifen was loaded with encapsulation efficiency between 65% and 75% (29.9-36.3 µg TMX/ mg NP). All selected systems showed spherical shape and nano-scale size. TMX-loaded NPs were in the range of 293-352 nm. TMX release from NP took place with different profiles depending on polymeric composition of the particles. After 60 days, 59.81% and 82.65% of the loaded drug was released. The cytotoxicity of unloaded NP in MCF7 and HeLa cells was very low. Cell uptake of NP took place in both cell types by unspecific internalization in a time dependent process. The administration of 6 and 10 µm TMX by TMX-loaded NP was effective on both cellular types, mainly in MCF7 cells.

  19. Effect on growth and cell cycle kinetics of estradiol and tamoxifen on MCF-7 human breast cancer cells grown in vitro and in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Bronzert, D; Vindeløv, L L

    1989-01-01

    The effects of estradiol and tamoxifen (TAM) on the estrogen-dependent human breast cancer cell line MCF-7 grown in vitro and in nude mice were compared. The effect on growth was determined by cell number in vitro and by tumor growth curves in nude mice. The effects on the cell cycle kinetics were...... determined by repeated flow cytometric DNA analyses in vitro and in vivo and by the technique of labeled mitosis in nude mouse-grown tumors. Under in vitro conditions, estradiol induced a pronounced increase in S-phase fraction and cell number. TAM inhibited growth of MCF-7 cells with a concomitant increase...... in the G1 phase from 60% to 75%. In nude mice, MCF-7 only formed tumors in estradiol-supplemented mice. No differences were observed in growth and cell kinetics between 0.1 and 1.0 mg of estradiol. Daily i.p. injections of TAM resulted in tumor growth inhibition with shrinkage of tumors. The flow...

  20. Feminist Therapy.

    Science.gov (United States)

    Laidlaw, Toni; Malmo, Cheryl

    1991-01-01

    Traces roots of feminist therapy and its independence from traditional and prevalent theories and therapy practices. Asserts that Freudian theory and humanistic assumptions are sexist and contribute to powerlessness of women. In contrast, feminist therapy is seen as dealing directly with client-counselor relationships, trust, advocacy, and…

  1. Gene Therapy

    Science.gov (United States)

    Gene therapy Overview Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease. Genes contain your ... that don't work properly can cause disease. Gene therapy replaces a faulty gene or adds a new ...

  2. [Synergistic effect of cell kinetics-directed chemo-endocrine therapy on experimental mammary tumors].

    Science.gov (United States)

    Ueki, H

    1987-11-01

    We tried to demonstrate that the cell kinetics-directed chemoendocrine therapy is more effective on hormone dependent breast cancer than empirical combination of the endocrine therapy and chemotherapy. Cell kinetics of each tumor was measured by flow cytometric analysis. Estrogen dependent human breast cancer cell line MCF-7 was used in vitro. In vivo, androgen dependent SC-115 carcinoma was transplanted to DDS mice. In vitro, tamoxifen was administered as the endocrine therapy. In vivo, we carried out testectomy on DDS mice. Effect of the endocrine therapy on the cell kinetics of the tumor was thought to be G1-S depression. High density 5FU was administered as the chemotherapeutic agents, whose content was 1 microgram/ml in vitro and 40 mg/kg in vivo. 5FU brought temporary decrease of cells in S phase. Only anteceding 5FU administration had synergistic effect in combination of 5FU and the endocrine therapy. 5FU was convinced to act more effectively on cells in S phase, so it was shown that cell kinetics-directed schedule was superior to the empirical treatment schedule in chemoendocrine therapy.

  3. What Is Music Therapy?

    Science.gov (United States)

    American Music Therapy Association Home Contact News Help/FAQ Members Only Login About Music Therapy & AMTA What is Music Therapy? Definition and ... is Music Therapy? Print Email Share What is Music Therapy What is Music Therapy? Music Therapy is ...

  4. Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study

    Directory of Open Access Journals (Sweden)

    Skoog Lambert

    2006-06-01

    Full Text Available Abstract Background Postmenopausal hormone-replacement therapy (HRT increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. Methods We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. Results HRT use in patients with estrogen receptor (ER protein positive tumors (n = 72 was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen. Conclusion Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.

  5. 8-prenylnaringenin and tamoxifen inhibit the shedding of irradiated epithelial cells and increase the latency period of radiation-induced oral mucositis. Cell culture and murine model

    Energy Technology Data Exchange (ETDEWEB)

    Ryck, Tine de; Impe, Annouchka van; Bracke, Marc E. [Ghent University, Laboratory of Experimental Cancer Research, Department Radiation Oncology and Experimental Cancer Research, Ghent (Belgium); Vanhoecke, Barbara W. [Ghent University, Laboratory of Experimental Cancer Research, Department Radiation Oncology and Experimental Cancer Research, Ghent (Belgium); Ghent University, Laboratory of Microbial Ecology and Technology (LabMET), Ghent (Belgium); Heyerick, Arne [Ghent University, Laboratory of Pharmacognosy and Phytochemistry, Ghent (Belgium); Vakaet, Luc; Neve, Wilfried de [Ghent University Hospital, Department of Radiation Oncology, Ghent (Belgium); Mueller, Doreen [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Dresden (Germany); Schmidt, Margret [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Dresden (Germany); German Cancer Consortium (DKTK) partner site Dresden and German Cancer Center (DKFZ), Heidelberg (Germany); Doerr, Wolfgang [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Dresden (Germany); Medical University, Department of Radiation Oncology, CCC, and CD-Laboratory RadOnc, Vienna (Austria)

    2015-05-01

    The major component in the pathogenesis of oral radiation-induced mucositis is progressive epithelial hypoplasia and eventual ulceration. Irradiation inhibits cell proliferation, while cell loss at the surface continues. We conceived to slow down this desquamation by increasing intercellular adhesion, regulated by the E-cadherin/catenin complex. We investigated if 8-prenylnaringenin (8-PN) or tamoxifen (TAM) decrease the shedding of irradiated human buccal epithelial cells in vitro and thus delay the ulcerative phase of radiation-induced mucositis in vivo. In vitro, aggregates of buccal epithelial cells were irradiated and cultured in suspension for 11 days. 8-PN or TAM were investigated regarding their effect on cell shedding. In vivo, the lower tongue surface of mice was irradiated with graded single doses of 25 kV X-rays. The incidence, latency, and duration of the resulting mucosal ulcerations were analyzed after topical treatment with 8-PN, TAM or solvent. 8-PN or TAM prevented the volume reduction of the irradiated cell aggregates during the incubation period. This was the result of a higher residual cell number in the treated versus the untreated irradiated aggregates. In vivo, topical treatment with 8-PN or TAM significantly increased the latency of mucositis from 10.9 to 12.1 and 12.4 days respectively, while the ulcer incidence was unchanged. 8-PN and TAM prevent volume reduction of irradiated cell aggregates in suspension culture. In the tongues of mice, these compounds increase the latency period. This suggests a role for these compounds for the amelioration of radiation-induced mucositis in the treatment of head and neck tumors. (orig.) [German] Die wesentliche Komponente in der Pathogenese der radiogenen Mukositis ist eine progressive epitheliale Hypoplasie und letztendlich Ulzeration. Die Bestrahlung hemmt die Zellproliferation, waehrend der Zellverlust an der Oberflaeche fortbesteht. Wir versuchten, diese Desquamation durch eine Stimulation der

  6. Cell death induced by tamoxifen in human blood lymphocytes cultivated in vitro = Morte celular induzida pelo tamoxifeno em linfócitos humanos cultivados in vitro

    Directory of Open Access Journals (Sweden)

    Selma Candelária Genari

    2010-10-01

    Full Text Available Many chemotherapeutic agents with a potential against solid tumors or leukemia can cause lymphopenia. Tamoxifen (TAM is a synthetic non-steroidal anti-estrogen drug employed in female breast cancer treatment. The present study investigated the capacity of TAM to induce cell death in human lymphocytes cultivated in vitro. Lymphocytes were obtained from young (25-30 years; n = 3 and elderly women (58-77 years; n = 3 and cultivated for 24 or 48h, with or without TAM (20 ƒÊM. After the culture, cell viability, immunocytochemical response and ultrastructure were evaluated. TAM affected lymphocytes in a time- dependent manner, and cells obtained from elderly women were the most sensitive to TAM. Immunocytochemicalanalysis evidenced higher frequency of apoptosis in treated cells, and the ultrastructural study revealed autophagic vacuoles, differing from the controls. In summary, the treated lymphocytes were affected by TAM, leading to cell death by apoptosis and autophagy.Muitos agentes quimioterapicos com potencial contra tumores solidos ou leucemias podem causar linfopenia. O Tamoxifeno (TAM e um agente antiestrogeno nao-esteroidal empregado no tratamento de cancer de mama feminino. O presente trabalho investigou a capacidade do TAM em induzir morte celular em linfocitos humanos cultivados in vitro. Oslinfocitos foram obtidos de mulheres jovens (25-30 anos; n = 3 e idosas (58-77 anos; n = 3 e cultivados por 24 ou 48h, com ou sem TAM (20 ƒÊM. Apos a cultura, foram analisadas a viabilidade celular, a resposta imunocitoquimica e a ultraestrutura. Os resultados indicam que o Tamoxifeno induziu morte celular em linfocitos de ambos os grupos, entretanto, as celulas das mulheres idosas apresentaram-se mais sensiveis ao tratamento. A analise imunocitoquimica mostrou maior frequencia de apoptose nas celulas tratadas e o estudo ultraestrutural revelou vacuolos autofagicos nos linfocitos expostos ao Tamoxifeno. Em conclusao, nosso estudo revelou que o TAM

  7. Effect of tamoxifen, methoxyprogesterone acetate and combined treatment on cellular proliferation and apoptosis in SKOV3/DDP cells via the regulation of vascular endothelial growth factor.

    Science.gov (United States)

    Wen, Lv; Hong, Ding; Yanyin, Wu; Mingyue, Zhang; Baohua, Li

    2013-05-01

    The aim of this study was to investigate the effect of tamoxifen (TAM), methoxyprogesterone acetate (MPA) and their combined treatment on cisplatin-resistant ovarian cancer SKOV3/DDP cells, as well as the potential mechanisms. MTT assay was used to investigate the effect of different concentrations (0.01, 0.1, 1, 10 and 100 μM) of TAM, MPA and their combined treatment on the proliferation of cisplatin-resistant ovarian cancer SKOV3/DDP cells. Flow cytometry was employed to analyze the cell cycle and apoptosis rate of SKOV3/DDP cells treated with medium concentration (10 μM) of TAM, MPA and their combined treatment. Change in the protein level of vascular endothelial growth factor (VEGF) in response to drug treatments was measured using Western-blot. The proliferation of SKOV3/DDP cells was inhibited by 1, 10 and 100 μM of TAM or MPA in a dose-dependent manner. Compared to the control group, 10 μM TAM could significantly arrest SKOV3/DDP cells in the G0/G1 stage and induce apoptosis (p < 0.01). However, 10 μM MPA only promoted cell apoptosis, while exhibited little effect on the cell cycle. We further found that 10 μM TAM could remarkably reduce the protein expression of VEGF, while 10 μM MPA only induce a slight reduction. Strikingly, the combined treatment of TAM and MPA exhibited additive effect on the proliferation, cell cycle, apoptosis rate and VEGF expression of SKOV3/DDP cells. We found that TAM, MPA and their combined treatment exhibited significant inhibitory effect on the cisplatin-resistant ovarian cancer SKOV3/DDP cells. Hence, TAM and MPA could be potential cytotoxic drugs to treat cisplatin-resistant patients with advanced ovarian cancer.

  8. Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats.

    Science.gov (United States)

    Long, Nathan; Long, Bertha; Mana, Asma; Le, Dream; Nguyen, Lam; Chokr, Sima; Sinchak, Kevin

    2017-03-01

    In the female rat, sexual receptivity (lordosis) can be facilitated by sequential activation of estrogen receptor (ER) α and G protein-coupled estrogen receptor 1 (GPER) by estradiol. In the estradiol benzoate (EB) primed ovariectomized (OVX) rat, EB initially binds to ERα in the plasma membrane that complexes with and transactivates metabotropic glutamate receptor 1a to activate β-endorphin neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). This activates MPN μ-opioid receptors (MOP), inhibiting lordosis. Infusion of non-esterified 17β-estradiol into the ARH rapidly reduces MPN MOP activation and facilitates lordosis via GPER. Tamoxifen (TAM) and ICI 182,780 (ICI) are selective estrogen receptor modulators that activate GPER. Therefore, we tested the hypothesis that TAM and ICI rapidly facilitate lordosis via activation of GPER in the ARH. Our first experiment demonstrated that injection of TAM intraperitoneal, or ICI into the lateral ventricle, deactivated MPN MOP and facilitated lordosis in EB-primed rats. We then tested whether TAM and ICI were acting rapidly through a GPER dependent pathway in the ARH. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and reduced MPN MOP activation within 30min compared to controls. These effects were blocked by pretreatment with the GPER antagonist, G15. Our findings demonstrate that TAM and ICI deactivate MPN MOP and facilitate lordosis in a GPER dependent manner. Thus, TAM and ICI may activate GPER in the CNS to produce estrogenic actions in neural circuits that modulate physiology and behavior. Published by Elsevier Inc.

  9. Effects of OK-432 (picibanil) on the estrogen receptors of MCF-7 cells and potentiation of antiproliferative effects of tamoxifen in combination with OK-432.

    Science.gov (United States)

    Aoyagi, H; Iino, Y; Takeo, T; Horii, Y; Morishita, Y; Horiuchi, R

    1997-01-01

    OK-432 (picibanil), a streptococcal preparation, has a strong biological response modifier (BRM) function and is expected to produce clinical improvement and prolongation of survival in treated cancer patients in Japan. We were interested in whether OK-432 augments estrogen receptor (ER) levels in breast cancer. To investigate the effect of the BRMs on cellular growth and the characteristics of ER and progesterone receptors (PgR) in the human breast cancer cell line MCF-7, we used OK-432, Krestin (PSK), a protein-bound polysaccharide extracted from Coriolus versicolor, and lentinan, a fungal branched (1...3)-beta-D-glycan. OK432 and PSK dose dependently inhibited DNA synthesis of MCF-7 cells, and the 50% inhibitory concentrations of OK-432 and PSK were 1.2 KE (klinische Einheit, clinical unit)/ml and 200 micrograms/ml, respectively. Lentinan showed no direct anticancer effect in vitro. We found that OK-432 induced a 2-fold increase in ER levels in MCF-7 cells at 0.005 KE/ml, but not in PgR. Lentinan and low-dose PSK did not change ER or PgR levels, but high-dose PSK decreased ER and PgR. We also studied the combined effect of OK-432 and antiestrogens, tamoxifen (TAM) and DP-TAT-59. The combined treatment with OK-432 and TAM showed an additive inhibitory effect on MCF-7 cells. These results suggest that OK-432 may augment the therapeutic effect of TAM in breast cancer.

  10. Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen

    International Nuclear Information System (INIS)

    Waalkes, Michael P.; Liu Jie; Ward, Jerrold M.; Diwan, Bhalchandra A.

    2006-01-01

    Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 μg/pup/day) or tamoxifen (TAM; 10 μg/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-α, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES

  11. Monitoring mammary tumor progression and effect of tamoxifen treatment in MMTV-PymT using MRI and magnetic resonance spectroscopy with hyperpolarized [1-13C]pyruvate

    DEFF Research Database (Denmark)

    Asghar Butt, Sadia; Søgaard, Lise V.; Ardenkjær-Larsen, Jan Henrik

    2015-01-01

    Purpose: To use dynamic magnetic resonance spectroscopy (MRS) of hyperpolarized 13C-pyruvate to follow the progress over time in vivo of breast cancer metabolism in the MMTV-PymT model, and to follow the response to the anti-estrogen drug tamoxifen. Methods: Tumor growth was monitored by anatomical...... significantly in the treated group. Conclusion: These hyperpolarized 13C MRS findings indicate that tumor metabolic changes affects kP. The measured kp did not relate to treatment response to the same extent as did tumor growth, histological evaluation, and in vitro determination of LDH activity. © 2014 Wiley...

  12. Measuring persistence to hormonal therapy in patients with breast cancer: accounting for temporary treatment discontinuation.

    Science.gov (United States)

    Huiart, Laetitia; Ferdynus, Cyril; Dell'Aniello, Sophie; Bakiri, Naciba; Giorgi, Roch; Suissa, Samy

    2014-08-01

    Several studies have been conducted to estimate persistence to hormonal therapy among women with breast cancer (BC). Most studies focus on first treatment discontinuation. Patients, however, can have numerous periods of treatment discontinuation or treatment exposure. Our objective is to estimate persistence to tamoxifen in patients with BC while accounting for temporary treatment discontinuations and this by using multi-state (MS) models. A cohort of 10,806 women with BC having received at least one prescription of tamoxifen between 1998 and 2008 was constituted from the UK General Practice Research Database. We fitted a semi-Markov model with three states to estimate the probability of being off treatment over a 5-year period while accounting for temporary treatment discontinuations (transition between on treatment and off treatment) and competing risks (recurrence of BC or death). Non-persistence, as estimated from the MS model, ranged from 12.1% (95% confidence interval [95%CI]: 9.2-15.1) at 1 year to 14.9% (95%CI: 11.7-18.1) at 5 years. Estimations of non-persistence based on the Kaplan-Meier model were higher, i.e., 29.3% (95%CI: 28.1-30.6) at 5 years, as well as those obtained from a competing risk model, i.e., 24.0% (95%CI: 22.9-25.1). Most temporary discontinuations (94.7%) lasted less than 6 months. Temporary treatment discontinuations are frequent and should be accounted for when measuring adherence to treatment. MS models can provide a useful framework for this sort of analysis insofar as they help describe patients' complex behavior. This may help tailor interventions that improve persistence to hormonal therapy among women with BC. Copyright © 2014 John Wiley & Sons, Ltd.

  13. Proton therapy

    International Nuclear Information System (INIS)

    Smith, Alfred R

    2006-01-01

    Proton therapy has become a subject of considerable interest in the radiation oncology community and it is expected that there will be a substantial growth in proton treatment facilities during the next decade. I was asked to write a historical review of proton therapy based on my personal experiences, which have all occurred in the United States, so therefore I have a somewhat parochial point of view. Space requirements did not permit me to mention all of the existing proton therapy facilities or the names of all of those who have contributed to proton therapy. (review)

  14. Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials.

    Science.gov (United States)

    Regan, Meredith M; Pagani, Olivia; Francis, Prudence A; Fleming, Gini F; Walley, Barbara A; Kammler, Roswitha; Dell'Orto, Patrizia; Russo, Leila; Szőke, János; Doimi, Franco; Villani, Laura; Pizzolitto, Stefano; Öhlschlegel, Christian; Sessa, Fausto; Peg Cámara, Vicente; Rodríguez Peralto, José Luis; MacGrogan, Gaëtan; Colleoni, Marco; Goldhirsch, Aron; Price, Karen N; Coates, Alan S; Gelber, Richard D; Viale, Giuseppe

    2015-11-01

    The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.

  15. 21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology.

    Science.gov (United States)

    Mamounas, Eleftherios P; Tang, Gong; Paik, Soonmyung; Baehner, Frederick L; Liu, Qing; Jeong, Jong-Hyeon; Kim, S Rim; Butler, Steven M; Jamshidian, Farid; Cherbavaz, Diana B; Sing, Amy P; Shak, Steven; Julian, Thomas B; Lembersky, Barry C; Wickerham, D Lawrence; Costantino, Joseph P; Wolmark, Norman

    2018-02-01

    The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node-positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen. The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years. In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72-1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69-1.47; p = 0.99), 0.84 (95% CI 0.62-1.14; p = 0.26), and 0.81 (95% CI 0.60-1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints. RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28).

  16. Efeito do tamoxifeno no perfil das proteínas plasmáticas em condição de diabetes mellitus tipo 1 Effect of tamoxifen on plasma proteins in diabetes mellitus type 1

    Directory of Open Access Journals (Sweden)

    Teresa Cristina P. Silva

    2005-01-01

    Full Text Available OBJETIVO: Considerando-se que importantes avanços científicos têm sido obtidos através de estudos com Diabetes mellitus experimental, e que a ação do tamoxifeno em humanos permanece obscura, o presente trabalho objetiva acompanhar as modificações promovidas pelo diabetes e tamoxifeno no perfil eletroforético das proteínas plasmáticas. MÉTODOS: Foram utilizados 27 ratos fêmeas Wistar (180-220g peso corporal, divididos randomicamente em 5 grupos: C1 (n=3, receberam veículo, C2 (n=3, sem tratamento, T (n=5, tratados com tamoxifeno, 0,3mg/kg/dia, D (n=8, diabéticos experimentais por estreptozotocina, 45mg/Kg e DT (n=8, diabéticos tratados com tamoxifeno. A eletroforese foi realizada em acetato de celulose, pH 8,6-8,8, cuba TECNOW, e as fitas foram coradas em Ponceau S. As proteínas totais foram determinadas pelo método do Biureto (Kit Labtest. Os proteinogramas foram obtidos em densitômetro BioSystems BTS-235. RESULTADOS: Albumina diminuiu progressivamente nos grupos T, D e DT; a fração a1 aumentou nos grupos T e DT; a fração a2 aumentou nos grupos T e D, havendo efeito aditivo no grupo DT; a fração b aumentou nos grupos T e D; a fração g aumentou nos grupos T, D e DT. CONCLUSÃO: Os resultados indicam uma resposta de fase aguda, com efeito aditivo do tamoxifeno e diabetes, sugerindo uma provável lesão hepática.PURPOSE: Considering that important scientific advances have been obtained through studies based on experimental Diabetes mellitus, and that tamoxifen action in humans remains unknown, the aim of the present work is to follow the modifications promoted by diabetes and tamoxifen in the electrophoretic profile of plasmatic proteins. METHODS: It was used 27 Wistar female rats (180-250 body weight, randomicaly divided into five groups: C1 (n=3, received vehicle, C2 (n=3, no treatment, T (n=5, treated with tamoxifen, 0.3mg/Kg/day, D (n=8, experimental diabetes by estreptozotocin, 45mg/Kg and DT (n=8, diabetic treated

  17. Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen

    Directory of Open Access Journals (Sweden)

    Chamnanphon M

    2013-05-01

    Full Text Available Montri Chamnanphon,1 Khunthong Pechatanan,2 Ekapob Sirachainan,3 Narumol Trachu,4 Wasun Chantratita,5 Ekawat Pasomsub,5 Wilai Noonpakdee,6 Insee Sensorn,1,7 Chonlaphat Sukasem11Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 2Department of Medicine, Phramongkutklao College of Medicine, 3Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 4Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 5Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 6Department of Biochemistry, Faculty of Science, Mahidol University, 7Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, ThailandPurpose: To investigate the impact of CYP2D6 and CYP2C19 polymorphisms in predicting tamoxifen efficacy and clinical outcomes in Thai breast cancer patients.Methods: Polymorphisms of CYP2D6 and CYP2C19 were genotyped by the AmpliChip™ CYP450 Test (Roche Molecular Diagnostics, Branchburg, NJ, USA for 57 patients, who were matched as recurrent versus nonrecurrent breast cancers (n = 33 versus n = 24, respectively, with a 5-year follow-up.Results: Based on the genotype data, five CYP2D6 predicted phenotype groups were identified in this study including homozygous extensive metabolizer (13 of 57, 22.80%, extensive/intermediate metabolizer (23 of 57, 40.40%, extensive/poor metabolizer (3 of 57, 5.30%, homozygous intermediate metabolizer (14 of 57, 24.50%, and intermediate/poor metabolizer (4 of 57, 7.00%, and three CYP2C19 genotype groups including homozygous extensive metabolizer (27 of 57, 47.40%, extensive/intermediate metabolizer (27 of 57, 47.40%, and homozygous poor metabolizer (3 of 57, 5.30%. The CYP2D6 variant alleles were *10 (52 of 114, 45.60%, *5 (5 of 114, 4.40%, *41 (2 of 114, 1.80%, *4 (1 of 114, 0

  18. Prospective comparison of breast pain in patients participating in a randomized trial of breast-conserving surgery and tamoxifen with or without radiotherapy

    International Nuclear Information System (INIS)

    Rayan, Gamal; Dawson, Laura A.; Bezjak, Andrea; Lau, Anthea; Fyles, Anthony W.; Yi, Q.-L.; Merante, Pat; Vallis, Katherine A.

    2003-01-01

    Purpose: To determine whether breast pain affects quality of life (QOL) after breast-conserving surgery and tamoxifen (TAM) with or without adjuvant breast radiotherapy (RT). Methods and Materials: A randomized clinical trial was carried out at the Princess Margaret Hospital between 1992 and 2000 to evaluate the need for breast RT in addition to TAM in women ≥50 years treated with breast-conserving surgery for T1-T2N0 breast cancer. A companion study to assess breast pain was carried out during the last 2 years of the randomized clinical trial. The short-form McGill Pain Questionnaire (SF-MPQ), the European Organization for Research and Treatment of Cancer (EORTC) QOL (QLQ-C30) and EORTC breast cancer module (QLQ-BR23) questionnaires were completed by patients within 1 week of randomization in the randomized clinical trial (baseline) and at 3, 6, and 12 months. Results: Eighty-six patients participated in the breast pain study; 41 received RT plus TAM and 45 received TAM alone. The median age was 70 years (range 51-80). The baseline pain and QOL scores were similar for the two groups. No significant difference was found between the two groups for each scale of the QLQ-C30 and QLQ-BR23 questionnaires at 3, 6, or 12 months (p>0.100), except that at 12 months, the score for role function (QLQ-C30) was higher in the RT plus TAM group than in the RT-only group (p=0.02). At 3 months, the difference between the mean scores for the SF-MPQ was 0.553 (p=0.47). At 12 months, the pain scores had decreased in both groups; the difference was 0.199 (p=0.71). The number of breast operations or surgical complications did not correlate with breast pain in either group. Acute RT toxicity scores did not correlate with breast pain or QOL scores at 12 months. Conclusion: These results suggest that breast RT does not significantly contribute to breast pain or adversely impact the QOL up to 12 months after treatment in postmenopausal patients with node-negative breast cancer who take

  19. Functional inhibition of Ubiquitin conjugating Enzyme (UBE2C) reduces proliferation and sensitizes cervical and breast cancer cells to radiation, doxorubicin, tamoxifen and letrozole

    International Nuclear Information System (INIS)

    Bose, Mayil Vahanan; Rawat, Akhilesh; Gopisetty, Gopal; Thangarajan, Rajkumar; Ganesharaja, Selvaluxmy

    2014-01-01

    Cervical cancer is the second most common cancer in women, worldwide. About 80% of cervical cancer cases occur in developing countries. Breast cancer has overtaken cervical cancer in most of the urban centers in India. In recent years, interest in the role of Ubiquitin conjugating Enzyme E2C (UBE2C) in cancer has shown a dramatic increase. Several studies have reported UBE2C as a potential oncogene and therapeutic target. The objective of the study was to elucidate radiation and chemo-sensitivity in response to functional inhibition of UBE2C in cervical and breast cancer cell lines. Taqman Real time PCR was performed to measure UBE2C levels in cervical and breast cancer cell lines. A dominant negative form of UBE2C (DN-UBE2C) was used to functionally inhibit wild type UBE2C. Cell proliferation and anchorage independent growth were measured by colorimetric assay and soft agar assay respectively. Radiation and chemo response of cell lines were assessed by colorimetric assay and clonogenic assay. Difference in sensitivity to radiation was observed among the cervical cancer cell lines studied. The growth rate of SiHa and HeLa transfected with DN- UBE2C was significantly reduced compared to vector control. Further, DN-UBE2C mediated radio-sensitivity was correlated with a significant decrease in resistance to radiation by SiHa and HeLa cells after transfection when compared to control cultures. Similarly, both the growth rate and the anchorage independent growth of MCF7 and MDAMB231 cells transfected with DN-UBE2C were significantly reduced compared to cells transfected with vector alone. MCF7 and MDAMB231 cells expressing DN-UBE2C were significantly more sensitive to different doses of radiation and doxorubicin compared to controls. In addition, DN-UBE2C transfected MCF7 cells were more sensitive to inhibition by tamoxifen and letrozole compared to vector controls. These results suggest that UBE2C can be used as a potential therapeutic target for cervical and breast

  20. Play Therapy

    Science.gov (United States)

    Lawver, Timothy; Blankenship, Kelly

    2008-01-01

    Play therapy is a treatment modality in which the therapist engages in play with the child. Its use has been documented in a variety of settings and with a variety of diagnoses. Treating within the context of play brings the therapist and the therapy to the level of the child. By way of an introduction to this approach, a case is presented of a six-year-old boy with oppositional defiant disorder. The presentation focuses on the events and interactions of a typical session with an established patient. The primary issues of the session are aggression, self worth, and self efficacy. These themes manifest themselves through the content of the child’s play and narration of his actions. The therapist then reflects these back to the child while gently encouraging the child toward more positive play. Though the example is one of nondirective play therapy, a wide range of variation exists under the heading of play therapy. PMID:19724720

  1. Hormone Therapy

    Science.gov (United States)

    ... it also can be a sign of endometrial cancer. All bleeding after menopause should be evaluated. Other side effects reported by women who take hormone therapy include fluid retention and breast soreness. This soreness usually lasts for a short ...

  2. Manual Therapy

    OpenAIRE

    Hakgüder, Aral; Kokino, Siranuş

    2002-01-01

    Manual therapy has been used in the treatment of pain and dysfunction of spinal and peripheral joints for more than a hundred years. Manual medicine includes manipulation, mobilization, and postisometric relaxation techniques. The aim of manual therapy is to enhance restricted movement caused by blockage of joints keeping postural balance, restore function and maintain optimal body mechanics. Anatomic, biomechanical, and neurophysiological evaluations of the leucomotor system is essential for...

  3. Adaptive therapy.

    Science.gov (United States)

    Gatenby, Robert A; Silva, Ariosto S; Gillies, Robert J; Frieden, B Roy

    2009-06-01

    A number of successful systemic therapies are available for treatment of disseminated cancers. However, tumor response is often transient, and therapy frequently fails due to emergence of resistant populations. The latter reflects the temporal and spatial heterogeneity of the tumor microenvironment as well as the evolutionary capacity of cancer phenotypes to adapt to therapeutic perturbations. Although cancers are highly dynamic systems, cancer therapy is typically administered according to a fixed, linear protocol. Here we examine an adaptive therapeutic approach that evolves in response to the temporal and spatial variability of tumor microenvironment and cellular phenotype as well as therapy-induced perturbations. Initial mathematical models find that when resistant phenotypes arise in the untreated tumor, they are typically present in small numbers because they are less fit than the sensitive population. This reflects the "cost" of phenotypic resistance such as additional substrate and energy used to up-regulate xenobiotic metabolism, and therefore not available for proliferation, or the growth inhibitory nature of environments (i.e., ischemia or hypoxia) that confer resistance on phenotypically sensitive cells. Thus, in the Darwinian environment of a cancer, the fitter chemosensitive cells will ordinarily proliferate at the expense of the less fit chemoresistant cells. The models show that, if resistant populations are present before administration of therapy, treatments designed to kill maximum numbers of cancer cells remove this inhibitory effect and actually promote more rapid growth of the resistant populations. We present an alternative approach in which treatment is continuously modulated to achieve a fixed tumor population. The goal of adaptive therapy is to enforce a stable tumor burden by permitting a significant population of chemosensitive cells to survive so that they, in turn, suppress proliferation of the less fit but chemoresistant

  4. Drug Therapy.

    Science.gov (United States)

    He, Ri-Hui; Tao, Ran

    2017-01-01

    This chapter first summarizes the therapy of addiction disorder, and elaborates on the progress of medication. First, the difference between dependency and addiction are introduced. The basic principles of the therapy of substance and non-substance addiction are then put forward. It is also pointed out in this chapter that with the progress of the study, the goal of addiction disorder therapy is expected to transfer from reducing the relapse and harm of the addiction to completely eliminating and recovering from it. This chapter also introduces the progress of psychological addiction elimination technology, especially the "Unconditioned Stimulus Retrieval Extinction Paradigm and Conditioned Stimulus Retrieval Extinction Paradigm" and PITDH technology. Finally it is pointed out that in addiction disorder therapy, comprehensive intervention has become a trend. With regard to the medication for addiction disorders, this chapter also includes the progress and deficiencies of substance and non-substance addiction. In terms of addiction disorder rehabilitation, the foundation of substance addiction is medication which is, however, limited for non-substance addiction. The key to the rehabilitation of addiction disorder is psycho-behavioral therapy, which is especially effective in eliminating craving.

  5. Neutron therapy

    International Nuclear Information System (INIS)

    Riesler, Rudi

    1995-01-01

    Standard radiotherapy uses Xrays or electrons which have low LET (linear energy transfer); in contrast, particles such as neutrons with high LET have different radiobiological responses. In the late 1960s, clinical trials by Mary Catterall at the Hammersmith Hospital in London indicated that fast neutron radiation had clinical advantages for certain malignant tumours. Following these early clinical trials, several cyclotron facilities were built in the 1980s for fast neutron therapy, for example at the University of Washington, Seattle, and at UCLA. Most of these newer machines use extracted cyclotron proton beams in the range 42 to 66 MeV with beam intensities of 15 to 60 microamps. The proton beams are transported to dedicated therapy rooms, where neutrons are produced from beryllium targets. Second-generation clinical trials showed that accurate neutron beam delivery to the tumour site is more critical than for photon therapy. In order to achieve precise beam geometries, the extracted proton beams have to be transported through a gantry which can rotate around the patient and deliver beams from any angle; also the neutron beam outline (''field shape'') must be adjusted to extremely irregular shapes using a flexible collimation system. A therapy procedure has to be appropriately organized, with physicians, radiotherapists, nurses, medical physicists and other staff in attendance; other specialized equipment, such as CT or MRI scanners and radiation simulators must be made available. Neutron therapy is usually performed only in radiation oncology departments of major medical centres

  6. Art Therapy

    DEFF Research Database (Denmark)

    Skov, Vibeke; Pedersen, Inge Nygaard

    2014-01-01

    Abstract Based on a Jungian approach, this article will introduce an integrative model to therapeutic change using art therapy methods as practical tools, with the aim of improving quality of life and in the prevention of depression. In a research study involving six participants, painting, clay...... work and drumming were used together with imagination and personal dialogues linked to the artwork. These art therapy processes attempted to combine the participant’s experience of inner and outer reality. The effect of gaining more knowledge about their inner reality using dreams and symbols......, was that participants gained a new understanding about their personal life. In addition, some participants were able to continue to use art therapy experiences as selfdevelopmental tools after the research study terminated. Jung’s description of the interactive relationship between the two living parts of the psyche...

  7. Oxygen Therapy

    Directory of Open Access Journals (Sweden)

    Bonnie Solmes

    2000-01-01

    Full Text Available LTOT is prescribed for people with chronic lung disease in whom there is a decrease in the ability of the lungs to supply enough oxygen to the body. The heart is obliged to pump faster to meet the body's oxygen requirements. This may place undue stress on the heart, resulting in palpitations, dizziness and fatigue. A low oxygen level in arterial blood is also harmful to the heart, the brain and the pulmonary blood vessels. Oxygen therapy is used to break this cycle. A person with low blood oxygen will often be able to accomplish more with less fatigue with the help of supplemental oxygen therapy. Shortness of breath is a mechanical problem resulting from the effects of chronic obstructive pulmonary disease. Oxygen therapy may or may not reduce shortness of breath, but it will help the lungs and heart to function with less stress.

  8. Music therapy

    DEFF Research Database (Denmark)

    Ridder, Hanne Mette Ochsner

    alternate with clear and lucid mental states. These states are important as it is here that it is possible to meet the person’s psychosocial needs. Ketil Normann’s conceps of periods of lucidity are presented and connected to clinical music therapy practice and how it is possible to use music in order...... as a consequence of person-centred care. Umeå University Medical Dissertations. New Series. Ridder, H.M. (2005). Music therapy as a way to enhance lucidity in persons with dementia in advanced stages. In: Esch, A.; Frohne-Hagemann, I.; Laqua, M.; Schirmer, H.; Seitz, E. (Eds.) Jahrbuch Musicktherapie. Forschung...... und Entwicklung Music Therapy Annual. Research and Development. 2005 (1), pp. 25-40. Reichert Verlag Wiesbaden....

  9. Radiation therapy

    International Nuclear Information System (INIS)

    Peschel, R.E; Fisher, J.J.

    1986-01-01

    The new insights and controversies concerning the radiobiological properties of malignant melanoma and how these relate to new clinical approaches are reviewed. The recent clinical experience with large individual fraction sizes is analyzed. The treatment of malignant melanoma in certain specialized sites is also described. An attempt is made to place in perspective the usefulness of radiation therapy in the treatment of this complex disease. Finally, certain new applications for radiation therapy both alone and in combustion with other treatment modalities are proposed that may ultimately prove appropriate for clinical trials

  10. Radiation therapy

    International Nuclear Information System (INIS)

    Matsuura, Keiichi; Miyoshi, Makoto; Jinguu, Ken-ichi

    1982-01-01

    Of the cases of lung cancer in which radiation therapy was given between 1961 and November 1981, 399 cases for which histological type was confirmed, and irradiated as follows were reviewed. The cases of squamous cell carcinoma and adenocarcinoma irradiated with more than 5,000 rad or more, those of undifferentiated carcinoma irradiated with 3,000 rad or more, and those irradiated pre- and post-operatively with 3,000 rad or more. The actual 5 year survival rate for stages I, II, III and IV were 29.6, 9.3, 7.5 and 1.9% respectively, and the survival rate tended to be better for adenocarcinoma than squamous cell carcinoma at stages I, II and III, but not different at stage IV. There was no difference between large cell, small cell and squamous cell carcinomas. Irradiation with 200 rad every other day or 150 rad daily was better than that with 200 rad, and daily irradiation with 150 rad was used since 1976. The therapy of stage III small cell carcinoma at the age of up to 80 years was improved with the combination of anticancer agents, maintenance therapy and immunotherapy, but these combined therapies were not significantly effective for the cancers with other histological types or at other stages. Although there was no significant difference in statistics for resectable cases, clinically, the results were experienced to be better after resection, and surgery was done in combination as much as possible. (Kaihara, S.)

  11. Dance Therapy.

    Science.gov (United States)

    Leventhal, Marcia B.

    1980-01-01

    Dance therapy deals with personal growth via body-mind interaction. A change in movement expression is believed to result in a personality or behavior change. The therapist is trained to become sensitive to movement expression as it relates to the psychological, motor, and cognitive development of the child. (JN)

  12. Shock therapies.

    Science.gov (United States)

    Dean, Erin

    2016-02-03

    Therapies administered by mental health nurses, aimed at "curing" gay people of their sexual preference were still in common use in the UK in the 1960s and early 1970s. Some nurses tried to avoid participating in these practices, but many believed that they were helping their patients, as a new book reveals.

  13. 5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

    Science.gov (United States)

    Wagner-Johnston, Nina D; Sloan, Jeff A; Liu, Heshan; Kearns, Ann E; Hines, Stephanie L; Puttabasavaiah, Suneetha; Dakhil, Shaker R; Lafky, Jacqueline M; Perez, Edith A; Loprinzi, Charles L

    2015-08-01

    Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. © 2015 American Cancer Society.

  14. Proton therapy

    International Nuclear Information System (INIS)

    Jongen, Y.

    1995-01-01

    Ideal radiotherapy deposits a large amount of energy in the tumour volume, and none in the surrounding healthy tissues. Proton therapy comes closer to this goal because of a greater concentration of dose, well defined proton ranges and points of energy release which are precisely known - the Bragg peak1. In the past, the development of clinical proton therapy has been hampered by complexity, size, and cost. To be clinically effective, energies of several hundred MeV are required; these were previously unavailable for hospital installations, and pioneering institutions had to work with complex, inadequate equipment originally intended for nuclear physics research. Recently a number of specialist organizations and commercial companies have been working on dedicated systems for proton therapy. One, IBA of Belgium, has equipment for inhouse hospital operation which encompasses a complete therapy centre, delivered as a turnkey package and incorporating a compact, automated, higher energy cyclotron with isocentric gantries. Their system will be installed at Massachusetts General Hospital, Boston. The proton therapy system comprises: - a 235 MeV isochronous cyclotron to deliver beams of up to 1.5 microamps, but with a hardware limitation to restrict the maximum possible dose; - variable energy beam (235 to 70 MeV ) with energy spread and emittance verification; - a beam transport and switching system to connect the exit of the energy selection system to the entrances of a number of gantries and fixed beamlines. Along the beam transport system, the beam characteristics are monitored with non-interceptive multiwire ionization chambers for automatic tuning; - gantries fitted with nozzles and beamline elements for beam control; both beam scattering and beam wobbling techniques are available for shaping the beam;

  15. Art Therapy: What Is Art Therapy?

    Science.gov (United States)

    ... individual, couples, family, and group therapy formats. Art therapy is an effective treatment for people experiencing developmental, medical, educational, and social or psychological impairment. Individuals who benefit from art therapy include ...

  16. Physical Therapy and Occupational Therapy in Progeria

    Science.gov (United States)

    Physical Therapy and Occupational Therapy in Progeria Information for Families and Caretakers from The Progeria Research Foundation ... Inc. All rights reserved. Page 2 of 5 Physical and Occupational Therapy in Progeria Hutchinson-Gilford Progeria ...

  17. Music Therapy: A Career in Music Therapy

    Science.gov (United States)

    About Music Therapy & Music Therapy Training M usic therapy is a healthcare profession that uses music to help individuals of all ages improve physical, cognitive, emotional, and social functioning. Music therapists work with children and adults with developmental ...

  18. Avaliação da Atividade Proliferativa no Epitélio Mamário Adjacente a Fibroadenoma em Mulheres Tratadas com Tamoxifeno Evaluation of Proliferative Activity in the Mammary Epithelium Adjacent to Fibroadenoma in Women Treated with Tamoxifen

    Directory of Open Access Journals (Sweden)

    Juarez Antônio de Sousa

    2000-08-01

    Full Text Available Objetivo: estudar a atividade proliferativa do epitélio mamário normal adjacente a fibroadenoma em mulheres na fase lútea do ciclo menstrual, tratadas com tamoxifeno. Pacientes e Métodos: estudou-se por técnica imuno-histoquímica, com o uso do anticorpo monoclonal MIB-1, a atividade proliferativa no epitélio mamário adjacente a fibroadenoma. O estudo foi randomizado e duplo-cego. As 44 mulheres com fibroadenoma foram divididas em 3 grupos: A (n = 16; placebo, B (n = 15; tamoxifeno, 10 mg e C (n = 13; tamoxifeno, 20 mg. O tamoxifeno foi utilizado por 22 dias, a partir do 2º dia do ciclo menstrual, e a biópsia realizada no 23º dia. Resultados: a porcentagem média de núcleos corados por 1000 células no grupo A foi 9,2, no grupo B, 4,5, e no grupo C, 3,2. O teste de Fisher revelou que o tamoxifeno reduziu de forma significante a imunoexpressão do MIB-1 nas doses de 10 e 20 mg em comparação com o grupo placebo (pPurpose: to study the monoclonal antibody MIB-1 in the normal breast epithelium adjacent to a fibroadenoma in women in the luteal phase of the menstrual cycle treated with tamoxifen. Patients and methods: the proliferative activity of the mammary epithelium adjacent to the fibroadenoma was studied by immunohistochemistry based on immunoexpression of the monoclonal antibody MIB-1. The study was randomized and double blind and was conducted on 44 women with fibroadenomas, divided into 3 groups: A (n = 16; placebo, B (n = 15; tamoxifen, 10 mg, and C (n = 13; tamoxifen, 20 mg. Tamoxifen was administered for 22 days starting on the 2nd day of the menstrual cycle and a biopsy was taken on the 23rd day. Results: the mean percentage of stained nuclei per 1000 cells was 9.2 in group A, 4.5 in group B, and 3.2 in group C. Fisher's test revealed that tamoxifen significantly reduced the immunoexpression of MIB-1 at the doses of 10 and 20 mg compared to the placebo group (p<0.0001, with no significant differences between doses in terms of

  19. Particle therapy

    Energy Technology Data Exchange (ETDEWEB)

    Raju, M.R.

    1993-09-01

    Particle therapy has a long history. The experimentation with particles for their therapeutic application got started soon after they were produced in the laboratory. Physicists played a major role in proposing the potential applications in radiotherapy as well as in the development of particle therapy. A brief review of the current status of particle radiotherapy with some historical perspective is presented and specific contributions made by physicists will be pointed out wherever appropriate. The rationale of using particles in cancer treatment is to reduce the treatment volume to the target volume by using precise dose distributions in three dimensions by using particles such as protons and to improve the differential effects on tumors compared to normal tissues by using high-LET radiations such as neutrons. Pions and heavy ions combine the above two characteristics.

  20. Radioiodine therapy

    International Nuclear Information System (INIS)

    Torres, J.F. Jr.; Deliso, H.B.

    1992-01-01

    For over 40 years now, radioiodine ( 131 I) has remained one of the most useful radionuclide for diagnosis and therapy in Nuclear Medicine. The wide application of radioiodine in the study of the thyroid gland and in the management of its disorders has been most rewarding. The medical literature is replete with reports of its efficacy, failures, and complications, but most of these studies have been conducted among Caucasian persons and in relatively affluent societies. Very few reports are available from the less developed and economically depressed areas of the world where thyroid disorders abound or and are even endemic. This chapter is an attempt to highlight the use of radioactive iodine therapy in the developing countries, particularly those in the Asian region

  1. Particle therapy

    International Nuclear Information System (INIS)

    Raju, M.R.

    1993-01-01

    Particle therapy has a long history. The experimentation with particles for their therapeutic application got started soon after they were produced in the laboratory. Physicists played a major role in proposing the potential applications in radiotherapy as well as in the development of particle therapy. A brief review of the current status of particle radiotherapy with some historical perspective is presented and specific contributions made by physicists will be pointed out wherever appropriate. The rationale of using particles in cancer treatment is to reduce the treatment volume to the target volume by using precise dose distributions in three dimensions by using particles such as protons and to improve the differential effects on tumors compared to normal tissues by using high-LET radiations such as neutrons. Pions and heavy ions combine the above two characteristics

  2. Music Therapy

    DEFF Research Database (Denmark)

    Trondalen, Gro; Bonde, Lars Ole

    2012-01-01

    music therapy orientations/models (Guided Imagery and Music, Nordoff-Robbins, Psychoanalytic, Cognitive-behavioral etc), their theoretical foundations and their practical approaches to health and wellbeing or ‘health musicking’. The relational context – the interplay of (expressive as well as receptive......Music therapy (MT) is most commonly defined as an intervention where “the therapist helps the client to promote health, using music experiences and the relationships developing through them” (Bruscia 1998). Also other definitions of MT agree that a therapeutic relationship is important for a music...... intervention to be considered MT. Other interventions that “use music for health-related goals, but in ways that do not qualify as music therapy” (Gold 2009), may be described as music medicine, or simply as music listening. In this text we elaborate on an overview chapter covering some of the different major...

  3. Music Therapy

    DEFF Research Database (Denmark)

    Sanfi, Ilan

    2012-01-01

    may cause detrimental long-term effects. Three studies have examined the effect of music therapy procedural support (MTPS) under needle procedures. Consequently, this study aims at examining the effects of MTPS in an RCT. Moreover, the study addresses clinical aspects of the applied MT intervention...... and provides research-based clinical tools. Methods 41 children (1 to 10 years) were enrolled and underwent a single PIVA procedure. The children were randomly assigned to either an MT or a comparable control group receiving PIVA. In addition, the music therapy (MT) group received individualised MTPS (i.......e. music alternate engagement) before, during, and after PIVA. The intervention was performed by a trained music therapist and comprised preferred songs, improvised songs/music, and instrument playing. The study was carried out in accordance with the rules in force regarding research ethics and clinical MT...

  4. Radioiodine therapy

    Energy Technology Data Exchange (ETDEWEB)

    Torres, Jr, J F; Deliso, H B

    1993-12-31

    For over 40 years now, radioiodine ({sup 131}I) has remained one of the most useful radionuclide for diagnosis and therapy in Nuclear Medicine. The wide application of radioiodine in the study of the thyroid gland and in the management of its disorders has been most rewarding. The medical literature is replete with reports of its efficacy, failures, and complications, but most of these studies have been conducted among Caucasian persons and in relatively affluent societies. Very few reports are available from the less developed and economically depressed areas of the world where thyroid disorders abound or and are even endemic. This chapter is an attempt to highlight the use of radioactive iodine therapy in the developing countries, particularly those in the Asian region

  5. Physical Therapy (For Parents)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Physical Therapy KidsHealth / For Parents / Physical Therapy Print en español Terapia física Physical Therapy Basics Doctors often recommend physical therapy (PT) ...

  6. Utility of {sup 18}F-fluoroestradiol ({sup 18}F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Frank I. [National Cancer Institute, NIH, Cancer Imaging Program, Bethesda, MD (United States); National Cancer Institute, Molecular Imaging Program, Bethesda, MD (United States); Gonzalez, E.M.; Kurdziel, K.A.; Ton, A.; Turkbey, B.; Choyke, P.L.; Lindenberg, M.L. [National Cancer Institute, Molecular Imaging Program, Bethesda, MD (United States); Kummar, S.; Do, K.; Collins, J.M.; Doroshow, J.H. [National Cancer Institute, Division of Cancer Treatment and Diagnosis and Center for Cancer Research, Bethesda, MD (United States); Shih, J. [National Cancer Institute, NIH, Biometric Research Program, Bethesda, MD (United States); Adler, S. [Leidos Biomedical Research, Inc., Clinical Research Directorate/Clinical Monitoring Research Program, Frederick, MD (United States); Jacobs, P.M. [National Cancer Institute, NIH, Cancer Imaging Program, Bethesda, MD (United States); Bhattacharyya, S. [Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD (United States); Chen, A.P. [National Cancer Institute, Early Clinical Trials Development Program, DCTD, Bethesda, MD (United States)

    2017-03-15

    Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. {sup 18}F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes {sup 18}F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with {sup 18}F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with {sup 18}F-FES 1-5 days post administration of Z-endoxifen. Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy. (orig.)

  7. [Gestalt therapy.].

    Science.gov (United States)

    Corbeil, J; Poupard, D

    1978-01-01

    The authors describe Gestalt Therapy. They retrace its fundamental theoretical axes. These are psychoanalysis, character analysis, the german Gestalt theory of perception, existentialism, and the Orient. Some principal concepts are then elaborated more fully such as the cycle of awareness, desensitization, excitation anxiety and the five defense mechanisms: retroflection, introjection, projection, deflection, and confluence. The nature and goals of the therapeutic process are also described before the presentation of some techniques specific to this approach such as enactment and role playing. Finally, certain basic Gestalt rules, which aim at facilitating and intensifying the communication process among group members, are enunciated.

  8. Genetically Guided Statin Therapy on Statin Perceptions, Adherence, and Cholesterol Lowering: A Pilot Implementation Study in Primary Care Patients

    Directory of Open Access Journals (Sweden)

    Josephine H. Li

    2014-03-01

    Full Text Available 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 primary outcome was the change in Beliefs about Medications Questionnaire, which measured patients’ perceived needs for statins and concerns about adverse effects, measured before and after SLCO1B1*5 results. Concurrent controls (n = 59 were identified through the EMR to compare secondary outcomes: new statin prescriptions, statin utilization, and change in LDL-cholesterol (LDL-c. GGST patients had trends (p = 0.2 towards improved statin necessity and concerns. The largest changes were the “need for statin to prevent sickness” (p < 0.001 and “concern for statin to disrupt life” (p = 0.006. GGST patients had more statin prescriptions (p < 0.001, higher statin use (p < 0.001, and greater decrease in LDL-c (p = 0.059 during follow-up. EMR delivery of SLCO1B1*5 results and recommendations is feasible in the primary care setting. This novel intervention may improve patients’ perceptions of statins and physician behaviors that promote higher statin adherence and lower LDL-c.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    BACKGROUND: New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear...... whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved...... of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate...

  10. Radiation therapy

    International Nuclear Information System (INIS)

    Bader, J.L.; Glatstein, E.

    1987-01-01

    The radiation oncologist encounters the critically ill immunosuppressed patient in four settings. First, the newly diagnosed cancer patient presents for initial evaluation and treatment, with immunosuppression from the cancer itself, malnutrition, concomitant infectious disease, prior drug or alcohol abuse or other medical problems. Second, the previously treated cancer patient presents with metastatic or recurrent primary cancer causing local symptoms. Immune dysfunction in this setting may be due to prior chemotherapy and/or radiation as well as any of the original factors. Third, the patient previously treated with radiation presents with a life-threatening problem possibly due to complications of prior therapy. In this setting, the radiation oncologist is asked to evaluate the clinical problem and to suggest whether radiation might be causing part or all of the problem and what can be done to treat these sequelae of radiation. Fourth, the patient with a benign diagnosis (not cancer) is seen with a problem potentially emeliorated by radiation (e.g., kidney transplant rejection, preparation for transplant, or intractable rheumatoid arthritis). This chapter reviews these four issues and presents clinical and radiobiologic principles on which recommendations for therapy are based

  11. Benefit of the addition of hormone therapy to neoadjuvant anthracycline-based chemotherapy for breast cancer: comparison of predicted and observed pCR.

    Science.gov (United States)

    Generali, Daniele; Corona, Silvia Paola; Pusztai, Lajos; Rouzier, Roman; Allevi, Giovanni; Aguggini, Sergio; Milani, Manuela; Strina, Carla; Frati, Albane

    2018-03-01

    Neoadjuvant hormonal therapy is generally considered a valid option for hormone receptor positive breast cancer (BC) patients who are unfit for chemotherapy or surgery. Whilst numerous studies analyzed efficacy of neoadjuvant chemotherapy (CT) or endocrine therapy (HT) alone in hormone receptor positive patients, there is a lack of research looking at the usefulness of a preoperative combinatorial approach of CT and HT in this patient subgroup. Using a predictive model previously described in the literature, developed to analyze the probability of benefit from preoperative chemotherapy, we were able to compare pathological complete response (pCR) rates expected with the use of CT alone with the pCR rates reported in a population of 192 patients treated with the combination of tamoxifen plus anthracycline-based CT at Cremona Hospital between 2003 and 2006. Even with a relatively small patient population, this approach provided insightful information for the selection of hormone receptor positive BC patients most likely to benefit from the use of preoperative HT and CT in combination. Whilst no statistically significant benefit was obtained with the addition of tamoxifen to neoadjuvant chemotherapy in the entire population, or in any of the molecular stratification subgroups, the analysis of the calibration curve showed that a combinatorial approach may improve pCR in patients with luminal B tumors. More specific trials should be designed to confirm our initial results. To the best of our knowledge, this is the first report investigating the efficacy of the combination of CT and HT in the neoadjuvant treatment of hormone receptor positive BC.

  12. Does fasting during Ramadan trigger non-adherence to oral hormonal therapy in breast cancer patients?

    International Nuclear Information System (INIS)

    Zeeneldin, A.A.; Gaber, A.A.; Taha, F.M.

    2012-01-01

    Purpose: To estimate the effect of fasting during Ramadan (the ninth lunar month) on adherence to oral hormonal therapies (OHT) among breast cancer (BC) patients. Patients and Methods: During Ramadan 2010, 139 BC patients were interviewed at the Egyptian National Cancer Institute. They were asked about fasting as well as intake of OHT in Ramadan and in the preceding month. Results: The median age was 50 years and most patients were postmenopausal with good performance status and non-metastatic disease. The median number of fasting days was 18% and 93% of patients were fasting 80% or more of Ramadan. Tamoxifen and aromatase inhibitors were used in 64% and 36%, respectively. Adherence to OHT during Ramadan and its preceding month were 94.2% and 95.7%, respectively (p = 0.77). In univariate analysis, non-adherence prior to Ramadan and shorter duration of OHT were predictors of non-adherence during Ramadan (P < 0.001, 0.003, respectively). Fasting, age, performance status, presence of metastases and type of hormonal therapy were not good predictors of adherence. Conclusions: While most of patients receiving OHT for BC are fasting during Ramadan, this does not negatively impact compliance with treatment

  13. The Impact of Endocrine Therapy on Cognitive Functions of Breast Cancer Patients: A Systematic Review.

    Science.gov (United States)

    Bakoyiannis, Ioannis; Tsigka, Eleousa-Alexandra; Perrea, Despina; Pergialiotis, Vasilios

    2016-02-01

    The purpose of the present review was to study the impact of endocrine therapy (ET) on the cognitive outcomes of breast cancer patients. We systematically searched the literature using the MEDLINE (1966-2015), Scopus (2004-2015), ClinicalTrials.gov (2008-2015) and Cochrane Central Register (CENTRAL) databases, as well as the references of the electronically retrieved articles. Twelve studies were included in the present systematic review, which assessed the cognitive function of 2756 patients. Among these patients, 2381 received ET, whereas the remaining 375 served as controls (placebo or no therapy). The majority of patients were postmenopausal, and the minimum follow-up period was 3 months and the maximum 2 years. Treatment with ET seems to be accompanied by altered cognitive abilities, including verbal memory, verbal fluency, motor speed, attention and working memory. Tamoxifen seems to be related to decreased cognitive performances compared with treatment with an aromatase inhibitor. ET among breast cancer patients seems to negatively alter the cognitive outcomes of breast cancer patients. However, the methodological heterogeneity of the included studies, as well as the relatively small follow-up period, render imperative the conduct of further studies in the field.

  14. Tamoxifen or letrozole versus standard methods for women with estrogen-receptor positive breast cancer undergoing oocyte or embryo cryopreservation in assisted reproduction

    NARCIS (Netherlands)

    Dahhan, Taghride; Balkenende, Eva; van Wely, Madelon; Linn, Sabine; Goddijn, Mariette

    2013-01-01

    Cryopreservation of oocytes or embryos preceded by controlled ovarian stimulation (COS) can increase the chance of future pregnancy in women with breast cancer who risk therapy-induced ovarian failure. In women with estrogen-receptor (ER) positive breast cancer, alternative COS protocols with

  15. The patterns of care study for breast-conserving therapy in Japan: Analysis of process survey from 1995 to 1997

    International Nuclear Information System (INIS)

    Mitsumori, Michihide; Hiraoka, Masahiro; Negoro, Yoshiharu; Yamauchi, Chikako; Shikama, Naoto; Sasaki, Shigeru; Yamamoto, Tokihiro; Teshima, Teruki; Inoue, Toshihiko

    2005-01-01

    Purpose: To present the results of a process survey on breast-conserving therapy (BCT) in Japan from 1995 to 1997. Methods and Materials: From September 1998 to December 1999, data on the treatment process of 865 randomly selected BCT patients were collected by extramural audits. Results: For primary surgery, wide excision or tumorectomy was performed in 372 patients (43.0%), and quadrantectomy or segmental mastectomy was performed in 493 patients (57%). The extent of axillary dissection was equal or beyond Level II in 590 patients (68.2%). Systemic chemotherapy was administered to 103 of 160 node-positive patients (64.4%) and 180 of 569 node-negative patients (31.6%). Tamoxifen was administered to 234 of 323 hormone receptor-positive patients (72.5%) and 68 of 130 hormone receptor-negative patients (52.3%). Photon energy of 10 MV was administered for whole breast irradiation in 38 patients (4.4%) without bolus. Conclusions: The extent of surgical resection for BCT was large in Japan. Pathologic assessment and the technique of radiation therapy were apparently suboptimal in some cases. Information on prognostic/predictive factors was not fully utilized to individualize systemic adjuvant therapy. Establishment and widespread use of guidelines for BCT for in Japan are desirable. Repeated surveys will demonstrate how such guidelines affect clinical practices

  16. Dystonia: Physical Therapy

    Science.gov (United States)

    ... Online Support Frequently Asked Questions Faces of Dystonia Physical Therapy Physical therapy may be an important component of treating ... everyday tasks, Since dystonia is a neurological disorder, physical therapy does not treat the dystonia directly but ...

  17. Brain Stimulation Therapies

    Science.gov (United States)

    ... Magnetic Seizure Therapy Deep Brain Stimulation Additional Resources Brain Stimulation Therapies Overview Brain stimulation therapies can play ... for a shorter recovery time than ECT Deep Brain Stimulation Deep brain stimulation (DBS) was first developed ...

  18. Laser therapy for cancer

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000905.htm Laser therapy for cancer To use the sharing features ... Lasers are also used on the skin. How Laser Therapy is Used Laser therapy can be used ...

  19. American Music Therapy Association

    Science.gov (United States)

    American Music Therapy Association Home Contact News Help/FAQ Members Only Login Quick Links Facts About Music Therapy Qualifications ... with AMTA Sponsor AMTA Events Social Networking Support Music Therapy When you shop at AmazonSmile, Amazon will ...

  20. [Physical therapy].

    Science.gov (United States)

    Chohnabayashi, Naohiko

    2008-01-01

    Recently, pulmonary rehabilitation program is widely considered one of the most effective and evidence-based treatment for not only chronic obstructive pulmonary disease (COPD) but many clinical situations including neuro-muscular disease, post-operative status and weaning period from the ventilator, etc. The essential components of a pulmonary rehabilitation program are team assessment, patient training, psycho-social intervention, exercise, and follow-up. In 2003, Japanese medical societies (J. Thoracic Society, J. Pul. Rehabilitation Society and J. Physiotherapist Society) made a new guideline for pulmonary rehabilitation, especially how to aproach the execise training. As for the duration after surgical operation, airway cleaning is the important technique to prevent post-operative complications including pneumonia. Postural dranage technique is well known for such condition, at the same time, several instruments (flutter vulve, positive expiratory mask, high frequecy oscillation, etc) were also used for the patient to expectrate airway mucus easier. Lung transplantation is a new method of treatment for the critically-ill patients with chronic respiratoy failure. Several techniques of physical therapy are must be needed before and after lung transplantation to prevent both pulmonary infection and osteoporosis.

  1. Growth inhibition in response to estrogen withdrawal and tamoxifen therapy of human breast cancer xenografts evaluated by in vivo 31P magnetic resonance spectroscopy, creatine kinase activity, and apoptotic index

    DEFF Research Database (Denmark)

    Kristensen, C A; Kristjansen, P E; Brünner, N

    1995-01-01

    index, and creatine kinase (CK) activity. Tumors of each line were grown in ovariectomized nude mice during stimulation from a s.c. 17 beta-estradiol pellet. At a tumor size of approximately 350 mm3, the pellet was removed from one-half of the animals. The remaining one-half served as controls...

  2. Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation.

    Science.gov (United States)

    Lee, Oukseub; Ivancic, David; Allu, Subhashini; Shidfar, Ali; Kenney, Kara; Helenowski, Irene; Sullivan, Megan E; Muzzio, Miguel; Scholtens, Denise; Chatterton, Robert T; Bethke, Kevin P; Hansen, Nora M; Khan, Seema A

    2015-12-01

    Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs. Athymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography-tandem mass spectroscopy. Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable. These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery.

  3. Complementary and Integrative Therapies

    Science.gov (United States)

    ... include: • Acupressure and acupuncture • Aromatherapy • Art therapy and music therapy • Chiropractic medicine and massage • Guided imagery • Meditation and ... should I avoid? • Is this complementary therapy (name therapy) safe? Is there research showing it is safe? • Are there side effects ...

  4. Radiotechnologies and gene therapy

    International Nuclear Information System (INIS)

    Xia Jinsong

    2001-01-01

    Gene therapy is an exciting frontier in medicine today. Radiologist will make an uniquely contribution to these exciting new technologies at every level by choosing sites for targeting therapy, perfecting and establishing routes of delivery, developing imaging strategies to monitor therapy and assess gene expression, developing radiotherapeutic used of gene therapy

  5. [Physical therapy for scars].

    Science.gov (United States)

    Masanovic, Marguerite Guillot

    2013-01-01

    Physical therapy consists notably of hand or mechanical massages, pressure therapy using various fabrics or splints, cryotherapy, laser therapy, etc. It forms part of the range of therapies used to treat pathological scars, including medical and surgical treatment. While the results are often satisfactory for hypertrophic scars, they remain uncertain for major keloids.

  6. Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

    Science.gov (United States)

    Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

    2013-02-01

    Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

  7. Endocrine therapy for postmenopausal women with hormone receptor–positive her2–negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement

    Science.gov (United States)

    Pritchard, K.I.; Gelmon, K.A.; Rayson, D.; Provencher, L.; Webster, M.; McLeod, D.; Verma, S.

    2013-01-01

    Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2–) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients—efect, sofea, confirm, and bolero-2—have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2– advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928

  8. Music therapy in kindergarten

    OpenAIRE

    Šírová, Michaela

    2017-01-01

    This work deals with the subject of music therapy in a special kindergarten for the children with combined disabilities. In the theoretical part it clarifies the concept and principle of music therapy and characterizes the types of disabilities that occur at researched clients. As a research method were used observation and interviews with three music therapists from the institution. KEYWORDS Music therapy, preschool education, special pedagogy, group music therapy,individual music therapy, p...

  9. Recovery of menstruation after long-term chemotherapy and endocrine therapy in pre-menopausal patients with breast cancer.

    Science.gov (United States)

    Sakurai, Kenichi; Enomoto, Katsuhisa; Amano, Sadao

    2011-04-01

    A luteinizing hormone-releasing hormone (LH-RH) agonist and tamoxifen (TAM) are used in hormonal therapy following pre- and post-operative chemotherapy in pre-menopausal advanced breast cancer patients who are positive for hormone receptors. However, it remains to be clarified how often patients recover menstruation after long-term LH-RH agonist plus TAM therapy. In this study, the incidence of menstruation recovery after therapy was examined. The subjects included 125 pre-menopausal patients with breast cancer who were positive for hormone receptors and had undergone surgery at our institution. They were treated with four cycles of the CEF regimen and four cycles of docetaxel (Doc) before surgery as adjuvant chemotherapy. Thereafter, they were treated with an LH-RH agonist plus TAM for 24 months and followed to determine menstruation recovery. Menstruation resumed in 24 cases (19.2%) after the last LH-RH agonist treatment session. It took 7.3 ± 2.8 months for the patients to recover menstruation. The rate of menstruation recovery was 42.1% in patients aged 40 or younger and 9.2% in those aged 41 or older; the difference was significant. The period until menstruation recovery tended to be longer in older patients at the end of treatment. The menstruation recovery rate after therapy was higher in younger women. However, since ovarian function may be lost even in younger patients, the potential consequences of this therapy should be fully explained beforehand to patients who may wish to become pregnant.

  10. Adherence to anti-estrogen therapy in seniors with breast cancer: how well are we doing?

    Science.gov (United States)

    Trabulsi, Nora; Riedel, Kristen; Winslade, Nancy; Gregoire, Jean-Pierre; Meterissian, Sarkis; Abrahamovicz, Michal; Tamblyn, Robyn; Mayo, Nancy; Meguerditchian, Ari

    2014-01-01

    A third of breast cancers (BC) occur in women ≥65 years (seniors). Anti-estrogen therapy (AET) significantly reduces BC recurrence and death. This study characterizes determinants of adherence to AET in seniors with BC. Provincial cancer registry and administrative claims data were accessed for all non-metastatic BC diagnosed in Quebec (1998-2005) to identify seniors treated for 5 years with AET. Multivariate linear regression was used to assess the association with patient, disease, and physician characteristics and the 5-year medication possession ratio (MPR) for each patient. 4,715 women were included (mean age: 72.9). Mean MPR was 83.5%, 79% of patients reached a 5-year MPR of ≥80%, and 34% discontinued AET at some point during treatment. The cumulative probability of discontinuation was 33.8% (mean time to discontinuation 2.3 years). The MPR decreased with increasing age and non-BC related hospitalizations, p seniors with BC remained a challenge and medication discontinuation rates were high. Advanced age, increasing number of hospitalizations, in situ disease, baseline use of antidepressants, Tamoxifen (versus aromatase inhibitors), early switches of AET type, and newly added medications significantly reduced the MPR. © 2014 Wiley Periodicals, Inc.

  11. Does fasting during Ramadan trigger non-adherence to oral hormonal therapy in breast cancer patients?

    Science.gov (United States)

    Zeeneldin, Ahmed Abdelmabood; Gaber, Ayman Abdelsamee; Taha, Fatma Mohamed

    2012-09-01

    To estimate the effect of fasting during Ramadan (the ninth lunar month) on adherence to oral hormonal therapies (OHT) among breast cancer (BC) patients. During Ramadan 2010, 139 BC patients were interviewed at the Egyptian National Cancer Institute. They were asked about fasting as well as intake of OHT in Ramadan and in the preceding month. The median age was 50years and most patients were postmenopausal with good performance status and non-metastatic disease. The median number of fasting days was 18% and 93% of patients were fasting 80% or more of Ramadan. Tamoxifen and aromatase inhibitors were used in 64% and 36%, respectively. Adherence to OHT during Ramadan and its preceding month were 94.2% and 95.7%, respectively (p=0.77). In univariate analysis, non-adherence prior to Ramadan and shorter duration of OHT were predictors of non-adherence during Ramadan (PRamadan, this does not negatively impact compliance with treatment. Copyright © 2012. Published by Elsevier B.V.

  12. [Plastic surgery for the treatment of gynaecomastia following hormone therapy in prostate carcinoma].

    Science.gov (United States)

    Ryssel, H; Germann, G; Köllensperger, E; Riedel, K

    2008-04-01

    Gynecomastia is a potential side effect of hormone therapy for prostate cancer. In large, randomized, placebo controlled studies approximately 50% or more of patients with prostate cancer experienced gynecomastia attributable to various mechanisms. Although it is mostly reported as mild to moderate, gynecomastia is one of the reasons most frequently cited for premature discontinuation of such treatment. Prophylactic radiotherapy and prophylactic tamoxifen have been shown to decrease the incidence of hormone-induced gynecomastia; nevertheless, there are still cases of refractory gynecomastia, and in these plastic surgery is needed for correction. Gynecomastia is a benign enlargement of the male breast, requiring no treatment unless it is a source of embarrassment and/or distress for the adolescent or man affected. The indications for surgical treatment of gynecomastia are founded on two main objectives: restoration of the male chest shape and diagnostic evaluation of suspected breast lesions. The authors believe that the complete circumareolar technique with no further scarring creates the best aesthetic results with fewer complications. When this is used in combination with liposuction very pleasing aesthetic results can be achieved.

  13. Assessment of complications in a randomized controlled study on multimodality therapy for patients following breast-conserving surgery

    International Nuclear Information System (INIS)

    Hiraoka, Masahiro; Inoue, Toshihiko; Kodama, Hiroshi; Sako, Masao

    2002-01-01

    We conducted a randomized controlled study to evaluate the safety and usefulness of a combined treatment of radiotherapy and chemotherapy with doxifluridine (5'-DFUR) plus tamoxifen (TAM) as an adjuvant therapy for breast cancer patients after conservative surgery. The complications observed in this trial are reported herein. A total of 550 patients were registered and randomized (based on factors such as T, N, with/without radiotherapy) to groups A and B. Drug regimens were: group A, 5'-DFUR 600 mg/body/day for 6 months and TAM 20 mg/body/day for 2 years; group B, 5'-DFUR 600 mg/body/day for 2 years and TAM 20 mg/body/day for 2 years. Radiotherapy (2 Gy x 5 times/week, for 5 weeks) was administered to 88.6% of evaluable patients (481/543). Radiation-related acute adverse reactions occurred in 28.5% of the 481 patients and moderate to severe reactions occurred in 1.5% of the patients. Delayed radiation-related adverse reactions occurred in 17.9% of group A patients and 25.6% of group B patients. Grade 3 reactions occurred in 6 of the group A patients (2.4%) and in 5 of the group B patients (1.9%); all adverse reactions subsided after dose reduction or discontinuation. These findings suggest that the combination therapy of irradiation and 5'-DFUR with TAM is safe for patients after breast conserving surgery. (author)

  14. Tamoxifen-inducible gene deletion reveals a distinct cell type associated with trabecular bone, and direct regulation of PTHrP expression and chondrocyte morphology by Ihh in growth region cartilage.

    Science.gov (United States)

    Hilton, Matthew J; Tu, Xiaolin; Long, Fanxin

    2007-08-01

    Indian hedgehog (Ihh) controls multiple aspects of endochondral skeletal development by signaling to both chondrocytes and perichondrial cells. Previous efforts to delineate direct effects of Ihh on chondrocytes by Col2-Cre-mediated ablation of Smoothened (Smo, encoding a transmembrane protein indispensable for Ihh signaling) has been only partially successful, due to the inability to discriminate between chondrocytes and perichondrial cells. Here we report a transgenic line (Col2-Cre) expressing under the control of the Colalpha1(II) promoter an inert form of Cre that is activatable by exogenous tamoxifen (TM); TM administration at proper times during embryogenesis induced Cre activity in chondrocytes but not in the perichondrium. By using this mouse line, we deleted Smo within subsets of chondrocytes without affecting the perichondrium and found that Smo removal led to localized disruption of the expression of parathyroid hormone-related protein (PTHrP) and the morphology of chondrocytes. Unexpectedly, TM invariably induced Cre activity in a subset of cells associated with the trabecular bone surface of long bones. These cells, when genetically marked and cultured in vitro, were capable of producing bone nodules. Expression of the Col2-Cre transgene in these cells likely reflected the endogenous Colalpha1(II) promoter activity as similar cells were found to express the IIA isoform of Colalpha1(II) mRNA endogenously. In summary, the present study has not only provided evidence that Ihh signaling directly controls PTHrP expression and chondrocyte morphology in the growth region cartilage, but has also uncovered a distinct cell type associated with the trabecular bone that appears to possess osteogenic potential.

  15. Music Therapy and Music Therapy Research. Response

    DEFF Research Database (Denmark)

    Pedersen, Inge Nygaard

    2002-01-01

    This response to Keynote by Prof. Even Ruud (N)"Music Education and Music Therapy seeks to define these two areas with specific focus on tools and methods for analysis of music as these methods are developed in music therapy. This includes that the music therapist, the music and the client create...

  16. Adlerian Marriage Therapy.

    Science.gov (United States)

    Carlson, Jon; Dinkmeyer, Don, Sr.

    1987-01-01

    Describes the assumptions, processes, and techniques used in Alderian marriage therapy. Describes purpose of therapy as assessing current beliefs and behaviors while educating the couple in new procedures that can help the couple establish new goals. (Author/ABL)

  17. Genes and Gene Therapy

    Science.gov (United States)

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  18. Complementary Pancreatitis Therapies

    Science.gov (United States)

    ... medication, and improve quality of life.1,2 Massage Therapy Massage therapy involves touch and different techniques of stroking ... of the body or be a full-body massage. Massage can be performed through one’s clothing or ...

  19. [Play therapy in hospital].

    Science.gov (United States)

    Gold, Katharina; Grothues, Dirk; Leitzmann, Michael; Gruber, Hans; Melter, Michael

    2012-01-01

    The following article presents an overview of current research studies on play therapy in the hospital. It highlights individual diagnoses for which play therapy has shown reasonable success. The aim of this review is to describe the current status of the scientific debate on play therapy for sick children in order to allow conclusions regarding the indications for which play therapy is or might be useful.

  20. Tumor therapy and pregnancy

    International Nuclear Information System (INIS)

    Joss, R.; Brunner, K.W.

    1982-01-01

    Many successfully treated tumour patients are children and juveniles. This raises questions as to the effects of tumour therapy on reproductiveness and offspring. The possible extent of damage to the male and female gonads caused by surgical, chemical, and radiological tumour therapy is investigated. Also, the problem of tumour therapy or women developing neoplasms during pregnancy. Pregnancies after successful tumour therapy are quite frequent today. Experience so far suggests that the rate of congenital deformities is not significantly increased. (orig.) [de

  1. Combined tumor therapy

    International Nuclear Information System (INIS)

    Wrba, H.

    1990-01-01

    This comprehensive survey of current methods and achievements first takes a look at the two basic therapies, devoting a chapter each to the surgery and radiotherapy of tumors. The principal subjects of the book, however, are the systemic, adjuvant therapy, biological therapies, hyperthermia and various other therapies (as e.g. treatment with ozone, oxygen, or homeopathic means), and psychotherapy. (MG) With 54 figs., 86 tabs [de

  2. Play Therapy: A Review

    Science.gov (United States)

    Porter, Maggie L.; Hernandez-Reif, Maria; Jessee, Peggy

    2009-01-01

    This article discusses the current issues in play therapy and its implications for play therapists. A brief history of play therapy is provided along with the current play therapy approaches and techniques. This article also touches on current issues or problems that play therapists may face, such as interpreting children's play, implementing…

  3. Evaluation of Inter Therapy

    DEFF Research Database (Denmark)

    Pedersen, Inge Nygaard

    2002-01-01

    This article (revised conference lecture from the 10th World Congress of Music Therapy, Oxford July 2002)) emphasizes the evaluation of the training of Inter Therapy for music therapy students at the MA training at Aalborg University. The students take turns in being client and therapist within...

  4. Health care factors associated with survival among women with breast cancer on hormone therapy in Rio de Janeiro, Brazil, 2004 – 2010

    Directory of Open Access Journals (Sweden)

    Cláudia de Brito

    Full Text Available ABSTRACT Objectives To better understand the role that health care plays in breast cancer survival by investigating the effects that hormone therapy adherence and other select health care variables, adjusted for clinical and sociodemographic factors, had among a population of women in Rio de Janeiro, Brazil. Methods This was a longitudinal study based on secondary data of 5 861 women treated with hormone therapy (tamoxifen or aromatase inhibitors at the National Cancer Institute of Brazil (INCA, from 1 January 2004 – 29 October 2010. Four different sources of data were integrated for analysis: INCA Pharmacy Sector Dispensation System; Hospital-based Cancer Registry; Integrated Hospital System and INCA Absolute System; and Mortality Information System. Analyses explored the effects of adherence to hormone therapy, disease care aspects, and sociodemographic, behavioral, and clinical variables, on the time of survival, using Kaplan-Meier and Cox proportional hazards models. Results The general survival rate was 94% in the first year after initiation of hormone therapy, and 71% in the fifth year. The Cox model indicated a higher hazard of death among women smokers, with more hospitalizations, more exams, and, among those who used, who used only aromatase inhibitors, as hormone therapy modality. The hazard was lower among women with a partner (stable relationship, a high school or college education a family history of cancer, and those who were treated by a mastologist, oncologist, and/or psychotherapist, who underwent surgery, and who adhered to hormone therapy. Conclusions The study indicated more vulnerable sub-groups and the aspects of care that provide best results, bringing new knowledge to improve assistance to this group of women.

  5. Music Therapy for Seniors

    OpenAIRE

    SLUNEČKOVÁ, Petra

    2014-01-01

    This bachelor thesis deals with the use of music therapy in the lives of seniors. The target of this thesis is to map the possibilities of using music therapy ways with seniors and to recommend a suitable music therapy resources on the basis of the research and evaluation of obtained dates. The theoretical part describes the term "the music therapy", e.g. concept, definition, types and forms, the development of music therapy, the history, methods and techniques. This age group is defined in t...

  6. Inhalation Therapy in Horses.

    Science.gov (United States)

    Cha, Mandy L; Costa, Lais R R

    2017-04-01

    This article discusses the benefits and limitations of inhalation therapy in horses. Inhalation drug therapy delivers the drug directly to the airways, thereby achieving maximal drug concentrations at the target site. Inhalation therapy has the additional advantage of decreasing systemic side effects. Inhalation therapy in horses is delivered by the use of nebulizers or pressured metered dose inhalers. It also requires the use of a muzzle or nasal mask in horses. Drugs most commonly delivered through inhalation drug therapy in horses include bronchodilators, antiinflammatories, and antimicrobials. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. [Music therapy and depression].

    Science.gov (United States)

    Van Assche, E; De Backer, J; Vermote, R

    2015-01-01

    Music therapy is a predominantly non-verbal psychotherapy based on music improvisation, embedded in a therapeutic relationship. This is the reason why music therapy is also used to treat depression. To examine the efficacy of music therapy and to report on the results of recent research into the value of music therapy as a treatment for depression. We reviewed the literature on recent research into music therapy and depression, reporting on the methods used and the results achieved, and we assessed the current position of music therapy for depression in the context of evidence-based scientific research. A wide variety of research methods was used to investigate the effects of using music therapy as a psychotherapy. Most studies focused usually on the added value that music therapy brings to the standard form of psychiatric treatment, when administered with or without psychopharmacological support. Music therapy produced particularly significant and favourable results when used to treat patients with depression. Current research into music therapy and depression points to a significant and persistent reduction in patients' symptoms and to improvements in their quality of life. However, further research is needed with regard to the best methods of illustrating the effects of music therapy.

  8. Hendee's radiation therapy physics

    CERN Document Server

    Pawlicki, Todd; Starkschall, George

    2016-01-01

    The publication of this fourth edition, more than ten years on from the publication of Radiation Therapy Physics third edition, provides a comprehensive and valuable update to the educational offerings in this field. Led by a new team of highly esteemed authors, building on Dr Hendee’s tradition, Hendee’s Radiation Therapy Physics offers a succinctly written, fully modernised update. Radiation physics has undergone many changes in the past ten years: intensity-modulated radiation therapy (IMRT) has become a routine method of radiation treatment delivery, digital imaging has replaced film-screen imaging for localization and verification, image-guided radiation therapy (IGRT) is frequently used, in many centers proton therapy has become a viable mode of radiation therapy, new approaches have been introduced to radiation therapy quality assurance and safety that focus more on process analysis rather than specific performance testing, and the explosion in patient-and machine-related data has necessitated an ...

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

    International Nuclear Information System (INIS)

    Lykkesfeldt, Anne E; Henriksen, Katrine L; Rasmussen, Birgitte B; Sasano, Hironobu; Evans, Dean B; Møller, Susanne; Ejlertsen, Bent; Mouridsen, Henning T

    2009-01-01

    New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer

  10. Radon therapy; Radon in der Therapie

    Energy Technology Data Exchange (ETDEWEB)

    Spruck, Kaija [Technische Hochschule Mittelhessen, Giessen (Germany). Inst. fuer Medizinische Physik und Strahlenschutz

    2017-04-01

    Radon therapies are used since more than 100 years in human medicine. Today this method is controversially discussed due to the possible increase of ionizing radiation induced tumor risk. Although the exact mode of biological radiation effect on the cell level is still not known new studies show the efficiency of the radon therapy without side effect for instance for rheumatic/inflammatory or respiratory disorders.

  11. Effects of clusterin over-expression on metastatic progression and therapy in breast cancer

    International Nuclear Information System (INIS)

    Flanagan, Louise; Whyte, Lorna; Chatterjee, Namita; Tenniswood, Martin

    2010-01-01

    Clusterin is a secreted glycoprotein that is upregulated in a variety of cell lines in response to stress, and enhances cell survival. A second nuclear isoform of clusterin that is associated with cell death has also been identified. The aim of this study was to determine the role(s) of the secretory isoform in breast tumor progression and metastasis. To investigate the role of secretory clusterin in the biology of breast cancer tumor growth and resistance to therapy we have engineered an MCF-7 cell line (MCF-7CLU) that over-expresses clusterin. We have measured the in vitro effects of clusterin over-expression on cell cycle, cell death, and sensitivity to TNFalpha and tamoxifen. Using an orthotopic model of breast cancer, we have also determined the effects of over-expression of clusterin on tumor growth and metastatic progression. In vitro, over-expression of secretory clusterin alters the cell cycle kinetics and decreases the rate of cell death, resulting in the enhancement of cell growth. Over-expression of secretory clusterin also blocks the TNFalpha-mediated induction of p21 and abrogates the cleavage of Bax to t-Bax, rendering the MCF-7CLU cells significantly more resistant to the cytokine than the parental cells. Orthotopic primary tumors derived from MCF-7CLU cells grow significantly more rapidly than tumors derived from parental MCF-7 cells and, unlike the parental cells, metastasize frequently to the lungs. These data suggest that secretory clusterin, which is frequently up-regulated in breast cancers by common therapies, including anti-estrogens, may play a significant role in tumor growth, metastatic progression and subsequent drug resistance in surviving cells

  12. Effects of clusterin over-expression on metastatic progression and therapy in breast cancer

    Directory of Open Access Journals (Sweden)

    Chatterjee Namita

    2010-03-01

    Full Text Available Abstract Background Clusterin is a secreted glycoprotein that is upregulated in a variety of cell lines in response to stress, and enhances cell survival. A second nuclear isoform of clusterin that is associated with cell death has also been identified. The aim of this study was to determine the role(s of the secretory isoform in breast tumor progression and metastasis. Methods To investigate the role of secretory clusterin in the biology of breast cancer tumor growth and resistance to therapy we have engineered an MCF-7 cell line (MCF-7CLU that over-expresses clusterin. We have measured the in vitro effects of clusterin over-expression on cell cycle, cell death, and sensitivity to TNFalpha and tamoxifen. Using an orthotopic model of breast cancer, we have also determined the effects of over-expression of clusterin on tumor growth and metastatic progression. Results In vitro, over-expression of secretory clusterin alters the cell cycle kinetics and decreases the rate of cell death, resulting in the enhancement of cell growth. Over-expression of secretory clusterin also blocks the TNFalpha-mediated induction of p21 and abrogates the cleavage of Bax to t-Bax, rendering the MCF-7CLU cells significantly more resistant to the cytokine than the parental cells. Orthotopic primary tumors derived from MCF-7CLU cells grow significantly more rapidly than tumors derived from parental MCF-7 cells and, unlike the parental cells, metastasize frequently to the lungs. Conclusions These data suggest that secretory clusterin, which is frequently up-regulated in breast cancers by common therapies, including anti-estrogens, may play a significant role in tumor growth, metastatic progression and subsequent drug resistance in surviving cells.

  13. 75 FR 50880 - TRICARE: Non-Physician Referrals for Physical Therapy, Occupational Therapy, and Speech Therapy

    Science.gov (United States)

    2010-08-18

    ... 0720-AB36 TRICARE: Non-Physician Referrals for Physical Therapy, Occupational Therapy, and Speech... referrals of beneficiaries to the Military Health System for physical therapy, occupational therapy, and... practitioners will be allowed to issue referrals to patients for physical therapy, occupational therapy, and...

  14. [Therapy of intermediate uveitis].

    Science.gov (United States)

    Doycheva, D; Deuter, C; Zierhut, M

    2014-12-01

    Intermediate uveitis is a form of intraocular inflammation in which the vitreous body is the major site of inflammation. Intermediate uveitis is primarily treated medicinally and systemic corticosteroids are the mainstay of therapy. When recurrence of uveitis or side effects occur during corticosteroid therapy an immunosuppressive treatment is required. Cyclosporine A is the only immunosuppressive agent that is approved for therapy of uveitis in Germany; however, other immunosuppressive drugs have also been shown to be effective and well-tolerated in patients with intermediate uveitis. In severe therapy-refractory cases when conventional immunosuppressive therapy has failed, biologics can be used. In patients with unilateral uveitis or when the systemic therapy is contraindicated because of side effects, an intravitreal steroid treatment can be carried out. In certain cases a vitrectomy may be used.

  15. Fertility and cancer therapy

    International Nuclear Information System (INIS)

    Maguire, L.C.

    1979-01-01

    With increased survival of increasing numbers of cancer patients as a result of therapy, the consequences, early and late, of the therapies must be realized. It is the treating physician's duty to preserve as much reproductive potential as possible for patients, consistent with adequate care. With radiotherapy this means shielding the gonads as much as possible, optimal but not excessive doses and fields, oophoropexy, or sperm collection and storage prior to irradiation. With chemotherapy it means the shortest exposure to drugs consistent with best treatment and prior to therapy the collection and storage of sperm where facilities are available. At present this is still an experimental procedure. Artificial insemination for a couple when the male has received cancer therapy is another alternative. Finally, it is the responsibility of physicians caring for patients with neoplasms to be knowledgeable about these and all other effects of therapy so that patients may be counseled appropriately and understand the implications of therapy for their life

  16. Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

    Science.gov (United States)

    Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

    2014-01-01

    Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

  17. Genetically Guided Statin Therapy

    Science.gov (United States)

    2017-03-01

    number of new statin prescriptions, and (4) patient reported quality of life, physical activity, perceptions regarding statin therapy , and pain as...outcomes known to be prevented by statin therapy , we examined hospitalizations for three diagnoses: acute myocardial infarction (MI), stroke, and...cholesterol. However, the ultimate goal of statin therapy is to decrease incidence of CAD, acute myocardial infarction and perhaps stroke. However, there is a

  18. Nuclear medicine therapy

    CERN Document Server

    Eary, Janet F

    2013-01-01

    One in three of the 30 million Americans who are hospitalized are diagnosed or treated with nuclear medicine techniques. This text provides a succinct overview and detailed set of procedures and considerations for patient therapy with unsealed radioactivity sources.  Serving as a complete literature reference for therapy with radiopharmaceuticals currently utilized in practice, this source covers the role of the physician in radionuclide therapy, and essential procedures and protocols required by health care personnel.

  19. A high level of estrogen-stimulated proteins selects breast cancer patients treated with adjuvant endocrine therapy with good prognosis

    DEFF Research Database (Denmark)

    L H Weischenfeldt, Katrine; Kirkegaard, Tove; Rasmussen, Birgitte B

    2017-01-01

    , univariate and multivariate analysis revealed HR (95% CI) and p values for disease-free survival (DFS) of 2.00 (1.20-3.22), 0.008 and 1.70 (1.01-2.84), 0.04 and for the overall survival (OS) of 2.33 (1.19-4.57), 0.01 and 1.90 (0.97-3.79), 0.06, respectively. The high ER activity profile did not disclose......BACKGROUND: Adjuvant endocrine therapy has significantly improved survival of estrogen receptor α (ER)-positive breast cancer patients, but around 20% relapse within 10 years. High expression of ER-stimulated proteins like progesterone receptor (PR), Bcl-2 and insulin-like growth factor receptor I...... enrolled in BIG 1-98, a randomized phase-III clinical trial comparing adjuvant letrozole, tamoxifen or a sequence of the two drugs. Immunohistochemical staining for ER, HER-2, PR, Bcl-2 and IGF-IR was performed and determined by Allred scoring (ER, PR and Bcl-2) or HercepTest (HER-2 and IGF-IR). RESULTS...

  20. American Physical Therapy Association

    Science.gov (United States)

    ... Do APTA represents more than 100,000 members: physical therapists, physical therapist assistants, and students of physical therapy. Other Popular Resources: - Member Directory - Annual Reports ...

  1. Is Bicarbonate Therapy Useful?

    Science.gov (United States)

    Hopper, Kate

    2017-03-01

    Despite concerns about the negative effects of metabolic acidosis, there is minimal evidence that sodium bicarbonate administration is an effective treatment. In addition, sodium bicarbonate therapy is associated with many adverse effects, including paradoxic intracellular acidosis, hypokalemia, hypocalcemia, hypernatremia, and hyperosmolality. Definitive recommendations regarding bicarbonate therapy are challenging as there is little high-quality evidence available. In most clinical scenarios of metabolic acidosis, treatment efforts should focus on resolution of the underlying cause, and sodium bicarbonate therapy should be used with caution, if at all. An exception to this is kidney disease, wherein sodium bicarbonate therapy may have a valuable role. Published by Elsevier Inc.

  2. Nanomedicine and cancer therapies

    CERN Document Server

    Sebastian, Mathew; Ninan, Neethu

    2012-01-01

    Nanotechnology has the power to radically change the way cancer is diagnosed, imaged, and treated. The holistic approach to cancer involves noninvasive procedures that emphasize restoring the health of human energy fields. Presenting a wealth of information and research about the most potent cancer healing therapies, this forward-thinking book explores how nanomedicine, holistic medicine, and other cancer therapies play important roles in treatment of this disease. Topics include nanobiotechnology for antibacterial therapy and diagnosis, mitochondrial dysfunction and cancer, antioxidants and combinatorial therapies, and optical and mechanical investigations of nanostructures for biomolecular detection.

  3. Medical Art Therapy

    Directory of Open Access Journals (Sweden)

    Birgul Aydin

    2012-03-01

    Full Text Available Art therapy is a form of expressive therapy that uses art materials. Art therapy combines traditional psychotherapeutic theories and techniques with an understanding of the psychological aspects of the creative process, especially the affective properties of the different art materials. Medical art therapy has been defined as the clinical application of art expression and imagery with individuals who are physically ill, experiencing physical trauma or undergoing invasive or aggressive medical procedures such as surgery or chemotherapy and is considered as a form of complementary or integrative medicine. Several studies have shown that patients with physical illness benefit from medical art therapy in different aspects. Unlike other therapies, art therapy can take the patients away from their illness for a while by means of creative activities during sessions, can make them forget the illness or lost abilities. Art therapy leads to re-experiencing normality and personal power even with short creative activity sessions. In this article definition, influence and necessity of medical art therapy are briefly reviewed.

  4. Biological therapies for spondyloarthritis.

    Science.gov (United States)

    Bruner, Vincenzo; Atteno, Mariangela; Spanò, Angelo; Scarpa, Raffaele; Peluso, Rosario

    2014-06-01

    Biological therapies and new imaging techniques have changed the therapeutic and diagnostic approach to spondyloarthritis. In patients with axial spondyloarthritis, tumor necrosis factor α (TNFα) inhibitor treatment is currently the only effective therapy in patients for whom conventional therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) has failed. TNFα inhibitor treatment is more effective in preventing articular damage in peripheral joints than in axial ones. It is important to treat patients at an early stage of disease to reduce disease progression; moreover it is necessary to identify causes of therapy inefficacy in preventing joint damage in the axial subset.

  5. Neutron Therapy Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The Neutron Therapy Facility provides a moderate intensity, broad energy spectrum neutron beam that can be used for short term irradiations for radiobiology (cells)...

  6. Therapy with radionuclides. Radionuklid-Therapie

    Energy Technology Data Exchange (ETDEWEB)

    Biersack, H.J.; Hotze, A.L. (Bonn Univ. (Germany). Klinik fuer Nuklearmedizin)

    1992-12-01

    Radioiodine therapy of benign and malignant thyroid diseases is a well-established procedure in Nuclear Medicine. However, the therapeutic use of radioisotopes in other diseases is relatively unknown among our refering physicians. The therapeutic effects of intraarticular (rheumatoid arthritis) and intracavitary (pleural and peritoneal carcinosis) applications yields good results. The radiophosphorus therapy in polycythemia vera rubra has always to be considered as an alternative to chemotherapy. The use of analgetics may be reduced by pain therapy of bone metastasis by injection of bone-seeking beta emitters like Rh-186 HEDP. Other procedures like therapeutic application of meta-iodo-benzylguanidine in neuroblastoma and malignant pheochromocytoma resulted in at least remissions of the disease. Radioimmunotherapy needs further evaluation before it can be recommended as a routine procedure. (orig.).

  7. Gene therapy and radionuclides targeting therapy in mammary carcinoma

    International Nuclear Information System (INIS)

    Song Jinhua

    2003-01-01

    Breast carcinoma's gene therapy is a hotspot in study of the tumor's therapy in the recent years. Currently the major therapy methods that in the experimentative and primary clinical application phases include immunological gene therapy, multidrug resistance gene therapy, antisense oligonucleotide therapy and suicide gene therapy. The gene targeting brachytherapy, which is combined with gene therapy and radiotherapy has enhanced the killer effects of the suicide gene and nuclide in tumor cells. That has break a new path in tumor's gene therapy. The further study in this field will step up it's space to the clinical application

  8. History of gene therapy.

    Science.gov (United States)

    Wirth, Thomas; Parker, Nigel; Ylä-Herttuala, Seppo

    2013-08-10

    Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Antiproton Cancer Therapy

    DEFF Research Database (Denmark)

    Bassler, Niels

    An essential part in cancer radiotherapy, is to direct a sufficiently high dose towards the tumour, without damaging the surrounding tissue. Different techniques such as intensity modulated radiation therapy and proton therapy have been developed, in order to reduce the dose to the normal tissue...

  10. Play Therapy. ERIC Digest.

    Science.gov (United States)

    Landreth, Garry; Bratton, Sue

    Play therapy is based on developmental principles and, thus, provides, through play, developmentally appropriate means of expression and communication for children. Therefore, skill in using play therapy is an essential tool for mental health professionals who work with children. Therapeutic play allows children the opportunity to express…

  11. Therapy of Lies

    Science.gov (United States)

    Price, Sean

    2012-01-01

    Conversion therapy comes in many forms, ranging from informal chats with counselors to aggressive physical coercion, but all are based on the belief that a gay male or a lesbian can be changed "back" to heterosexual behavior. It is not just alarmed parents who turn to this therapy. Many LGBT individuals seek out such treatment in an effort to…

  12. Therapy in Motion.

    Science.gov (United States)

    Costonis, Maureen Needham, Ed.

    This book contains a collection of articles on the subject of movement therapy. It can be used as a set of supplementary readings for an academic course in dance therapy or a psychiatric residency program. It includes an exhaustive bibliography on this field for students and practioners in this field. Four principal themes have been selected as a…

  13. [Dance/Movement Therapy.

    Science.gov (United States)

    Fenichel, Emily, Ed.

    1994-01-01

    This newsletter theme issue focuses on dance, play, and movement therapy for infants and toddlers with disabilities. Individual articles are: "Join My Dance: The Unique Movement Style of Each Infant and Toddler Can Invite Communication, Expression and Intervention" (Suzi Tortora); "Dynamic Play Therapy: An Integrated Expressive Arts Approach to…

  14. Electroconvulsive Therapy and Suicide.

    Science.gov (United States)

    Tanney, Bryan L.

    1986-01-01

    When the effectiveness and mortality-morbidity of electroconvulsive therapy (ECT) are compared with those of drug therapies, it appears that ECT is an effective and preferred treatment strategy. It remains underutilized as a modality of suicide prevention. Addresses controversies that presently limit the use of this treatment. (Author/ABB)

  15. Massage Therapy Research

    Science.gov (United States)

    Field, Tiffany; Diego, Miguel; Hernandez-Reif, Maria

    2007-01-01

    Massage therapy has been notably effective in preventing prematurity, enhancing growth of infants, increasing attentiveness, decreasing depression and aggression, alleviating motor problems, reducing pain, and enhancing immune function. This review covers massage therapy research from the last decade, as an update to the American Psychologist 1998…

  16. Radiation Therapy - Multiple Languages

    Science.gov (United States)

    ... W XYZ List of All Topics All Radiation Therapy - Multiple Languages To use the sharing features on this page, ... Information Translations Vietnamese (Tiếng Việt) Expand Section Radiation Therapy - Tiếng Việt (Vietnamese) ... Health Information Translations Characters not displaying correctly on this page? See language display issues . Return to the MedlinePlus Health Information ...

  17. Boganmeldelse - Music Therapy Research

    DEFF Research Database (Denmark)

    Ridder, Hanne Mette Ochsner

    2006-01-01

    . Alligevel følger her en anbefaling af bogen: for musikterapeuter er det en bog, man ikke kommer uden om. Music Therapy Research, på dansk Musikterapiforskning, er en gennemrevideret, ja faktisk nyudgivelse, af bogen Music Therapy Research: Quantitative and Qualitative Perspectives, som udkom i 1995. Også...

  18. Pediatric Music Therapy.

    Science.gov (United States)

    Lathom-Radocy, Wanda B.

    This book on music therapy includes relevant medical, psychological, and developmental information to help service providers, particularly music therapists, and parents to understand children with disabilities. The first two chapters describe the process of assessment and delineation of goals in music therapy that leads to the design of the music…

  19. Photodynamic Therapy for Cancer

    Science.gov (United States)

    ... et al. Photodynamic therapy. Journal of the National Cancer Institute 1998; 90(12):889–905. [PubMed Abstract] Gudgin Dickson EF, Goyan RL, Pottier RH. New directions in photodynamic therapy. Cellular and Molecular Biology 2002; 48(8):939–954. [PubMed Abstract] Capella ...

  20. Radiation Therapy Side Effects

    Science.gov (United States)

    Radiation therapy has side effects because it not only kills or slows the growth of cancer cells, it can also affect nearby healthy cells. Many people who get radiation therapy experience fatigue. Other side effects depend on the part of the body that is being treated. Learn more about possible side effects.

  1. Art Therapy: A Bibliography.

    Science.gov (United States)

    Gantt, Linda, Comp.; Schmal, Marilyn Strauss, Comp.

    The bibliography on art therapy presents 1175 citations (1940-1973) drawn from searches of the medical indexes, computer systems of the National Library of Medicine and the National Institute of Mental Health, other bibliographies, Centre International de Documentation Concernant les Expressions Plastiques, and the American Journal of Art Therapy.…

  2. Experiential Learning and Therapy.

    Science.gov (United States)

    Hatala, Elaine

    This paper describes the experiential therapy program at the Bowling Green Adolescent Center (New Jersey). This model supports the view that the therapeutic process of addiction treatment is accelerated and enhanced by providing the patients with experiential interventions. Experiential therapy includes goal setting, hands-on participation,…

  3. Activity Therapy: An Alternative Therapy for Adolescents.

    Science.gov (United States)

    Kottman, Terry T.; And Others

    1987-01-01

    Discusses the benefits of activity therapy for preteens and adolescents, where the client is engaged in nonverbal modes of relationship--games, free play, movement, drama, music, art or other activities, as the chief therapeutic media in which conflicts are resolved and intellectual and emotional energies freed. Reviews the literature, describes…

  4. Animal-Assisted Therapy and Occupational Therapy

    Science.gov (United States)

    Andreasen, Gena; Stella, Tiffany; Wilkison, Megan; Szczech Moser, Christy; Hoelzel, Allison; Hendricks, Laura

    2017-01-01

    The use of animals for therapeutic purposes has been documented in the literature for centuries. This review will highlight evidence of the benefits of animal-assisted therapy as well as provide a plethora of resources for therapists interested in learning more about how animals can provide restorative benefits for their clients.

  5. Tumor targeted gene therapy

    International Nuclear Information System (INIS)

    Kang, Joo Hyun

    2006-01-01

    Knowledge of molecular mechanisms governing malignant transformation brings new opportunities for therapeutic intervention against cancer using novel approaches. One of them is gene therapy based on the transfer of genetic material to an organism with the aim of correcting a disease. The application of gene therapy to the cancer treatment had led to the development of new experimental approaches such as suicidal gene therapy, inhibition of oncogenes and restoration of tumor-suppressor genes. Suicidal gene therapy is based on the expression in tumor cells of a gene encoding an enzyme that converts a prodrug into a toxic product. Representative suicidal genes are Herpes simplex virus type 1 thymidine kinase (HSV1-tk) and cytosine deaminase (CD). Especially, physicians and scientists of nuclear medicine field take an interest in suicidal gene therapy because they can monitor the location and magnitude, and duration of expression of HSV1-tk and CD by PET scanner

  6. Medical therapy in acromegaly.

    LENUS (Irish Health Repository)

    Sherlock, Mark

    2011-05-01

    Acromegaly is a rare disease characterized by excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. The disease is associated with increased morbidity and premature mortality, but these effects can be reduced if GH levels are decreased to <2.5 μg\\/l and IGF-1 levels are normalized. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients\\' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, radiotherapy and medical therapies, such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant. Medical therapy is currently most widely used as secondary treatment for persistent or recurrent acromegaly following noncurative surgery, although it is increasingly used as primary therapy. This Review provides an overview of current and future pharmacological therapies for patients with acromegaly.

  7. Pharmacological therapy for amblyopia

    Directory of Open Access Journals (Sweden)

    Anupam Singh

    2017-01-01

    Full Text Available Amblyopia is the most common cause of preventable blindness in children and young adults. Most of the amblyopic visual loss is reversible if detected and treated at appropriate time. It affects 1.0 to 5.0% of the general population. Various treatment modalities have been tried like refractive correction, patching (both full time and part time, penalization and pharmacological therapy. Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia. Various drugs have also been tried of which carbidopa & levodopa have been popular. Most of these agents are still in experimental stage, though levodopa-carbidopa combination therapy has been widely studied in human amblyopes with good outcomes. Levodopa therapy may be considered in cases with residual amblyopia, although occlusion therapy remains the initial treatment choice. Regression of effect after stoppage of therapy remains a concern. Further studies are therefore needed to evaluate the full efficacy and side effect profile of these agents.

  8. Music therapy improvisation

    Directory of Open Access Journals (Sweden)

    Mira Kuzma

    2001-09-01

    Full Text Available In this article, the technique of music therapy – music therapy improvisation is introduced. In this form of music therapy the improvising partners share meaning through the improvisation: the improvisation is not an end in itself: it portrays meaning that is personal, complex and can be shared with the partner. The therapeutic work, then, is meeting and matching the client's music in order to give the client an experience of "being known", being responded through sounds and being able to express things and communicate meaningfully. Rather than the client playing music, the therapy is about developing the engagement through sustained, joint improvisations. In music therapy, music and emotion share fundamental features: one may represent the other, i.e., we hear the music not as music but as dynamic emotional states. The concept of dynamic structure explains why music makes therapeutic sense.

  9. Accelerators for cancer therapy

    International Nuclear Information System (INIS)

    Lennox, Arlene J.

    2000-01-01

    The vast majority of radiation treatments for cancerous tumors are given using electron linacs that provide both electrons and photons at several energies. Design and construction of these linacs are based on mature technology that is rapidly becoming more and more standardized and sophisticated. The use of hadrons such as neutrons, protons, alphas, or carbon, oxygen and neon ions is relatively new. Accelerators for hadron therapy are far from standardized, but the use of hadron therapy as an alternative to conventional radiation has led to significant improvements and refinements in conventional treatment techniques. This paper presents the rationale for radiation therapy, describes the accelerators used in conventional and hadron therapy, and outlines the issues that must still be resolved in the emerging field of hadron therapy

  10. Music therapy in dementia

    DEFF Research Database (Denmark)

    McDermott, Orii; Crellin, Nadia; Ridder, Hanne Mette Ochsner

    2013-01-01

    Objective Recent reviews on music therapy for people with dementia have been limited to attempting to evaluate whether it is effective, but there is a need for a critical assessment of the literature to provide insight into the possible mechanisms of actions of music therapy. This systematic review......, five studies investigated hormonal and physiological changes, and five studies focused on social and relational aspects of music therapy. The musical interventions in the studies were diverse, but singing featured as an important medium for change. Conclusions Evidence for short-term improvement...... in mood and reduction in behavioural disturbance was consistent, but there were no high-quality longitudinal studies that demonstrated long-term benefits of music therapy. Future music therapy studies need to define a theoretical model, include better-focused outcome measures, and discuss how the findings...

  11. Proton therapy physics

    CERN Document Server

    2012-01-01

    Proton Therapy Physics goes beyond current books on proton therapy to provide an in-depth overview of the physics aspects of this radiation therapy modality, eliminating the need to dig through information scattered in the medical physics literature. After tracing the history of proton therapy, the book summarizes the atomic and nuclear physics background necessary for understanding proton interactions with tissue. It describes the physics of proton accelerators, the parameters of clinical proton beams, and the mechanisms to generate a conformal dose distribution in a patient. The text then covers detector systems and measuring techniques for reference dosimetry, outlines basic quality assurance and commissioning guidelines, and gives examples of Monte Carlo simulations in proton therapy. The book moves on to discussions of treatment planning for single- and multiple-field uniform doses, dose calculation concepts and algorithms, and precision and uncertainties for nonmoving and moving targets. It also exami...

  12. Pharmacological therapy for amblyopia

    Science.gov (United States)

    Singh, Anupam; Nagpal, Ritu; Mittal, Sanjeev Kumar; Bahuguna, Chirag; Kumar, Prashant

    2017-01-01

    Amblyopia is the most common cause of preventable blindness in children and young adults. Most of the amblyopic visual loss is reversible if detected and treated at appropriate time. It affects 1.0 to 5.0% of the general population. Various treatment modalities have been tried like refractive correction, patching (both full time and part time), penalization and pharmacological therapy. Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia. Various drugs have also been tried of which carbidopa & levodopa have been popular. Most of these agents are still in experimental stage, though levodopa-carbidopa combination therapy has been widely studied in human amblyopes with good outcomes. Levodopa therapy may be considered in cases with residual amblyopia, although occlusion therapy remains the initial treatment choice. Regression of effect after stoppage of therapy remains a concern. Further studies are therefore needed to evaluate the full efficacy and side effect profile of these agents. PMID:29018759

  13. [Therapy-resistant and therapy-refractory arterial hypertension].

    Science.gov (United States)

    Wallbach, M; Koziolek, M J

    2018-05-02

    Therapy-resistant and therapy-refractory arterial hypertension differ in prevalence, pathogenesis, prognosis and therapy. In both cases, a structured approach is required, with the exclusion of pseudoresistance and, subsequently, secondary hypertension. Resistant hypertension has been reported to be more responsive to intensified diuretic therapy, whereas refractory hypertension is presumed to require sympathoinhibitory therapy. Once the general measures and the drug-based step-up therapy have been exhausted, interventional procedures are available.

  14. Targeted enzyme prodrug therapies.

    Science.gov (United States)

    Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

    2010-09-01

    The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

  15. Massage therapy research review.

    Science.gov (United States)

    Field, Tiffany

    2016-08-01

    In this review, massage therapy has been shown to have beneficial effects on varying conditions including prenatal depression, preterm infants, full-term infants, autism, skin conditions, pain syndromes including arthritis and fibromyalgia, hypertension, autoimmune conditions including asthma and multiple sclerosis, immune conditions including HIV and breast cancer and aging problems including Parkinson's and dementia. Although many of the studies have involved comparisons between massage therapy and standard treatment control groups, several have compared different forms of massage (e.g. Swedish versus Thai massage), and different active therapies such as massage versus exercise. Typically, the massage therapy groups have experienced more positive effects than the control or comparison groups. This may relate to the massage therapy providing more stimulation of pressure receptors, in turn enhancing vagal activity and reducing cortisol levels. Some of the researchers have assessed physical, physiological and biochemical effects, although most have relied exclusively on self-report measures. Despite these methodological problems and the dearth of research from the U.S., the massage therapy profession has grown significantly and massage therapy is increasingly practiced in traditional medical settings, highlighting the need for more rigorous research. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Influence of race on outcome in patients treated with breast conserving therapy

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, T; Heimann, R; Powers, C; Vijayakumar, S; Ewing, C; Halpern, H; Michel, A; Rubin, S; Weichselbaum, R

    1995-07-01

    PURPOSE: Race is reported to correlate with outcome in breast cancer with African Americans (AA) having worse outcome compared to whites. However, little data is available from large standardized series of patients with early stage breast cancer. We report here the influence of race on local control (LC), disease free survival (DFS), cause specific survival (CSS) and overall survival (OS) for patients treated at our center with breast conserving therapy (BCT). MATERIALS AND METHODS: From a database of 925 patients treated between 1977 and 1993 with BCT for early stage invasive breast cancer, a total of 892 patients were available for study after excluding non-AA/non-white patients. Median age of patients was 56 years. Median follow-up was 35 months (range, 2 to 166). All patients underwent lumpectomy and radiation therapy(RT). Seven hundred eighty-six (88%) patients had axillary dissection. Median RT dose was 6000cGy with 90% of patients receiving 6000cGy or more. Two hundred fifty (28%) had chemotherapy, 327(37%) had tamoxifen and 64(7%) had both. T stage distribution was as follows: 632 T1 (71%), 244 T2 (27%), 12 T3 (1%) and 4 unknown (<1%). One hundred eighty six (21%) patients were pathologically node positive. There were 354 AA (40%) and 538 white (60%) patients. The chi-square test was used to compare distribution of prognostic factors between races. Outcome was evaluated by Kaplan-Meier actuarial method and logrank test. Sub-groups analyzed for outcome differences by race included T stage, tumor size, nodal status, grade, receptor status, age, menopausal status and family history. Multivariate analysis was performed by Cox proportional hazard model. RESULTS: No significant differences between AA and whites were seen in age, menopausal status, family history, T stage, N stage, number of nodes involved, histologic grade, total RT dose or chemotherapy. However, a larger percentage of whites received tamoxifen (43 vs 27%)(p<0.001), had low nuclear grade (19 vs 9

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